817 results on '"Castrate-resistant prostate cancer"'
Search Results
152. Single-Centre Experience of the Use of Palliative Radiotherapy in Metastatic Castrate-Resistant Prostate Cancer between 2003/2004 and 2018/2019
- Author
-
Heather Payne, William Kinnaird, and Reena Davda
- Subjects
Oncology ,medicine.medical_specialty ,Single centre ,Palliative radiotherapy ,business.industry ,Internal medicine ,medicine ,MEDLINE ,Castrate-resistant prostate cancer ,Radiology, Nuclear Medicine and imaging ,business - Published
- 2020
153. Potential role of rituximab in metastatic castrate-resistant prostate cancer
- Author
-
Poorva Bindal, Jessica M. Clement, Lisa M. Holle, and Sharif Aa Jalil
- Subjects
Male ,Oncology ,Bendamustine ,medicine.medical_specialty ,medicine.medical_treatment ,Follicular lymphoma ,Castrate-resistant prostate cancer ,Targeted therapy ,Androgen deprivation therapy ,03 medical and health sciences ,Prostate cancer ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Aged ,business.industry ,Androgen Antagonists ,medicine.disease ,Prostatic Neoplasms, Castration-Resistant ,030220 oncology & carcinogenesis ,Rituximab ,business ,Infiltration (medical) ,030215 immunology ,medicine.drug - Abstract
Nearly all men with prostate cancer who are treated with androgen deprivation therapy develop disease progression. There is considerable evidence to suggest that CXCL 13 released by tumor cells leads to B-cell infiltration into the prostate cells. This B-cell infiltration has been postulated to play a role in development of disease progression following androgen-deprivation therapies. We present a case of a patient who achieved remission of metastatic castrate-resistant prostate cancer after receiving rituximab and bendamustine for the treatment of follicular lymphoma. The findings in this report suggest that further investigation is warranted for utilizing B-cell targeted therapy in delaying progression of castrate-resistant prostate cancer.
- Published
- 2018
154. Refining the use of cabazitaxel in metastatic castrate-resistant prostate cancer
- Author
-
Stéphane Culine
- Subjects
Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,010304 chemical physics ,business.industry ,Castrate-resistant prostate cancer ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Prostatic Neoplasms, Castration-Resistant ,Cabazitaxel ,Internal medicine ,0103 physical sciences ,Humans ,Medicine ,Taxoids ,business ,medicine.drug - Published
- 2018
155. EXTREQOL Identifies Ongoing Challenges in Maximising Quality of Survival in Men with Metastatic Castrate-resistant Prostate Cancer
- Author
-
Susan Catt, Valerie Jenkins, Shirley May, L. Matthews, Heather Payne, and Malcolm David Mason
- Subjects
Oncology ,medicine.medical_specialty ,030504 nursing ,business.industry ,media_common.quotation_subject ,Castrate-resistant prostate cancer ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,Quality (business) ,0305 other medical science ,business ,media_common - Published
- 2018
156. Valeur pronostique de la testostéronémie lors de l’hormonothérapie intermittente du cancer de la prostate
- Author
-
P. Pillot, A. Vallat, J. Irani, C. Lebâcle, and Centre hospitalier universitaire de Poitiers (CHU Poitiers)
- Subjects
Gynecology ,03 medical and health sciences ,medicine.medical_specialty ,0302 clinical medicine ,business.industry ,Urology ,[SDV]Life Sciences [q-bio] ,030232 urology & nephrology ,Castrate-resistant prostate cancer ,Medicine ,business ,3. Good health - Abstract
Resume Introduction Le traitement du cancer de la prostate (CaP) par suppression androgenique intermittente a ete propose dans le but de diminuer les effets secondaires tout en gardant un controle carcinologique equivalent a un traitement continu. Par ailleurs, des etudes ont suggere que le pronostic du CaP traite par suppression androgenique etait correle a l’importance de l’effondrement de la testosteronemie. Le but de cette etude etait d’evaluer l’association entre la valeur de la testosteronemie en fin de premiere phase hors traitement (phase « OFF ») et le delai avant l’apparition d’une resistance a la castration. Materiel et methodes Nous avons analyse de maniere retrospective 69 dossiers de patients sous traitement hormonal intermittent (THI). Le passage en phase OFF etait propose aux patients apres au moins six mois d’hormonotherapie par analogue de la LH RH et un PSA 3,4 ng/mL. Les survies sans resistance a la castration, sans metastase et globale ont ete comparees entre les groupes ainsi que la frequence des complications. L’impact de la duree initiale d’hormonotherapie continue sur l’apparition d’une resistance a la castration et sur les parametres chronologiques du THI a egalement ete etudie. Resultats La testosteronemie a la fin de la premiere et de la 2e phase OFF n’etait pas associee aux delais avant l’apparition d’une resistance a la castration (p = 0,5), la survenue de metastase (p = 0,4) et le deces (p = 0,3). Elle n’etait pas associee a la frequence des complications et des effets indesirables. La duree initiale d’hormonotherapie continue n’etait pas associee a l’apparition d’une resistance a la castration (p = 0,6) ni a la duree moyenne des phases OFF (p = 0,5) et du traitement intermittent (p = 0,8). Conclusion Cette etude n’a pas montre d’impact de la valeur de la testosteronemie en fin de phase OFF (avant reprise de la suppression androgenique) sur les survies globales, sans resistance a la castration et sans metastase. De meme, cette valeur n’etait pas associee a la frequence des complications liees au cancer ou a la suppression androgenique. La duree initiale d’hormonotherapie continue n’etait pas associee a l’apparition d’une resistance a la castration ni aux parametres chronologiques du THI.
- Published
- 2019
157. PARP inhibitor and CX-5461 combination therapy as a novel treatment strategy for castrate-resistant prostate cancer
- Author
-
Richard B. Pearson, Nicholas Choo, Ross D. Hannan, Mitchell G. Lawrence, Shahneen Sandhu, Luc Furic, Elaine Sanij, Laura H Porter, Gail P. Risbridger, David Pook, Hong Wang, and Renea A. Taylor
- Subjects
Combination therapy ,business.industry ,PARP inhibitor ,Castrate-resistant prostate cancer ,Cancer research ,Medicine ,Treatment strategy ,General Medicine ,business - Published
- 2019
158. HES6 drives a critical AR transcriptional programme to induce castration‐resistant prostate cancer through activation of an E2F1‐mediated cell cycle network
- Author
-
Charles E. Massie, Antonio Ramos-Montoya, Sarah L. Vowler, N L Sharma, Helene Bon, David E. Neal, Vasiliki Theodorou, Helen Ross-Adams, Richard F. Wooster, H Scott, Sarah Jurmeister, Greg Shaw, Joan Boren, Anne Y. Warren, Nuria Galeano-Dalmau, Maria Vias, Alastair D. Lamb, Roslin Russell, Ian G. Mills, William J. Howat, and Thomas L. Carroll
- Subjects
Male ,Molecular Sequence Data ,Cell Cycle Proteins ,Biology ,gene expression signature ,Prostate cancer ,Mice ,SDG 3 - Good Health and Well-being ,androgen receptor ,castrate-resistant prostate cancer ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,E2F1 ,Animals ,Humans ,Transcription factor ,Research Articles ,Regulation of gene expression ,Gene Expression Profiling ,Prostatic Neoplasms ,E2F1 Transcription Factor ,Sequence Analysis, DNA ,Cell cycle ,medicine.disease ,3. Good health ,Androgen receptor ,Repressor Proteins ,Disease Models, Animal ,Gene Expression Regulation ,Receptors, Androgen ,Cancer research ,Molecular Medicine ,HES6 ,Stem cell ,PLK1 - Abstract
Castrate‐resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c‐Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co‐factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up‐regulated in aggressive human prostate cancer and drives castration‐resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6‐associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient‐specific therapeutic strategies.
- Published
- 2019
159. LBA-25 RESIST-PC PHASE 2 TRIAL: 177LU-PSMA-617 RADIONUCLIDE THERAPY FOR METASTATIC CASTRATE-RESISTANT PROSTATE CANCER
- Author
-
Rouzbeh Esfandiari, Kathleen Nguyen, Magnus Dahlbom, Wolfgang P. Fendler, Michael Lassmann, Ebrahim S. Delpassand, Jeannine Gartmann, Jeremie Calais, Johannes Czernin, Matthias Eiber, Pan Thin, and Ken Herrmann
- Subjects
Oncology ,medicine.medical_specialty ,177Lu-PSMA-617 ,business.industry ,Urology ,Internal medicine ,Radionuclide therapy ,Castrate-resistant prostate cancer ,medicine ,Phases of clinical research ,business - Abstract
INTRODUCTION AND OBJECTIVES:Introduction: This is an investigator-initiated open-label prospective bi-centric single-arm phase 2 clinical trial (NCT03042312) of 177Lu-PSMA-617 radionuclide therapy ...
- Published
- 2019
160. PD15-11 SURVIVAL RATES AND ECONOMIC OUTCOMES IN CHEMOTHERAPY-NAïVE METASTATIC CASTRATE RESISTANT PROSTATE CANCER PATIENTS TREATED WITH ABIRATERONE ACETATE OR ENZALUTAMIDE
- Author
-
Onur Baser, Krishnan Ramaswamy, Neil M. Schultz, Daniel J. George, Stanislav Lechpammer, Li Wang, Ahong Huang, and Jack Mardekian
- Subjects
Oncology ,medicine.medical_specialty ,genetic structures ,business.industry ,Urology ,030232 urology & nephrology ,Abiraterone acetate ,Castrate-resistant prostate cancer ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,chemistry ,Internal medicine ,medicine ,Enzalutamide ,business ,Cancer death ,Chemotherapy naive - Abstract
INTRODUCTION AND OBJECTIVES:Prostate cancer (PC) is the 2nd leading cause of cancer death among US males and accounts for a great proportion of health expenditures. The objective of this study was ...
- Published
- 2019
161. Androgen receptor (AR) splice variant 7 and full-length AR expression is associated with clinical outcome: a translational study in patients with castrate-resistant prostate cancer
- Author
-
Guido Jenster, Eleni Efstathiou, Andrea Sbrana, Federico Paolieri, Eleonora Rofi, Marzia Del Re, Luca Galli, Camillo Porta, Stefania Crucitta, Alfredo Falcone, Romano Danesi, Riccardo Morganti, Ron H.N. van Schaik, Giulia Gianfilippo, Clinical Chemistry, and Urology
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Plasma samples ,business.industry ,Urology ,Alternative splicing ,Castrate-resistant prostate cancer ,medicine.disease ,Androgen receptor ,03 medical and health sciences ,Prostate cancer ,030104 developmental biology ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Overall survival ,Treatment strategy ,In patient ,business - Abstract
Objectives: To investigate if full-length androgen receptor (AR-FL) is associated with resistance to androgen receptor (AR)-directed therapy independently and/or combined with AR splice variant 7 (AR-V7). Patients and Methods: Plasma samples were prospectively collected from 73 patients with castrate-resistant prostate cancer before first- or second-line AR-directed therapy. mRNA was isolated from exosomes and AR-FL and AR-V7 were analysed by droplet digital PCR. Results: AR-FL was detected in all patients and 22% of them were AR-V7-positive at baseline. AR-FL expression was significantly higher in AR-V7-positive vs AR-V7-negative patients (P < 0.0001). After stratifying patients by tertile for AR-FL expression, progression-free survival (PFS) was 22 vs 18 vs 4 months for lower vs intermediate vs higher tertile, respectively (P = 0.0003). The median PFS and overall survival were significantly longer in AR-V7-negative vs AR-V7-positive patients (20 vs 4 months, P < 0.0001; not reached vs 9 months, P < 0.0001, respectively). Conclusions: Resistance to AR-directed therapy was associated with the presence of AR-V7; however, AR-FL expression may help better refine response and survival of patients to AR-directed therapy. Both biomarkers, if validated in prospective trials, could be used to select the best treatment strategy.
