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Background COPD patients have