- Published
- 2019
162. Emerging Non-Canonical Small-Molecule Inhibitors of Androgen Receptor (AR) and AR Interactome Partners for the Treatment of Castrate-Resistant Prostate Cancer
- Author
-
Angela N. Ko, André Ri, Marius S. Pop, Nicholas B. Struntz, and David B. Freeman
- Subjects
Androgen receptor ,Non canonical ,Chemistry ,Castrate-resistant prostate cancer ,Cancer research ,Interactome ,Small molecule - Published
- 2018
163. The burden of symptomatic skeletal events in castrate-resistant prostate cancer patients with bone metastases at three Canadian uro-oncology centres
- Author
-
Louise Perrault, Raina M. Rogoza, Neil E. Fleshner, Ewan J.D. Robson, Alan So, Jacques Le Lorier, Melanie Poulin-Costello, and Fred Saad
- Subjects
medicine.medical_specialty ,Bone disease ,business.industry ,Urology ,Incidence (epidemiology) ,Castrate-resistant prostate cancer ,medicine.disease ,Confidence interval ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Internal medicine ,Cancer centre ,medicine ,Resource use ,030212 general & internal medicine ,General hospital ,business ,Original Research - Abstract
Introduction: Metastatic bone disease in castrate-resistant prostate cancer risks significant morbidity, including symptomatic skeletal events. We estimated the healthcare resource costs of managing skeletal events. Methods: A retrospective chart review was conducted for patients who died from or were treated palliatively for metastatic castrate-resistant prostate cancer from 2006–2013 at Centre Hospitalier de l'Universite de Montreal (Montreal), Princess Margaret Cancer Centre (Toronto), or Vancouver General Hospital (Vancouver). Results: Of 393 patients, 275 (70%) experienced 833 events (85 per 100 patient-years), with a median (95% confidence interval) time (months) to first event of 17.6 (15.3, 21.7). The mean metastatic bone disease-related healthcare resource use cost (2014 Canadian dollars) estimate for patients without symptomatic skeletal events was $9550 and between $22 101 (observed) and $34 615 (adjusted) for patients with at least one event. Fewer patients in Montreal (55%) experienced events compared to Toronto (79%) or Vancouver (76%). Median time (months) to first event was longer in Montreal (25.0 [18.5, 32.6]) than in Toronto (14.6 [9.7, 16.8] or Vancouver (17.3 [14.8, 24.0]). More patients received bone-targeted therapy in Montreal (64%) and Toronto (60%) than in Vancouver (24%). Bone-targeted therapy was mostly administered every 3–4 weeks in Montreal and every 3–4 months in Toronto. Conclusions: Metastatic bone disease-related healthcare resource use costs for Canadian castrate-resistant prostate cancer patients are high. Symptomatic skeletal events occurred frequently, with the incremental cost of one or more events estimated between $12 641 and $25 120. Symptomatic skeletal event incidence and bone-targeted therapy use varied considerably between three Canadian uro-oncology centres. An important limitation is that only patients who died from prostate cancer were included, potentially overestimating costs.
- Published
- 2018
164. Abstract PO-077: Study evaluating metastatic castrate resistant prostate cancer (mCRPC) treatment using 177Lu-PNT2002 PSMA therapy after second-line hormonal treatment (SPLASH) - Trial in progress
- Author
-
Vikas Prasad, Ur Metser, Jessica Jensen, Neil Fleshner, Neal D. Shore, Scott T. Tagawa, Oliver Sartor, Kim N. Chi, Jeremie Calais, Johannes Czernin, and Matthias Eiber
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Castrate-resistant prostate cancer ,Cancer ,Treatment options ,medicine.disease ,Second line ,Internal medicine ,Toxicity ,medicine ,Radioligand ,business ,Membrane antigen ,Hormone - Abstract
Background: Treatment options with minimal toxicity and novel mechanisms of action are urgently needed to improve clinical outcomes from mCRPC. Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) represents a new treatment for patients with PSMA-avid mCRPC. 177Lu-PNT2002 (also known as [Lu-177]-PSMA-I&T) is a PSMA-targeting agent and studies have shown demonstrable promising initial data. This trial seeks to prospectively evaluate the efficacy of 177Lu-PNT2002 for men with progressive mCRPC after androgen receptor axis-targeted (ARAT) therapy. Methods: This is a multi-center, open-label, phase III study. All patients must be at least 18 years of age, have documented progressive mCRPC at time of screening, high PSMA expression by PSMA PET/CT per blinded independent central review (BICR), chemotherapy naïve for CRPC and unfit or unwilling to receive chemotherapy. The study will commence with a 25-patient dosimetry lead-in. In the dosimetry phase, patients will receive up to four cycles of 177Lu-PNT2002 at 6.8 GBq every 8 weeks. In the randomization phase, approximately 390 patients will be randomized in a 2:1 ratio to receive 177Lu-PNT2002 (Arm A) versus enzalutamide or abiraterone (with prednisone or dexamethasone) (Arm B). Patients randomized to Arm B have an option to crossover to 177Lu-PNT2002 treatment after BICR-assessed radiologic progression. The primary endpoint is Radiological progression-free survival (rPFS) assessed by BICR using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG3) (bone) criteria. Key secondary endpoints include objective response rate, duration of response, PSA response, and overall survival. The study is powered at 90% to test the alternative hypothesis of a hazard ratio (HR) ≤ 0.66 at an α of 0.025. ClinicalTrials.gov identifier: NCT04647526. Citation Format: Kim N. Chi, Ur Metser, Johannes Czernin, Jeremie Calais, Vikas Prasad, Matthias Eiber, Neal Shore, Jessica Jensen, Neil Fleshner, Scott Tagawa, Oliver Sartor. Study evaluating metastatic castrate resistant prostate cancer (mCRPC) treatment using 177Lu-PNT2002 PSMA therapy after second-line hormonal treatment (SPLASH) - Trial in progress [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-077.
- Published
- 2021
165. Association of health-related quality of life (HRQOL) variations with biological biomarkers for patients with metastatic castrate-resistant prostate cancer (MCRPC) treated by abiraterone/prednisone combination or prednisone
- Author
-
A. Frontczak, Thierry Nguyen, Ulrich Stein, Hamadi Almotlak, Morgan Goujon, Tristan Maurina, Guillaume Mouillet, Emilie Charton, Amélie Anota, Calcagno Fabien, and Antoine Thiery-Vuillemin
- Subjects
Oncology ,Health related quality of life ,Cancer Research ,medicine.medical_specialty ,business.industry ,Castrate-resistant prostate cancer ,Abiraterone ,chemistry.chemical_compound ,Quality of life ,chemistry ,Prednisone ,Internal medicine ,Overall survival ,Medicine ,Endocrine system ,business ,medicine.drug - Abstract
54 Background: A potential link between Health-Related Quality of life (HRQoL) and oncologic outcomes such as overall survival or progression-free survival has been underlined for endocrine therapies in patients with metastatic castrate resistant prostate cancer (mCRPC). Other surrogates such as circulating tumor cells (CTCs) or PSA can be used to evaluate disease control. This study explored the associations between HRQoL and biological biomarkers for patients with mCRPC treated by abiraterone / prednisone or prednisone within registration phase III trial COU-AA-301. Methods: Baseline differences of HRQoL evaluated with FACT-P total score (FACT-P TS) according to biological parameters (including CTCs and PSA) and links between HRQoL's change and variations of these parameters were assessed. The primary objective was to estimate the association between improvement or deterioration in FACT-P TS and the variations of CTCs and PSA. All analyses were conducted using clinically meaningful improvement and deterioration in FACT-P TS and subscales. Results: Among 1130 patients enrolled, 1111 (98.3%) had a baseline FACT-P TS available. At baseline, a favorable CTCs count was associated with higher FACT-P TS compared to unfavorable CTCs (difference in means 8 points, [95% CI, 4 to 12] p < 0.001). At 3 months, there were differences in mean change from baseline FACT-P TS favoring patients with biomarkers response, with clinically meaningful difference for CTCs (12.7 points, [95% CI, 6 to 19.5%] p < 0.001) and PSA (11.64 points, [95% CI, 9.3 to 14] p < 0.0001). Biological progression was associated with higher risk of FACT-P TS worsening for PSA (Odds Ratio (OR) 2.8 [95% CI, 1.9 to 4.2]) with more frequent FACT-P TS improvement in case of response for CTCs (OR 3.14 [95% CI, 1.3 to 7.7]) and PSA (OR 2.9 [95% CI 2.1 to 4]). Significantly longer time until definitive deterioration was observed for patients with CTCs or PSA response (p < 0.001) and shorter time in case of progression (p < 0.001). Conclusions: QUA-lify is the first study to show an association between HRQoL and biomarkers outcomes in patients with mCRPC treated with endocrine therapy in a post-taxane setting. This concept is reinforced by the consistency of the association for all analyses carried out.
- Published
- 2021
166. ARTO trial (NCT03449719), a randomized phase II trial enrolling oligometastatic castration-resistant prostate cancer patients treated with first-line abiraterone acetate with or without stereotactic body radiation therapy: Preliminary results comprehensive of biochemical outcomes and circulating tumor cells analysis
- Author
-
Andrea Gaetano Allegra, Beatrice Detti, M. Aquilano, Giulio Francolini, Icro Meattini, Isacco Desideri, L.P. Ciccone, Mauro Loi, Vanessa Di Cataldo, Giulia Salvatore, Pamela Pinzani, Pietro Garlatti, Francesca Salvianti, V. Salvestrini, Barbara Guerrieri, Lorenzo Livi, Monica Mangoni, Mariangela Sottili, G. Stocchi, and C. Bellini
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Stereotactic body radiation therapy ,First line ,Abiraterone acetate ,Castrate-resistant prostate cancer ,Castration resistant ,medicine.disease ,Androgen receptor ,chemistry.chemical_compound ,Prostate cancer ,Circulating tumor cell ,chemistry ,Internal medicine ,Medicine ,business - Abstract
118 Background: Androgen Receptor Targeted Agents (ARTA) represent one of the main treatment options for metastatic castrate resistant prostate cancer (mCRPC). Addition of stereotactic radiation therapy (SBRT) to ablate metastatic foci may improve clinical outcomes in oligometastatic setting. ARTO trial (NCT03449719) is a randomized phase II trial testing the benefit of upfront SBRT on all sites of metastatic disease in oligo-mCRPC patients undergoing I line therapy with Abiraterone Acetate (AA). In this preliminary analysis, we report results after 6 months of follow up, together with an exploratory analysis of androgen receptor splice variants (ARV7/ARFL) Prostate Specific Antigen (PSA) and Prostate Specific Membrane Antigen (PSMA) expression on Circulating Tumor Cells (CTCs) detected in this cohort of patients. Methods: 31 patients affected by oligo-mCRPC (defined as < 3 non-visceral metastatic lesions) were randomized to receive I line AA therapy with or without SBRT on all metastatic sites. Baseline blood samples to detect CTCs and evaluate their ARV7, ARFL, PSA and PSMA expression were taken before AA treatment start. Assessments comprehensive of clinical examination and serum PSA were performed every three months. Toxicity was assessed by the Common Terminology Criteria for Adverse Events toxicity scale (CTCAE v.4.03). Results: Thirteen and 18 patients were enrolled in the treatment and control arm, respectively. Nineteen metastatic lesions were treated with SBRT in the treatment arm. At 6 months, complete response (defined as a serum PSA level < 0.2 ng/dl) and biochemical response (defined as a PSA reduction > 50% if compared to baseline) were achieved in 6 vs 4 and in 10 vs 8 patients in the treatment vs control arm, respectively. One patient in the treatment arm died for other causes, 1 biochemical progression occurred in the control arm. No adverse events occurred in both arms of treatment. CTCs analysis was available for 10 patients, out of whom 4 were found positive for CTCs (1 and 3 from the treatment and control arm, respectively). ARV7 and ARFL were expressed in 1 patient from the control arm, PSMA was expressed in all CTC positive patients, PSA was expressed in 2 patients from the control and one from the treatment arm. Conclusions: SBRT+AA in oligo-mCRPC patients was safe and yielded promising biochemical results. CTCs detection in this selected cohort of oligo-mCRPC was lower if compared to historical data of unselected mCRPC patients. Data about ARV7, ARFL, PSA and PSMA expression represent an interesting snapshot of biomarker arrangement in this setting. Clinical trial information: NCT03449719.
- Published
- 2021
167. A phase II, multicenter, randomized, open-label study to evaluate the safety and tolerability of proxalutamide (GT0918) in subjects with metastatic castrate-resistant prostate cancer (mCRPC)
- Author
-
Yong Yang, Qinggui Meng, Zhongquan Sun, Guowei Shi, Jie Jin, Zhiquan Hu, Ying-Hao Sun, Tie Zhou, Ben Liu, Youzhi Tong, Lijun Chen, Qiaoxia Zhou, Weibing Sun, Cheng Fu, Yinhuai Wang, Dalin He, Dingwei Ye, Jingen Wang, Jiwen Cheng, and Xishuang Song
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Open label study ,Tolerability ,business.industry ,Internal medicine ,medicine ,Antagonist ,Castrate-resistant prostate cancer ,Proxalutamide ,business - Abstract
108 Background: GT0918 is a 2nd generation of AR antagonist and capability to down-regulate AR level. This study is an open-label, randomized, multicenter, Ph II study to evaluate the safety and efficacy in patients with mCRPC, and to determine the optimal dose for Ph III study. Methods: Patients with historically confirmed mCRPC who progressed after/intolerant to/reluctant to receive Docetaxel and previously treated with abiraterone or enzalutamide were excluded. All the patients received up to 6 cycles or, unacceptable toxicity, or loss of clinical benefit as recommended by PCWG3. Primary endpoint was prostate-specific antigen (PSA) reduction from baseline. Secondary endpoints included time to PSA progression (TTPP), objective response rate (ORR), progression free survival (PFS), disease control rate (DCR) and safety profiles. Results: As of June 30, 2019, 108 treated with GT0918 at three dose levels: 100 mg (n =37), 200 mg (n = 35) and 300 mg (n = 36), the median age of patients was 70.0 years (range 63-77), 88% of patients had stage IV disease at the initial diagnosis and 69.4% had Gleason score ≥ 8. The median duration of disease was 2.88 years. All received prior endocrine therapy, 35.2% received prior chemotherapy, 29.6% received Docetaxel. The median PSA at baseline was 35.285ng/ml, PSA response rate (≥50 % reduction from baseline) was 41.9%. The median time to PSA progression was not reached. There was no significant difference among three arms. Of 19 evaluable patients with target lesions at baseline, the ORR was 15.8% (all were PR) assessed by IRC with RECIST v 1.1, with 20.0% (1/5), 22.2% (2/9), 0 (0/5) at 100, 200, 300 dose level, respectively. The DCR assessed by IRC was 78.9% (CR 0+PR15.8%+SD 63.2%). Of 26 evaluable patients with target lesions at baseline, the ORR was 19.2% assessed by investigators (CR 3.8%+PR 15.4%), with 11.1% (1/9), 20.0% (2/10), 28.6% (2/7) at 100, 200, 300 dose level, respectively. Overall, AEs were experienced by most of patients (94.4 %, n=102). AEs leading to drug interruption were reported in 13 patients (12.0%), 9 (8.3%)of them were suspected to be drug related. AEs leading to discontinuation were reported in 6 patients (5.6%), 3(2.8%) were possibly related to GT0918. 14 patients (13.0%) experienced Grade 3 and 4 AEs. 17 patients (15.7%)experienced SAE, 5(4.6%) of them were suspected to be related to study drug. Most of AEs were mild or moderate. The common suspected AE (≥10%) were asthenia (17.6%, n=19), anemia (14.8%, n=16), AST increased (14.8%, n=16), ALT increased (13.0%, n=14), decreased appetite (13.0%, N=14), white blood cell count decreased (12.0%, n=13), proteinuria (12.0%, n=13). Conclusions: GT0918 showed a manageable safety profile. This study provided preliminary anti-tumor activity in patients with mCRPC. 200mg/day is recommended dose for Ph III trial. Clinical trial information: CTR20170177.
- Published
- 2021
168. Outcomes in men with metastatic castrate-resistant prostate cancer treated with early platinum-based chemotherapy following an unsatisfactory response to androgen receptor (AR) inhibition as part of the phase II dynamic allocation modular sequential (DynAMo) trial
- Author
-
Miao Zhang, Eleni Efstathiou, Jennifer Wang, Jianbo Wang, Christopher J. Logothetis, Jingjing Liu, Amado J. Zurita, Patricia Troncoso, Paul V. Viscuse, Jianhua Zhang, Ana Aparicio, Shi-Ming Tu, Patrick G. Pilie, Paul G. Corn, Sumit K. Subudhi, John C. Araujo, and Rebecca S. S. Tidwell
- Subjects
Androgen receptor ,Cancer Research ,Chemotherapy ,medicine.anatomical_structure ,Oncology ,Prostate ,business.industry ,medicine.medical_treatment ,Cancer research ,medicine ,Castrate-resistant prostate cancer ,business - Abstract
83 Background: Most prostate cancers are driven by the androgen receptor (AR) and have significant responses to AR inhibition. However, approximately 20-30% respond poorly to AR signaling inhibitors and have an atypical and virulent clinical course. Previous studies have shown that early declines in PSA and CTC on treatment are linked with “AR-responsiveness” in metastatic castration resistant prostate cancer (mCRPC). Few non-androgen directed therapies are approved for AR-unresponsive patients though combination cabazitaxel and carboplatin showed efficacy in this patient population in a phase I/II trial (Corn et al. Lancet Oncol, 2019). We hypothesized that early addition of chemotherapy in AR-unresponsive patients would improve outcomes. Methods: In a modular phase II trial (NCT02703623), men with mCRPC treated with abiraterone acetate plus prednisone and apalutamide were classified at week 8 as having a ‘satisfactory’ decline in PSA (≥ 50% from baseline) and CTC (≤5/7.5mL) or ‘unsatisfactory’. Patients with ‘unsatisfactory’ declines had carboplatin and cabazitaxel added to the AR inhibitors. Primary objectives included the estimation of the overall survival (OS) of patients in this cohort. Results: 198 men were registered. 59 (31.5%) of 187 evaluable had ‘unsatisfactory’ marker declines. Patients were primarily white/non-Hispanic men (81%) over the age of 60 (78%) with ECOG score of 0 (75%). Median baseline PSA and CTC were 11.3 ng/mL and 9.0 cells/mL respectively. Median follow-up was 31.7 months with median OS 19.2 months (95% CI 14.8-27.8). Median TTF was 9.0 months (6.9-11.0). Related adverse events included decreased WBC (39%; 15% G3+), anemia (56%; 7% G3+), and lymphopenia (59%; 8% G3+). There was one grade 5 sepsis of unknown attribution. Conclusions: Although early platinum-based chemotherapy offers a durable response in a subset of AR unresponsive patients, there were patients that continued to have rapid progression. We will present additional clinical and molecular data (IHC, RNA-seq, WES) in an attempt to further differentiate AR responders from AR non-responders. Clinical trial information: NCT02703623.
- Published
- 2021
169. Genomic landscape of CDK12 mutated metastatic castrate-resistant prostate cancer (mCRPC)
- Author
-
Meagan Montesion, Hanna Tukachinsky, Brennan Decker, Philippe E. Spiess, Joseph M. Jacob, Natalie Danziger, Gennady Bratslavsky, Ethan Sokol, Douglas A. Mata, Jeffrey M. Venstrom, Petros Grivas, Andrea Necchi, Jeffrey S. Ross, and Richard S.P. Huang
- Subjects
Cancer Research ,Prostate cancer ,Oncology ,business.industry ,Immune checkpoint inhibitors ,Cancer research ,Castrate-resistant prostate cancer ,Medicine ,business ,medicine.disease ,Unmet needs ,CDK12 - Abstract
165 Background: Identifying prostate cancer patients likely to benefit from immune checkpoint inhibitors (ICPI) remains an unmet need. Specific loss-of-function genomic alterations (GA) in CDK12 are associated with focal tandem duplications linked to fusion-induced production of neoantigens and are a promising candidate biomarker for ICPI. Using comprehensive genomic profiling (CGP) we compared the GA landscape of CDK12 altered (CDK12mut+) and unaltered (CDK12mut-) tumors. Methods: 4,918 mCRPC tumors were sequenced using a hybrid capture-based FDA-approved CGP assay. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining -49% and high staining ≥50% expression. Results: Overall, 315 (6.4%) of the mCRPC cases were CDK12mut+ (Table). CDKmut+ cases had significantly fewer GA in TMPRSS2: ERG (P < .0001), TP53 (P < .0001), PTEN (P < .0001), ATM (P = .001), PIK3CA (P = .003), RB1 (P = .02), BRCA2 (P < .0001) and APC (P = .002). CDK12mut+ cases featured higher frequencies only in CCND1 (P < .0001), BRAF (P = .007) and ERBB2 (P < .001) as well as in cell cycle regulatory genes including MDM2/4 (P < .0001), CDK4 (P < .0001) and CDK6 (P = .002). CDK12mut+ cases featured more frequent MSI-H status (P = .007), significantly higher median TMB (P < .001) and more frequent low positive (1-49% staining) PD-L1 expression (P = .02). High (≥50%) PD-L1 expression was rarely identified in either cohort. Conclusions: CDK12mut+ mCRPC demonstrates a unique genomic profile with significant differences compared with CDK12mut- mCRPC. Lower frequencies of GA associated with homologous recombination defect and mTOR pathway may impact the use of platinum agents, as well as PARPi and PIK3CA/Akt/mTOR inhibitors. Opportunities for targeted therapies for BRAF and ERBB2 driven mCRPC may be enriched in the CDK12mut+ tumors and raise the possibility of combination therapy strategies although the numbers of patients are small and validation is needed. The slightly higher MSI High status, median TMB and PD-L1 staining may be associated with additional benefit from ICPI and warrants further prospective investigation. [Table: see text]
- Published
- 2021
170. Overall survival of patients with metastatic castrate-resistant prostate cancer (mCRPC) who have PTEN tumor suppressor gene loss of function
- Author
-
Roxana Ioana Sufan, Husam Albarmawi, Ibrahim Abbass, Sacha Satram, Tu My To, Shilpa Gupta, Christopher Craggs, and Sami Mahrus
- Subjects
Cancer Research ,biology ,Tumor suppressor gene ,business.industry ,Phosphatase ,Castrate-resistant prostate cancer ,Oncology ,biology.protein ,Cancer research ,Overall survival ,PTEN ,Tensin ,Medicine ,business ,Loss function - Abstract
58 Background: It is estimated that more than 40% of patients with mCRPC have functional loss of phosphatase and tensin homolog (PTEN) tumor suppressor gene, which is associated with unfavorable prognosis and reduced response to androgen receptor-targeting therapy. We describe patient characteristics and survival outcomes by PTEN LOF status among patients with mCRPC in real-world clinical practice. Methods: We conducted a retrospective cohort study using data from the nationwide Flatiron Health-Foundation Medicine mCRPC Clinico-Genomic database (FH-FMI CGDB), a de-identified database linking data derived from electronic health records with genomic data derived from FMI comprehensive genomic profiling (CGP) tests. The study included patients ≥18 years old, with a primary diagnosis of mCRPC between 1/1/2013 and 6/30/2019 who underwent FMI CGP testing and who had a valid PTEN LOF status. Patients were included if their PTEN report date and mCRPC diagnosis date occurred before death or censoring. PTEN LOF status was identified via FMI’s CGP testing. Kaplan-Meier (KM) methods assessed overall survival (OS) by PTEN LOF status from the date of mCRPC diagnosis (later of metastasis and castration resistance) until death or end of study follow-up. A stratified Cox regression model was used to estimate the hazard of death. The Cox model was adjusted for age, race and sequence of metastasis/CRPC diagnoses, and was stratified by the year of mCRPC diagnosis. Adjustments to account for left-truncation and survivorship bias were made in the KM analysis and the Cox regression model. Results: Among the 458 patients who met the eligibility criteria, 174 (38%) had PTEN LOF. The majority of the study sample (76%) was diagnosed with castration-resistance after metastasis. The PTEN LOF group had a higher percentage of white patients (80% vs. 68%; p= 0.01) compared to the PTEN non-LOF group. The mean age of the study sample was 68 years, and there was no difference in mean age at diagnosis by PTEN LOF status ( p= 0.17). Based on the KM estimates adjusted for left-truncation, the median OS was 14.3 months (95% confidence interval [CI]: 11.1-19.7) in the PTEN LOF group compared to 18.3 months (95%CI: 15.5-21.5) in the PTEN non-LOF group (log-rank p= 0.049). In the multivariable Cox model, the PTEN LOF group had numerically 30% higher risk of death compared to the PTEN non-LOF group (hazard ratio = 1.30; 95% CI: 0.99-1.71; p= 0.057). Conclusions: Among real-world patients with mCRPC in the CGDB, PTEN LOF could be associated with poorer survival outcomes, potentially highlighting the unmet need among these patients. Additional studies with larger cohorts are needed to better evaluate the survival outcomes of patients with PTEN LOF. Therapeutic agents acting on the PTEN/PI3K/AKT/mTOR pathway are being tested in clinical trials, and could potentially improve outcomes in this subgroup of patients with mCRPC.
- Published
- 2021
171. Neutrophil-to-lymphocyte ratio (NLR) as a prognostic indicator of treatment response to novel hormones in metastatic castrate-resistant prostate cancer: Real-world data from a single institution
- Author
-
Gillian Marks, Katia Pasciuti, Kate Smith, Magdalena Kubiak, Mark Prentice, Sarah Needleman, and Emily Scott
- Subjects
Oncology ,Cancer Research ,Treatment response ,medicine.medical_specialty ,business.industry ,Castrate-resistant prostate cancer ,Disease ,medicine.disease ,Malignancy ,Prostate cancer ,Internal medicine ,medicine ,Neutrophil to lymphocyte ratio ,Single institution ,business ,Hormone - Abstract
52 Background: Prostate cancer is the most common solid malignancy in men. Despite advances in radical management, a proportion of patients develop castrate resistant metastatic disease (mCRPC). Management options in mCRPC include the novel hormones Enzalutamide (E) or Abiraterone Acetate (AA). There is limited knowledge of clinical factors suggesting improved response to either E or AA to guide clinician choice. Systemic inflammation caused by tumor activity may predict response to E or AA. The NLR is a marker of systemic inflammation which has been assessed previously. We present findings from a single institution evaluation of NLR for E and AA. Methods: Men receiving E or AA for mCRPC between March 2018 - February 2020 at our institution were identified. Baseline characteristics and pre-specified metrics including hematology, age and disease burden as well as time on treatment and survival data were retrospectively taken from hospital systems and collated into a single dataset. Time on treatment was used as a surrogate for progression free survival (PFS). Patients could switch therapies if they developed dose limiting toxicity within 3 months of treatment as per UK guidelines. AUROC curve analysis was applied to determine NLR cut off for E and AA cohorts specific for PFS. Results: 128 patients are included in the final analysis; 65 patients received E, 63 AA. Cohorts were well balanced with a median age at initial treatment of 75 (range 46-102) for AA and 74 (range 48-91) for E. The median Gleason score for AA was 8 and 9 for E. Patients receiving AA were more likely to have greater than 3 bone metastases (85% vs 74%). Patients receiving E were more likely to have visceral disease, 13% vs 10%. NLR cutoff, determined by AUROC curve analysis was 3.09 for E with an AUC of 0.782 (p
- Published
- 2021
172. HHV-8 positive clinically advanced castrate-resistant prostate cancer (mCRPC): A potentially distinct molecular subset
- Author
-
Richard S.P. Huang, Natalie Danziger, Philippe E. Spiess, Brennan Decker, Joseph M. Jacob, Jeffrey S. Ross, Hanna Tukachinsky, Andrea Necchi, Petros Grivas, Douglas A. Mata, Jeffrey M. Venstrom, Ethan Sokol, Gennady Bratslavsky, Ole Gjoerup, and Douglas I. Lin
- Subjects
Cancer Research ,business.industry ,viruses ,Castrate-resistant prostate cancer ,virus diseases ,medicine.disease ,In vitro ,Prostate cancer ,medicine.anatomical_structure ,Oncology ,Prostate ,Cancer research ,medicine ,business - Abstract
163 Background: Herpesvirus HHV-8 has been detected in normal prostate tissue and has been linked to the acquisition of androgen-independent growth of prostate cancer cells in vitro, early development of anti-androgen therapy resistance, and more aggressive disease in a subset of patients with mCRPC. We used comprehensive genomic profiling (CGP) to test the hypothesis that HHV-8 associated mCRPC is a distinct molecular subset of mCRPC featuring altered AR signaling compared to HHV-8 negative mCRPC. Methods: Using a hybrid capture-based FDA-approved CGP assay, a series of 4,918 mCRPC were sequenced to evaluate all classes of genomic alterations (GAs). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). HHV-8 status was determined by CGP-based identification of unique viral reads. Results: Overall, 128 (2.6%) of the mCRPC cases harbored HHV-8 sequences (Table). The patient age distribution was similar in the HHV-8+ and HHV-8− groups. GAs in AR, predominantly amplifications, and RAD21 were slightly reduced in HHV-8+ mCRPC cases (P = .01 for both). The frequencies of GAs in genes associated with mCRPC including PTEN, BRCA2, ATM, CDK12, and the TMPRSS2: ERG fusion were similar in the two groups. HHV-8+ patients were less likely to be of European ancestry (P = 0.001). Putative biomarkers associated with immunotherapy response (MSI status, TMB, and PD-L1 expression) were also similar in the two groups. Conclusions: HHV-8+ mCRPC is a rare sub-type of mCRPC with lower frequency of AR GAs compared to HHV-8− mCRPC cases, suggesting a potential role of HHV-8 in inducing androgen-independent prostate cancer growth. Additional alterations associated with potentially enhanced PARP inhibitor response seen in HHV-8+ mCRPC (e.g., RAD21) suggest that early performance of CGP may inform precision treatment strategies to be tested in clinical trials. [Table: see text]
- Published
- 2021
173. Associations of circulating cell-free DNA (cfDNA) and clinical outcomes in metastatic castrate-resistant prostate cancer (mCRPC)
- Author
-
Polina Imas, Mathew Yang, Daniel H. Shevrin, and Kamalakar Gulukota
- Subjects
Cancer Research ,Genomic profiling ,Oncology ,business.industry ,Cancer research ,Castrate-resistant prostate cancer ,Medicine ,business ,Gene ,Circulating Cell-Free DNA - Abstract
137 Background: Genomic profiling of patients (pts) with mCRPC is becoming more widely utilized to assist in prognosis and treatment. Liquid biopsies offer a non-invasive method of assessing gene alterations but questions remain regarding their validity, as well as the association of these alterations with relevant clinical outcomes. Methods: We present a retrospective analysis of 82 pts who underwent genomic profiling at the onset of mCRPC using the Guardant360 cfDNA assay. Clinical outcomes data was recorded in a structured note in the electronic medical record that allowed discrete data elements to be stored and analyzed. Patients received standard treatment with Abiraterone (Abi) and Enzalutamide (Enza) as well as chemotherapy. Relevant clinical outcome endpoints included overall survival (OS) and time on treatment with Abi and Enza (TT). These endpoints were compared between patients grouped by their gene alterations and treatment. Univariate and multivariate association analyses were performed. Results: The structured note was found to be valuable in capturing relevant discrete clinical outcomes data for detailed analysis. Median OS for the 82 pts was 58 months. 15 pts had insufficient cfDNA to perform the assay and these pts had a significantly longer OS than the 67 pts with sufficient cfDNA (median not reached vs 36 months, p = 0.004). The most commonly altered genes were AR and TP53 with 45% pts having alterations in both genes. Our analysis showed significantly shorter OS with BRAF (24 months, p = 0.008) and NF1 (20 months, p = 0.036) alterations. However, the significance was lost after multiple hypothesis correction. We observed that pts with co-occurrence of AR and BRAF had a significantly shorter OS (18.7 months, p = 0.031). BRCA2 mutations were observed in 9 pts and were associated with a significantly shorter TT (23 vs 38 months, p = 0.022) but lost significance after multiple hypothesis correction. Patients who received Abi followed by Enza had a significantly longer TT compared to pts who received the reverse sequence (38 months vs 23 months, p = 0.02). Conclusions: In this retrospective analysis, we did not identify any significant associations between specific gene alterations and relevant clinical outcomes. We observed a trend of shorter OS with BRAF and NF1 alterations and a shortened OS with co-occurrence of AR and BRAF alterations. These associations will require validation in a larger study. The presence of sufficient DNA to perform the assay was associated with shorter OS. The treatment sequence of Abi followed by Enza showed longer TT than the reverse sequence. The structured note allowed capture of relevant clinical outcomes data and is currently being utilized in a larger prospective genomic study of mCRPC.
- Published
- 2021
174. Racial disparities in efficacy of first-line abiraterone in metastatic castrate-resistant prostate cancer (mCRPC)
- Author
-
Qi Long, Ravi B. Parikh, Ronac Mamtani, Vivek Narayan, Neha Vapiwala, and Mallika Marar
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,First line ,Castrate-resistant prostate cancer ,body regions ,Abiraterone ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Medicine ,cardiovascular diseases ,business ,Prospective cohort study ,human activities - Abstract
20 Background: Prospective studies suggest that abiraterone (Abi) use in mCRPC is associated with improved progression-free survival in African-American (AA) patients (pts) compared to non-Hispanic White (NHW) pts. It is unclear whether racial disparities in Abi effectiveness exist for pts with mCRPC treated in real-world practice. Methods: In this retrospective cohort study, we used the nationwide Flatiron Health electronic health record-derived de-identified database to select pts who received first-line (1L) systemic therapy for mCRPC between January 1, 2012 and December 31, 2018. Propensity score-based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier and Cox regression models of comparative effectiveness, using age, race, comorbidity index, prostate-specific antigen (PSA), baseline steroid or opioid use, insurance status, practice type, practice Abi prescribing rate, and practice region as covariates. The primary exposure was treatment with 1L Abi. Overall survival (OS) was the primary outcome, and time-to-next-treatment (TTNT), using Fine-Gray models with death as a competing risk, was the secondary outcome. Racial disparities between Abi vs. no Abi groups were explored with stratified analyses by race and race-treatment interaction terms. Results: Of 3808 pts, 1729 (45.4%) received 1L Abi, 1255 (33.0%) received 1L enzalutamide, and 549 (14.4%) received 1L docetaxel. The cohort included 2165 (68.7%) NHW and 404 (10.6%) AA pts. Pts receiving Abi were older (mean age 74 vs. 72) and more likely to be treated at academic centers (8% vs. 6%) than pts not receiving Abi. Among pts receiving Abi, AAs had improved OS compared to NHWs (Table). Compared to receipt of a non-Abi regimen, receipt of Abi was not associated with OS among AA pts but was associated with decreased OS among NHW pts. A significant race-by-treatment interaction for OS existed among patients receiving 1L Abi (interaction coeff = 0.27 95% CI = 0.02-0.53). There were no race-based disparities found in TTNT. Conclusions: In a large real-world analysis of pts who received 1L systemic therapy for mCRPC, AAs who received Abi had improved OS compared to NHWs – a finding consistent with ABI-RACE (NCT01940276). Among NHW pts, 1L Abi was associated with decreased OS. These real-world data suggest race-based differences in therapeutic response to Abi and future prospective evidence is needed to assess drivers of differential Abi efficacy in mCRPC. [Table: see text]
- Published
- 2021
175. Frequency, management, and resource use of adverse events (AEs) in nonmetastatic castrate-resistant prostate cancer (nmCRPC) patients receiving apalutamide or enzalutamide: A real-world study
- Author
-
Shan Jiang, A. Reginald Waldeck, Shelby Corman, Cynthia Macahilig, Sreevalsa Appukkuttan, Arif Hussain, Nehemiah Kebede, Kajan Gnanasakthy, and Della Varghese
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,education ,Apalutamide ,Castrate-resistant prostate cancer ,Androgen receptor ,chemistry.chemical_compound ,Darolutamide ,chemistry ,Internal medicine ,mental disorders ,Frequency management ,Resource use ,Medicine ,Enzalutamide ,Adverse effect ,business ,psychological phenomena and processes - Abstract
217 Background: Second generation androgen receptor inhibitors (SGARIs), apalutamide (APA) and enzalutamide (ENZ) and darolutamide, are approved in the United States (US) for the treatment of nmCRPC. The objectives of this study were to describe the frequency of AEs and actions taken to manage AEs among nmCRPC patients treated with APA or ENZ and their downstream resource implications. Methods: This is a further descriptive analysis of a retrospective chart review study conducted in 43 US nmCRPC-treating sites. In our sample, the 43 physicians identified 699 nmCRPC patients initiating treatment with APA (N = 368) or ENZ (N = 333) with 2 patients receiving both, between February 1, 2018 and December 31, 2018 and AEs were collected as reported in regular clinical practice. A representative subset of patients, experiencing at least 1 AE for either APA (N = 125) or ENZ (N = 125), were selected randomly from the initial cohort, and their detailed chart data were extracted to understand the actions taken to manage AEs. Results: Of the initial cohort of nmCRPC patients, 72.0% and 78.7% of men receiving APA (N = 368) and ENZ (N = 333) experienced ≥1 AE, respectively. The three most common AEs reported were fatigue/asthenia (APA, 30.2%; ENZ, 38.7%), hot flush (APA, 14.1%; ENZ, 13.5%), and arthralgia (APA, 14.4%; ENZ, 12.9%). Cognitive and mental changes were observed in 5.4% (APA) and 7.8% (ENZA) men. The subset analysis of randomly selected patients experiencing ≥1 AE (APA, 125; ENZ, 125) were mostly Caucasian (APA, 72.8%; ENZ, 71.2%), ECOG score 0-1 (APA, 84%; ENZ, 88%), median prostate specific antigen (PSA) value 13 ng/ml and 11 ng/ml (APA, ENZ; respectively). Actions to address AEs included treatment of AE, SGARI discontinuation, dose reduction and hospitalization (Table). Specifically, treatment discontinuation due to AE was observed in 8.0% (APA) and 12.8 (%) of men. AEs were often not resolved (APA, 43.6%; ENZ, 39.4%), and the median duration of days to resolve AEs were 60.0 for APA and 56.0 for ENZ. Conclusions: This real-world study highlights the clinical and resource use burden of AEs among nmCRPC patients treated with APA and ENZ. The results demonstrate the importance of safety and tolerability as key considerations in shared clinician-patient decision-making regarding SGARI therapy in nmCRPC. [Table: see text]
- Published
- 2021
176. Genomic/genetic testing patterns for patients with metastatic castrate-resistant prostate cancer: Results from a real-world study in the United States
- Author
-
Andrea Leith, Amanda Ribbands, Matthew Last, Alicia Gayle, Sarah Payne, Charles McCrea, Lingfeng Yang, Joseph E. Burgents, and Sameer Ghate
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,medicine.drug_class ,business.industry ,Castrate-resistant prostate cancer ,Androgen ,Olaparib ,Abiraterone ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,Enzalutamide ,Rucaparib ,business ,Genetic testing - Abstract
49 Background: In May 2020, Olaparib was approved for HRRm mCRPC post progression on abiraterone and enzalutamide, and rucaparib was approved for BRCAm mCPRC following progression on androgen receptor targeted inhibitors and prior taxane therapy for mCRPC. HRRm are associated with approximately 25% of mCRPC and may be derived from germline or somatic origin. Somatic and germline alterations can be detected by tumour testing, but to differentiate between these, independent germline testing is needed. This study examined real-world genomic/genetic testing (GT) patterns in patients (pts) diagnosed with mCRPC in the United States (US). Methods: Data were drawn from the Adelphi Prostate Cancer Disease Specific Programme; a point-in-time survey administered to oncologists (onc), urologists (uro) and surgeons (sur) between January and August 2020 in the US. Physicians (phys) completed an attitudinal survey and a patient record form for the next four to nine mCRPC pts seen. Study variables included patient demographics, clinical factors and GT patterns. HRRm testers were defined as phys who tested for HRRm. Pts were identified as positive, negative or unknown depending on the outcome of the HRRm test. Results: A total of 72 phys (69% onc/ 29% uro/ 1% sur; 40% academic vs. 60% community) reported on 346 mCRPC pts. 41% of phys were based in the Northeast, 24% Midwest, 23% South and 13% in the West region of the US. 65 phys (90%) reported having access to overall GT; of these 5% identified as having access to germline tests only, while 94% were able to test for germline and somatic mutations. Challenges to conducting GT overall were ‘cost per test’ (50%), ‘having to send out for the tests (within country)’ (25%), ‘inadequate sample available’ (25%) and ‘patient refusal’ (25%). GT was typically conducted at identification of castrate-resistance (52%), metastases (51%) and at initial diagnosis (49%). 72% of total phys were HRRm testers; for these, patient characteristics primarily driving HRRm testing included Ashkenazi Jewish heritage (63%) and ECOG of 2-4 (58%). Other common drivers were family history, young diagnosis age and hormone therapy failure (all 46%). 132 (38% of 326) mCRPC pts were tested for HRRm; 39% of tested pts were identified with a HRRm. Most common HRRm tested were BRCA1 (90%), BRCA2 (89%) and ATM (55%). Conclusions: In this study majority of US phys had access to GT, but testing was only performed in 38% of pts with mCRPC. The higher than expected % of pts identified with an HRRm suggest that molecular testing was prioritised in high risk populations, as identified by the phys. With the recent approval of olaparib and rucaparib, GT may become more routine in clinical practice to identify eligible pts. Broader testing may also depend on addressing other barriers to testing including cost and testing logistics/practicalities.
- Published
- 2021
177. Circulating Tumour Cells Indicate the Presence of Residual Disease Post-Castration in Prostate Cancer Patient-Derived Xenograft Models.
- Author
-
Hassan S, Blick T, Wood J, Thompson EW, and Williams ED
- Abstract
Castrate-resistant prostate cancer (CRPC) is the lethal form of prostate cancer. Epithelial mesenchymal plasticity (EMP) has been associated with disease progression to CRPC, and prostate cancer therapies targeting the androgen signalling axis, including androgen deprivation therapy (ADT), promote EMP. We explored effects of castration on EMP in the tumours and circulating tumour cells (CTCs) of patient-derived xenograft (PDX)-bearing castrated mice using human-specific RT-qPCR assays and immunocytochemistry. Expression of prostate epithelial cell marker KLK3 was below detection in most tumours from castrated mice (62%, 23/37 mice), consistent with its known up-regulation by androgens. Endpoint tumour size after castration varied significantly in a PDX model-specific pattern; while most tumours were castration-sensitive (BM18, LuCaP70), the majority of LuCaP105 tumours continued to grow following castration. By contrast, LuCaP96 PDX showed a mixed response to castration. CTCs were detected in 33% of LuCaP105, 43% of BM18, 47% of LuCaP70, and 54% of LuCaP96 castrated mice using RPL32 mRNA measurement in plasma. When present, CTC numbers estimated using human RPL32 expression ranged from 1 to 458 CTCs per ml blood, similar to our previous observations in non-castrated mice. In contrast to their non-castrated counterparts, there was no relationship between tumour size and CTC burden in castrated mice. Unsupervised hierarchical clustering of the gene expression profiles of CTCs collected from castrated and non-castrated mice revealed distinct CTC sub-groups within the pooled population that were classified as having mesenchymal, epithelial, or EMP hybrid gene expression profiles. The epithelial signature was only found in CTCs from non-castrated mice. Hybrid and mesenchymal signatures were detected in CTCs from both castrated and non-castrated mice, with an emphasis towards mesenchymal phenotypes in castrated mice. Post-castration serum PSA levels were either below detection or very low for all the CTC positive samples highlighting the potential usefulness of CTCs for disease monitoring after androgen ablation therapy. In summary, our study of castration effects on prostate cancer PDX CTCs showed that CTCs were often detected in the castrate setting, even in mice with no palpable tumours, and demonstrated the superior ability of CTCs to reveal residual disease over the conventional clinical biomarker serum PSA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hassan, Blick, Wood, Thompson and Williams.)
- Published
- 2022
- Full Text
- View/download PDF
178. Adapting to the long pandemic.
- Author
-
Davis JW
- Published
- 2022
- Full Text
- View/download PDF
179. Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer.
- Author
-
Nordeen, Steven K., Su, Lih-Jen, Osborne, Gregory A., Hayman, Perry M., Orlicky, David J., Wessells, Veronica M., van Bokhoven, Adrie, and Flaig, Thomas W.
- Subjects
- *
PROSTATE cancer , *ANDROGEN receptors , *CASTRATION-resistant prostate cancer , *ANDROGENS , *PROSTATE cancer patients , *CLINICAL trials - Abstract
Since the Nobel Prize-winning work of Huggins, androgen ablation has been a mainstay for treatment of recurrent prostate cancer. While initially effective for most patients, prostate cancers inevitably develop the ability to survive, grow, and metastasize further, despite ongoing androgen suppression. Here, we briefly review key preclinical studies over decades and include illustrative examples from our own laboratories that suggest prostate cancer cells titrate androgen signaling to optimize growth. Such laboratory-based studies argue that adaptations that allow growth in a low-androgen environment render prostate cancer sensitive to restoration of androgens, especially at supraphysiologic doses. Based on preclinical data as well as clinical observations, trials employing high-dose testosterone (HDT) therapy have now been conducted. These trials suggest a clinical benefit in cancer response and quality of life in a subset of castration-resistant prostate cancer patients. Laboratory studies also suggest that HDT may yet be optimized further to improve efficacy or durability of response. However, laboratory observations suggest that the cancer will inevitably adapt to HDT, and, as with prior androgen deprivation, disease progression follows. Nonetheless, the adaptations made to render tumors resistant to hormonal manipulations may reveal vulnerabilities that can be exploited to prolong survival and provide other clinical benefits. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
180. Prostate Cancer with Bone Metastases: Addressing Chronic Pain from the Perspective of the Radiation Oncology Nurse Practitioner.
- Author
-
Pituskin, Edith and Fairchild, Alysa
- Abstract
To discuss the symptom burden experienced among patients with castrate-resistant prostate cancer and bone metastases and the role of the oncology nurse practitioner in evaluation for palliative radiotherapy. These include PubMed, international consensus documents, and clinician experience. Men with advanced prostate cancer may live for several years after diagnosis of bone metastases; however, pain and other difficult symptoms are problematic. Pain is effectively treated with palliative radiotherapy, but careful assessment and intervention of other difficult symptoms must be addressed over time. Nurse practitioners in radiation oncology should be well-versed in the disease trajectory of this patient population. Careful symptom inquiry and comprehensive physical examination is a key responsibility. Palliative radiotherapy, alongside analgesics and supportive care measures, can effectively reduce symptoms and improve quality of life in men with prostate cancer metastatic to bone. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
181. First experiences with Lu-177 PSMA therapy in combination with Pembrolizumab or after pretreatment with Olaparib in single patients
- Author
-
Meinrad Beer, Vikas Prasad, Ambros J. Beer, Neil Fleshner, Christian Bolenz, Jochen Steinacker, Thomas Wiegel, Friedemann Zengerling, and Matthias Eiber
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Castrate-resistant prostate cancer ,Conventional treatment ,Pembrolizumab ,Immunotherapy ,medicine.disease ,Olaparib ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Radionuclide therapy ,Glutamate carboxypeptidase II ,Squamous cell carcinoma of the skin ,Medicine ,Radiology, Nuclear Medicine and imaging ,business - Abstract
Synergistic effects of immunotherapy with pembrolizumab or drugs targeting DNA damage e.g. olaparib could be used to overcome the limitations of radioligand therapy (RLT) with Lu-177 prostate specific membrane antigen (PSMA) in metastasized castrate resistant prostate cancer (mCRPC) patients. Here, we present two patients receiving such combination / sequential therapies. Methods: RLT was performed at 6-8 week intervals after they either exhausted or were considered unfit for all approved conventional treatment. Patient 1 was on pembrolizumab for his squamous cell carcinoma of the skin whereas patient 2 received RLT sequentially 4 weeks after a 3 months monotherapy with olaparib. Results: Both patients tolerated RLT without any significant hematotoxicity. Patient 2 showed radiological and biochemical response whereas patient 1 achieved PSA stabilization after 3 therapy cycles. Conclusion: These cases indicate that RLT in combination with pembrolizumab or sequentially after olaparib might be well tolerated in single patients.
- Published
- 2020
182. Association Between Black Race And Improved Survival Following Sipuleucel-T Immunotherapy In Metastatic Castrate-Resistant Prostate Cancer: Implications For Immune Biology And Integration Of Radiation Therapy With Immunotherapy
- Author
-
Vinayak Muralidhar, Edward Christopher Dee, Kent W. Mouw, Paul Nguyen, Oliver Sartor, X.X. Wei, and Brandon A. Mahal
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Radiation ,business.industry ,medicine.medical_treatment ,Castrate-resistant prostate cancer ,Improved survival ,Immunotherapy ,Black race ,Radiation therapy ,Sipuleucel-T ,Immune system ,Internal medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,business ,medicine.drug - Published
- 2020
183. Choline PET guided salvage intensity modulated radiation therapy (sIMRT) for Oligometastatic Castrate Resistant Prostate Cancer (OCRPC)
- Author
-
B.J. Stish, Lance A. Mynderse, William S. Harmsen, Tyler J. Wilhite, Thomas M. Pisansky, F. Abraha, S.S. Park, C.R. Choo, H.C. Gits, David M. Routman, K.R. Olivier, J.F. Quevedo, E.D. Kwon, R. Karnes, Krishan R. Jethwa, and Brian J. Davis
- Subjects
business.industry ,Urology ,Cancer research ,Castrate-resistant prostate cancer ,Choline pet ,Medicine ,Intensity-modulated radiation therapy ,lcsh:Diseases of the genitourinary system. Urology ,lcsh:RC870-923 ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,business ,lcsh:RC254-282 - Published
- 2020
184. Clinical pharmacology profile of an oral selective androgen receptor down-regulator, AZD3514: Implications on the design of ongoing castrate-resistant prostate cancer clinical studies
- Author
-
Michael Dymond, Gareth James, Glen Clack, Angela W. Dymond, Simon Smith, Paul A. Dickinson, Masako Hirata, and Marc-Antoine Fabre
- Subjects
Androgen receptor ,Oncology ,medicine.medical_specialty ,Clinical pharmacology ,law ,business.industry ,Internal medicine ,Regulator ,medicine ,Castrate-resistant prostate cancer ,General Medicine ,business ,law.invention - Published
- 2016
185. Targeting the androgen receptor in metastatic castrate-resistant prostate cancer: A review
- Author
-
Archana Anantharaman and Terence W. Friedlander
- Subjects
Male ,0301 basic medicine ,Intracrine ,Urology ,Castrate-resistant prostate cancer ,urologic and male genital diseases ,Bioinformatics ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Castration Resistance ,Androgen Receptor Antagonists ,medicine ,Humans ,Protein Isoforms ,splice ,business.industry ,medicine.disease ,Androgen receptor ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,Oncology ,Receptors, Androgen ,030220 oncology & carcinogenesis ,Potential biomarkers ,Disease Progression ,Cancer research ,business ,Signal Transduction ,Hormone - Abstract
Despite recent advances in the treatment of advanced prostate cancer (PCa), metastatic castrate-resistant PCa remains incurable at this time. The androgen receptor (AR) plays a key role in the development and progression of PCa, continuing to be active in most patients even after the development of castration resistance. Here, we aim to more closely review the mechanisms by which AR signaling is maintained, including AR overexpression/overamplification, intracrine androgen synthesis, AR mutations, and the development of AR splice variants. We also review therapies targeting each of these mechanisms. We also discuss the potential role of AR-CAG repeats and AR splice variants as potential biomarkers of response to hormonal manipulation therapies.
- Published
- 2016
186. Implementation of the AUA Castration Resistant Prostate Cancer Guidelines into Practice: Establishing a Multidisciplinary Clinic
- Author
-
Abby M. Moeller, Michael S. Cookson, and Kelly L. Stratton
- Subjects
Gynecology ,medicine.medical_specialty ,Patient care team ,business.industry ,Urology ,030232 urology & nephrology ,Castrate-resistant prostate cancer ,Quality care ,Castration resistant ,medicine.disease ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Multidisciplinary approach ,medicine ,030212 general & internal medicine ,Intensive care medicine ,business - Abstract
Introduction AUA (American Urological Association) published guidelines on the treatment of castration resistant prostate cancer in August 2013. Urologists have remained integral members of a multifaceted team of professionals treating patients with prostate cancer. We discuss approaches to implementing a guidelines based, multidisciplinary, advanced prostate cancer treatment clinic. Methods A supplemented PubMed® search was performed to identify published literature evaluating the treatment of castration resistant prostate cancer. Attention was placed on studies assessing a multidisciplinary approach to treating patients with castrate resistant prostate cancer. A review of currently approved agents is provided with emphasis on administration from an integrated clinic. Results Treatment of patients with advanced prostate cancer remains a significant function of many urology clinics. Guidelines assist urologists with providing patients with the most appropriate care along with multispecialty collaboration. Several organizational approaches have been attempted, including all-in-one clinics, onsite clinics and virtual multidisciplinary clinics. Through close collaboration with medical oncologists, radiation oncologists and support staff patients with advanced prostate cancer can obtain the highest quality care. Conclusions Urologists remain an integral member of the multidisciplinary approach to treating castrate resistant prostate cancer. AUA guidelines for castration resistant prostate cancer are a useful tool that can be incorporated into virtual multidisciplinary clinics. Through a team approach patients receive timely and appropriate care.
- Published
- 2016
187. Clinical experience with radium-223 in the treatment of patients with advanced castrate-resistant prostate cancer and symptomatic bone metastases
- Author
-
John P. Logue and Christina Hague
- Subjects
Radium-223 ,Oncology ,medicine.medical_specialty ,Urology ,Castrate-resistant prostate cancer ,Reviews ,Improved survival ,lcsh:RC870-923 ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Quality of life ,Prostate ,Internal medicine ,medicine ,business.industry ,lcsh:Diseases of the genitourinary system. Urology ,medicine.disease ,Review article ,Surgery ,medicine.anatomical_structure ,Survival benefit ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
The treatment of metastatic castrate-resistant prostate cancer (mCRPC) has grown over the past decade. The majority of patients develop bone metastases, which pose a significant burden on morbidity and mortality, especially skeletal-related events. Whilst demonstrating a favourable safety profile and improving symptoms, radiopharmaceuticals have until recently failed to show a survival benefit. However, since the large phase III randomized ALSYMPCA trial, the calcium mimetic properties of radium-223 (Ra223) have improved patients’ quality of life and improved survival whilst keeping toxicities to a minimum. This review article summarizes the clinical data including our real life experience on the usage of the alpha emitter Ra223 in mCRPC, paying particular attention to how clinicians should best monitor response.
- Published
- 2016
188. Crosstalk between RON and androgen receptor signaling in the development of castration resistant prostate cancer
- Author
-
Suleman S. Hussain, Peng Meng, Pawel A. Osmulski, Addanki P. Kumar, Tim H M Huang, Roble Bedolla, Huiyoung Yun, Amanda L. Profit, Izhar Singh Batth, and Robert L. Reddick
- Subjects
Male ,0301 basic medicine ,Gerontology ,Oncology ,medicine.medical_specialty ,FLIP ,medicine.drug_class ,Castrate-resistant prostate cancer ,urologic and male genital diseases ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,DU145 ,MST1R ,Internal medicine ,LNCaP ,Biomarkers, Tumor ,Tumor Cells, Cultured ,medicine ,Humans ,Epithelial–mesenchymal transition ,Cell Proliferation ,business.industry ,apoptosis ,Receptor Protein-Tyrosine Kinases ,Prognosis ,RON ,Androgen ,medicine.disease ,3. Good health ,Androgen receptor ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,Receptors, Androgen ,030220 oncology & carcinogenesis ,castrate resistant prostate cancer ,business ,Signal Transduction ,Research Paper - Abstract
// Izhar Batth 1, 8 , Huiyoung Yun 2 , Suleman Hussain 2 , Peng Meng 1, 7 , Pawel Osmulski 3 , Tim Hui-Ming Huang 3, 5 , Roble Bedolla 1 , Amanda Profit 4 , Robert Reddick 4 , Addanki Kumar 1, 2, 3, 5, 6 1 Department of Urology, The University of Texas Health Science Center, San Antonio, TX, USA 2 Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA 3 Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA 4 Department of Pathology, The University of Texas Health Science Center, San Antonio, TX, USA 5 Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, TX, USA 6 The University of Texas Health Science Center at San Antonio and South Texas Veterans Health Care System, San Antonio, TX, USA 7 Current address: Life Sciences Division, Lawrence Berkley National Laboratory, Berkley, CA, USA 8 Current address: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Addanki Kumar, e-mail: kumara3@uthscsa.edu Keywords: castrate resistant prostate cancer, apoptosis, FLIP, RON, MST1R Received: November 18, 2015 Accepted: January 29, 2016 Published: February 9, 2016 ABSTRACT Castrate-resistant prostate cancer (CRPC) is the fatal form of prostate cancer. Although reactivation of androgen receptor (AR) occurs following androgen deprivation, the precise mechanism involved is unclear. Here we show that the receptor tyrosine kinase, RON alters mechanical properties of cells to influence epithelial to mesenchymal transition and functions as a transcription factor to differentially regulate AR signaling. RON inhibits AR activation and subset of AR-regulated transcripts in androgen responsive LNCaP cells. However in C4-2B, a castrate-resistant sub-line of LNCaP and AR-negative androgen independent DU145 cells, RON activates subset of AR-regulated transcripts. Expression of AR in PC-3 cells leads to activation of RON under androgen deprivation but not under androgen proficient conditions implicating a role for RON in androgen independence. Consistently, RON expression is significantly elevated in castrate resistant prostate tumors. Taken together our results suggest that RON activation could aid in promoting androgen independence and that inhibition of RON in combination with AR antagonist(s) merits serious consideration as a therapeutic option during hormone deprivation therapy.
- Published
- 2016
189. NPRL2 reduces the niraparib sensitivity of castration-resistant prostate cancer via interacting with UBE2M and enhancing neddylation.
- Author
-
Zhao, Xin, Jiang, Li, Hu, Daixing, Tang, Yu, Zhao, Guozhi, Du, Xiaoyu, Luo, Shengjun, and Tang, Wei
- Subjects
- *
CASTRATION-resistant prostate cancer , *WESTERN immunoblotting , *PROSTATE cancer , *PROGNOSIS , *PROTEIN analysis , *UBIQUITIN ligases - Abstract
In this study, we explored the regulatory effects of nitrogen permease regulator 2-like (NPRL2) on niraparib sensitivity, a PARP inhibitor (PARPi) in castrate-resistant prostate cancer (CRPC). Data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) program were retrospectively examined. Gene-set enrichment analysis (GSEA) was conducted between high and low NRPL2 expression prostate adenocarcinoma (PRAD) cases in TCGA. CCK-8 assay, Western blot analysis of apoptotic proteins, and flow cytometric analysis of apoptosis were applied to test niraparib sensitivity. Immunofluorescent (IF) staining and co-immunoprecipitation (co-IP) were conducted to explore the proteins interacting with NPRL2. Results showed that the upregulation of a canonical protein-coding transcript of NPRL2 (ENST00000232501.7) is associated with an unfavorable prognosis. Bioinformatic analysis predicts a physical interaction between NPRL2 and UBE2M, which is validated by a following Co-IP assay. This interaction increases NPRL2 stability by reducing polyubiquitination and proteasomal degradation. Depletion of NPRL2 or UBE2M significantly increases the niraparib sensitivity of CRPC cells and enhances niraparib-induced tumor growth inhibition in vivo. NPRL2 cooperatively enhances UBE2M-mediated neddylation and facilitates the degradation of multiple substrates of Cullin-RING E3 ubiquitin ligases (CRLs). In conclusion, this study identified a novel NPRL2-UBE2M complex in modulating neddylation and niraparib sensitivity of CRPC cells. Therefore, targeting NPRL2 might be considered as an adjuvant strategy for PARPi therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
190. An Overview of Current Screening and Management Approaches for Prostate Cancer
- Author
-
Omar N. Akram, Gohar Mushtaq, and Mohammad Amjad Kamal
- Subjects
Male ,Pharmacology ,Oncology ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Clinical Biochemistry ,Castrate-resistant prostate cancer ,Prostatic Neoplasms ,Early detection ,medicine.disease ,Circulating biomarkers ,Prostate cancer ,Internal medicine ,Epidemiology ,Animals ,Humans ,Medicine ,Approaches of management ,Treatment resistance ,business ,Early Detection of Cancer - Abstract
Prostate cancer is the fourth leading cause of mortality in Australian men. The prevalence and incidence is increasing in both developed and developing nations, thus there is a need for better screening and management of this disorder. While there is no direct known cause of prostate cancer, management is largely focused on early detection and treatment strategies. Of particular concern is advanced prostate cancer which can manifest as castrate resistant prostate cancer characterized by therapy resistance. This short review outlines the global epidemiology of prostate cancer, clinical manifestations, risk factors, current screening strategies including first line clinical screening as well as the use of circulating biomarkers, and treatment of prostate cancer through mainstream therapeutics as well as the cutting edge peptide and nano-technology based therapeutics that are being implemented or in the process of development to overcome therapeutic obstacles in the treatment of prostate cancer.
- Published
- 2015
191. 687TiP ARC-6: A phase Ib/II, open-label, randomized platform study evaluating the efficacy and safety of AB928-based treatment combinations in patients with metastatic castrate resistant prostate cancer
- Author
-
S.K. Subudhi, Joseph Kim, O. Gardner, M. Paoloni, A. Chaudhry, K. Krishnan, Michael A. Carducci, D. Wise, M. Grady, S.T. Liu, and H. Gilbert
- Subjects
Arc (geometry) ,Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Castrate-resistant prostate cancer ,In patient ,Hematology ,Open label ,business - Published
- 2020
192. 636P A study of sustained androgen signaling dependence in metastatic castrate resistant prostate cancer (mCRPC)
- Author
-
Ana Aparicio, Justin A. Weldon, Ioannis Alafis, K. Karalis, Myrto Boukovala, Paul G. Corn, Nicholas Spetsieris, Eleni Efstathiou, S. M. Tu, Sumit K. Subudhi, John C. Araujo, Christopher J. Logothetis, Amado Zurita-Saavedra, and M. Karlou
- Subjects
medicine.medical_specialty ,business.industry ,Castrate-resistant prostate cancer ,Abiraterone acetate ,Hematology ,Unmet needs ,Clinical trial ,Safety profile ,chemistry.chemical_compound ,Oncology ,chemistry ,Family medicine ,Prognostic model ,medicine ,business ,health care economics and organizations ,Prognostic models ,Clinical progression - Abstract
Background: Advanced androgen signaling inhibition, a prevailing therapy approach in advanced prostate cancer, incurs variable response Therapy selection guided by predictors is an unmet need Methods: We reviewed MDACC GU department and Hellenic Sister Institute records for Abiraterone Acetate (AA) treated mCRPC patients (pts) with extraordinary response (absence of radiographic/clinical progression for ≥3 years) We compared to reported findings for COU-AA-302 and real world experience to identify candidate predictors of outcome We applied a previously proposed COU-AA-302 response prognostic model Archived diagnostic and subsequent tumor specimens were retrieved for molecular characterization Results: Forty four of 430 reviewed mCRPC pts had extraordinary response Table depicts features Median time to AA discontinuation was 5 8 yr (range 3-12 5+) and 20 pts are on treatment Safety profile is acceptable with no overt increase in fractures or cardiovascular, metabolic morbidity All pts experienced >50% PSA decline with nadir ≤0 1 in 80%, occurring within 5mo (median) (range
- Published
- 2020
193. 662P Genomic/genetic testing (GT) patterns for patients with metastatic castrate-resistant prostate cancer (mCRPC): Interim results from a real-world study in Europe (EU5)
- Author
-
Andrea Leith, A. Ribbands, Alicia Gayle, S. Payne, J. Burgents, S. Ghate, Charles McCrea, and Lingfeng Yang
- Subjects
Oncology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Internal medicine ,Interim ,medicine ,Castrate-resistant prostate cancer ,Hematology ,business ,Genetic testing - Published
- 2020
194. Abstract 1668: Mutational landscape and pharmacological profiling of a panel of prostate PDX models including hormone-naïve, hormone-sensitive and castrate-resistant prostate cancer specimens
- Author
-
Myriam Lassalle, Herve Lang, Véronique Lindner, Yves Allory, Claire Béraud, Thierry Massfelder, E. Potiron, Philippe Lluel, and Yolande Misseri
- Subjects
Cancer Research ,medicine.anatomical_structure ,Oncology ,business.industry ,Prostate ,Castrate-resistant prostate cancer ,Cancer research ,Medicine ,Hormone naive ,business ,Hormone-sensitive - Abstract
Prostate Cancer (PCa) is the second most frequent cancer in men worldwide and the fifth leading cause of cancer death with an incidence rate of 13.5%. PCa is driven by multiple genomic alterations, with distinct patterns and clinical implications. These genomic alterations occurring both early and later in the natural history of the disease (ranging from localized disease, initially responsive to androgen deprivation therapy, to Castrate Resistant Prostate Cancers -CRPC) allow classification of PCa in several molecular subtypes with potential clinical relevance. Patient-Derived Xenograft (PDX) models have become the most reliable in vivo human cancer models. Developing such models that capture the biological heterogeneity and mutational landscape of PCa, remains a challenge, but is essential for delivery of precision medicine in metastatic castrate resistant stages. In this study, we present the genomic and transcriptomic landscapes, as well as the pharmacological status of an established bank of seven (7) prostate PDX models ranging from hormone naïve to hormone-resistance PCa specimens. Samples of PCa along with normal corresponding tissues were obtained directly from patients at surgery. Fragments were subcutaneously xenografted into immunocompromised mice to establish PDX models. After the first growth in mice, they were serially passaged in vivo and considered to be established from P3. To ensure model stability, PDX tumors at multiple passages and patients' primary tumors were processed for histological, transcriptomic (Affymetrix U133 plus 2.0 microarray) and STR profile analyses. Genomic characteristics (WES, CNA) were also investigated. Finally, the responses of the PDX models to androgen deprivation and docetaxel were also evaluated. 7 PDX models were successfully established (> P3 in mice) out of 253 primary prostatic tumors collected from surgery. Within those models, one matched pair of responsive adenocarcinoma and neuroendocrine castration-resistant (NE-CRPC) models from the same patient was generated. Histological, transcriptomic and STR profiling validated the stability of the models compared to the parental tumor. The genomic analyses revealed i) the mutational burden rise with the resistance to treatments of the models, correlating with clinical results ii) an increase of metastatic genes loss in the NE-CRPC compared to the corresponding hormone sensitive adenocarcinoma. Furthermore, for all the PDX models generated, genomic and mutational analyses revealed specific molecular features and allowed molecular classification depending on tumor stage. Based on the molecular taxonomy of primary prostate cancers, the presented panel covers the different progression steps of the pathology. Considering the scarcity of useful models for PCa and the difficulties to develop such models, the prostate PDX models collection presented here should clearly help understanding disease progression and supporting precision medicine approaches for patients with advanced PCa. Citation Format: Myriam Lassalle, Claire Béraud, Hervé Lang, Véronique Lindner, Yves Allory, Eric Potiron, Thierry Massfelder, Philippe Lluel, Yolande Misseri. Mutational landscape and pharmacological profiling of a panel of prostate PDX models including hormone-naïve, hormone-sensitive and castrate-resistant prostate cancer specimens [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1668.
- Published
- 2020
195. Comparison of outcomes for patients with metastatic castrate resistant prostate cancer treated by urologists or medical oncologists with first line abiraterone acetate or enzalutamide: A population-based study
- Author
-
N. Fleshner, Dixon T.S. Woon, L. Martin, C.J.D. Wallis, A. Finelli, C. Douglas, and R. Saskin
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Urology ,First line ,Abiraterone acetate ,Castrate-resistant prostate cancer ,lcsh:Diseases of the genitourinary system. Urology ,lcsh:RC870-923 ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Population based study ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,Enzalutamide ,business - Published
- 2020
196. Association of BRCA alteration (alt) type with real-world (RW) outcomes to PARP inhibitors (PARPi) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC)
- Author
-
Tamara Snow, Emily Castellanos, Emmanuel S. Antonarakis, Margaret Elizabeth McCusker, Jeremy Snider, Alexa B. Schrock, Brian M. Alexander, Russell Madison, Jon Chung, Jeffrey M. Venstrom, Ethan Sokol, Jeffrey S. Ross, and Gaurav Singal
- Subjects
Cancer Research ,business.industry ,Poly ADP ribose polymerase ,Castrate-resistant prostate cancer ,Reversion ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,In patient ,Homologous Recombination Deficiency ,business ,030215 immunology - Abstract
5527 Background: Inactivating alts in BRCA1/2 result in homologous recombination deficiency and are predictive of PARPi response in mCRPC. BRCA reversion mutations, which restore the protein function, are frequently observed in acquired resistance to PARPi. In tumors harboring homozygous gene deletions ( BRCAdel) reversions cannot develop; thus, we hypothesize that BRCAdel pts may have prolonged benefit from PARPi compared to pts harboring other BRCA alterations. Methods: Pts were included from the Flatiron Health (FH)-Foundation Medicine (FMI) de-identified clinico-genomic database (CGDB). Inclusion criteria were diagnosis of mCRPC, treatment in the FH network and an FMI comprehensive genomic profiling result between 1/1/2011 - 9/30/2019. Time to therapy discontinuation (TTD) and overall survival (OS) from start of PARPi were estimated with Kaplan-Meier analysis and unadjusted/adjusted (age at PARPi initiation, line number, practice type) hazard ratios (HR/aHR) from Cox proportional hazards models adjusted for survival bias. Results: Out of 829 mCRPC cases, BRCA1/2 alts were detected in 15 (1.8%) and 71 (8.6%) respectively, with 2 cases included in both groups. 26% of BRCAalts were BRCAdel, 67% were coding mutations, and 7% were genomic rearrangements. 25 (28%) BRCAalt pts were treated with PARPi, 11/25 in the 1st or 2nd line setting including 43% of BRCAdel and 44% of other BRCAalt cohorts. Median age at PARPi initiation was 70 yrs and 88% were treated in community practices. TTD was significantly longer in the BRCAdel (n = 7) cohort vs. other BRCAalt cohort (n = 18) (22.7 vs. 9.2 months; HR: 0.16 [0.03-0.74]; aHR: 0.13 [0.02 – 0.92]) while a statistically nonsignificant difference in median OS was observed (31.5 vs. 11.9 months; HR: 0.20 [0.02-1.58]; aHR: 0.24 [0.02-3.15]). In comparison, no statistically significant difference in TTD was observed for BRCAdel (n= 7) vs. other BRCAalts (n=19) pts treated with 1st line hormonal therapies (abiraterone or enzalutamide) (3.4 vs. 5.7 months; HR: 1.16 [0.45-2.98]; aHR: 0.72 [0.25-2.10]). Follow up analysis with more pts and somatic/germline status and zygosity of BRCAalts will be presented. Conclusions: These data suggest a differential benefit from PARPi therapy across BRCAalt subgroups. This observation may in part be explained by the inability to develop reversion mutations to restore BRCA function in tumors with BRCAdel. Further studies are warranted to fully assess the association of BRCAalt type with outcomes to PARPi-based treatments.
- Published
- 2020
197. Real-world experience with sipuleucel-T (Sip-T) in Asian men with castrate-resistant prostate cancer (CRPC)
- Author
-
John Azzolina, Jingsong Zhang, Matthew Harmon, Scott C. Flanders, Jiahua Pan, Xiao X. Wei, and Ming Liu
- Subjects
Oncology ,Clinical trial ,Cancer Research ,medicine.medical_specialty ,Sipuleucel-T ,business.industry ,Internal medicine ,Castrate-resistant prostate cancer ,medicine ,business ,medicine.drug - Abstract
e17588 Background: Clinical trials of sip-T predominately included white men (over 90%). Previously we explored outcomes with sip-T in white and black patients (pts) (Kantoff PW, NEJM 2010; Sartor AO, ASCO 2019, #5035). In this retrospective analysis of data from electronic medical record and practice management systems, we explored the hypothesis that Asian and white pts who receive sip-T for CRPC exhibit similar overall survival. Methods: Data came from > 100 US community urology practices, predominantly large urology group practice associations. White and Asian pts were matched based on 5 criteria: sip-T treatment year; treatment pattern for oral and sip-T; metastatic site (Bone v. Nodal v. Visceral); prostate-specific antigen (PSA) within 10%; and age at treatment. Parameters retrieved include those listed in the table. Overall survival (OS) was analyzed using Kaplan Meier (KM) methodology with Cox Proportional Hazards Modelling used to generate the hazard ratio (HR) with Asians as the reference. Descriptive summary statistics were generated for other parameters. Results: The analysis identified 102 white and 77 Asian pts; treatment ranged from 2012 to 2019 with 60% receiving sip-T after 2016, impacting the ability to examine long-term outcomes. Characteristics of the 2 groups were broadly similar, although more Asians had Gleason scores ≥8 than whites (Table). In the KM analysis, most pts were censored. While the KM survival curves separate around month 25, favoring Asian pts, the difference is not significant (HR, 0.69 [95% CI: 0.4, 1.4]; P = 0.277). Conclusions: These real-world data do not show a significant difference in OS between Asian and white men. Both groups exhibited relatively low median PSAs near 5 ng/mL, an observation correlated with longer OS in previous studies. [Table: see text]
- Published
- 2020
198. A first-in-man phase I/II study of OBI-3424, an AKR1C3-selective bis-alkylating agent prodrug, in subjects with advanced cancer, including hepatocellular carcinoma (HCC) and castrate-resistant prostate cancer (CRPC)
- Author
-
Tillman E. Pearce, Pei Hsu, Claire F. Verschraegen, and Apostolia Maria Tsimberidou
- Subjects
Cancer Research ,business.industry ,Cellular differentiation ,Castrate-resistant prostate cancer ,Reductase ,Prodrug ,Ligand (biochemistry) ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Nuclear receptor ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Cancer research ,Medicine ,business ,030215 immunology ,Hormone - Abstract
TPS3658 Background: Aldo-keto reductase family 1 member C3 (AKR1C3) modulates cellular differentiation and proliferation through indirect regulation of ligand access to hormone and nuclear receptor signaling. AKR1C3 is expressed at high levels in various human cancers, including HCC. In prostate cancer cells exposed to anti-androgen therapies, AKR1C3 is adaptively upregulated. CRPC is a potential indication for this targeted alkylating agent. AKR1C3 tumor expression is associated with poor patient survival and resistance to cancer therapies. OBI-3424 is a nitro-benzene prodrug of a nitrogen mustard that can be selectively cleaved in the presence of AKR1C3 enzyme into a bis-alkylating agent capable of forming intra- and inter-strand crosslinks with DNA, thereby resulting in cell death. The selectivity of OBI-3424 for AKR1C3 distinguishes it from traditional alkylating agents, which are nonselective. The primary objectives of the study are to evaluate the safety and tolerability of single-agent OBI-3424. The dose-escalation phase will determine the dose-limiting toxicities (DLT), maximum tolerable dose (MTD), and recommended Phase 2 dose (RP2D) of OBI-3424 through assessment of PK of OBI-3424 and OBI-2660 in plasma and urine. After determining the maximum tolerated dose (MTD), the study will enroll subjects with advanced HCC or CRPC, two tumor types with a high likelihood of overexpression of AKR1C3, into the dose expansion portion of the study according to a Simon two-stage phase 2 design. This phase is designed to assess the objective response rate, and progression-free survival in patients with HCC and CRPC. Immunohistochemistry assays are being developed to assess tumor expression of AKR1C3 for this study. The clinical safety and relationship of efficacy to AKR1C3 tumor expression will serve to guide further clinical development of OBI-3424 in these two unmet need settings. Methods: Based on the toxicology and PK results in cynomolgus monkeys, the starting dose is one sixth of the human equivalent dose of the highest non-severely toxic dose observed. Doses of 1, 2, 4, 6, 8, 12, and 14 mg/m2 will be used. OBI-3424 is administered intravenously (IV) over 30 minutes on days 1 and 8 of each 21-day cycle. Subjects without clinically significant disease progression may continue on treatment for up to 2 years, if they do not experience a DLT or other significant toxicity. Clinical trial information: NCT03592264 .
- Published
- 2020
199. First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI)
- Author
-
Mary Harlow Garfield, Ronald Peck, Daniel P. Petrylak, Marcia Dougan Moore, Xin Gao, Ian Taylor, Howard A. Burris, and Nicholas J. Vogelzang
- Subjects
Cancer Research ,business.industry ,Proteolysis targeting chimera ,Castrate-resistant prostate cancer ,Phase i study ,Androgen receptor ,03 medical and health sciences ,Abiraterone ,chemistry.chemical_compound ,0302 clinical medicine ,Oncology ,chemistry ,Proteasome ,030220 oncology & carcinogenesis ,Cancer research ,Enzalutamide ,Medicine ,In patient ,business ,030215 immunology - Abstract
3500 Background: Proteolysis Targeting Chimera (PROTAC) protein degraders induce selective degradation of targeted proteins by engaging the ubiquitin proteasome system. ARV-110 is an orally bioavailable PROTAC that specifically degrades AR ≥ 95% and achieves anti-tumor activity in ENZ-naïve and -resistant prostate cancer xenograft models. Methods: To define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ARV-110, pts with ≥ 2 prior therapies for mCRPC, including ENZ and/or ABI, received ARV-110 orally once daily. Dose escalation is per 3+3 design. Endpoints include dose limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics (PK), biomarkers (e.g., AR mutation analysis), RECIST and PSA response. Results: By January 2020, 18 pts were dosed: 35 mg (N = 3), 70 mg (N = 4), 140 mg (N = 8), 280 mg (N = 3). 12 pts received both ENZ and ABI; 14 received prior chemotherapy. 1 of 18 pts experienced a DLT (280 mg) of Grade (Gr) 4 elevated AST/ALT followed by acute renal failure while taking rosuvastatin (ROS). A 2nd pt had Gr 3 AST/ALT with ROS that resolved off ROS, permitting ARV-110 retreatment. ROS plasma concentrations demonstrated significant increases concurrent with AST/ALT elevations in both pts. Subsequently, ROS was prohibited without further ≥Gr 2 AST/ALT AEs. No other related Gr 3/4 AEs were reported. ARV-110 PK was generally dose proportional and at 140 mg reached levels associated with preclinical anti-tumor activity. 15 pts were evaluable for PSA response (excludes 1 pt stopped after 1 dose for early progression and 2 pts initiated 2 weeks before cutoff, all at 140 mg). Of these, 8 pts initiated dosing at ≥140 mg. 2 pts achieved confirmed PSA declines of >50%, both at 140 mg. Prior therapy in both pts included ENZ and ABI, chemotherapy, bicalutamide and radium-223 plus other regimens. 1 pt had 2 AR mutations known to confer ENZ resistance. The 2nd pt also achieved an unconfirmed RECIST partial response (confirmatory scan pending). Both responses were ongoing at data cutoff (8+ and 21+ weeks of treatment). Conclusions: To date, ARV-110 has an acceptable safety profile. Concurrent ROS is now prohibited. MTD has not yet been established; determination of RP2D continues. ARV-110 demonstrates antitumor activity in mCRPC after ENZ/ABI with 2 ongoing confirmed PSA responses, one of which was associated with tumor reduction. Updated data for this first PROTAC in clinical testing will be presented. Clinical trial information: NCT03888612 .
- Published
- 2020
200. Phase Ib study assessing different sequencing regimens of atezolizumab (anti-PD-L1) and sipuleucel-T (SipT)in patients who have asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer
- Author
-
Charles J. Rosser, Jared David Acoba, David Jon Tamura, Mark C. Scholz, Yosuke Hirasawa, Jeffrey Huang, Sumanta K. Pal, and Tanya B. Dorff
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Immune checkpoint inhibitors ,Anti pd 1 ,Castrate-resistant prostate cancer ,Asymptomatic ,03 medical and health sciences ,Sipuleucel-T ,0302 clinical medicine ,Atezolizumab ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,In patient ,medicine.symptom ,business ,030215 immunology ,medicine.drug - Abstract
e17564 Background: Combining an immune checkpoint inhibitor with a tumor vaccine may leverage complementary mechanisms of action for treatment of mCRPC. Atezolizumab, a fully human anti–PD-L1 IgG1 antibody, is an approved treatment option in multiple indications; while SipT, an autologous cellular immunotherapeutic, is approved for treatment of metastatic castrate resistant prostate cancer (mCRPC). We present a phase Ib study evaluating safety, tolerability and objective response rate of atezolizumab + SipT in patients with mCRPC (NCT03024216). Methods: Eligible patients who had asymptomatic or minimally symptomatic progressive mCRPC and met standard criteria for sipuleucel-T were randomized to receive either atezolizumab 1200 mg IV every 3 weeks for 2 doses then SipT IV every 2 weeks for a total of three infusions (Arm 1) or SipT IV every 2 weeks for a total of three infusions followed by atezolizumab 1200 mg IV every 3 weeks for 2 doses (Arm 2). The primary endpoint was safety, while secondary endpoints included objective tumor response (PCWG2 and modified RECISTv1.1 criteria) and comparing systemic immune responses after induction between the arms. Results: As of February 6, 2020, 37 pts (median follow-up 7.4 months, median age 75 yrs [range 53.0–86.0]; median number of previous treatments 4 [range 1-8], 75.7% ECOG PS = 0) were enrolled. Three patients did not complete induction therapy (1 – withdrew consent, 1 developed toxicity, and 1 progressed). There were no grade 5 toxicities attributed to study drugs and grade 4 toxicities were noted in 2 patients, 1 in each arm (Arm 1 bronchitis and Arm 2 hypotension). Eight grade 3 toxicities were noted in arm 1 (hyponatremia, pulmonary embolus x3, bone pain, hypophosphatemia, shock, tooth fracture from a fall), while 4 grade 3 toxicities were noted in arm 2 (anemia, hypertension x 2, pneumonia). None of the grade 3 or 4 SAEs were noted to be irAEs. At 6 months, there were 11 SD (7 in Arm 1 and 4 in Arm 2), 18 PD and 7 unevaluable (3 withdrew from study and 4 have yet to reach 6 month evaluation). At this time, PFS was noted to be 8.2 months in Arm 1 and 5.8 months in Arm 2 (p = 0.054). Conclusions: The safety profile of the combination of atezolizumab with sipuleucel-T appears manageable in a heavily pre-treated population and consistent with those agents administered as monotherapy. Responses were seen but no CR. Immune activation studies may shed light on which sequence is optimal. Clinical trial information: NCT03024216 .
- Published
- 2020
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.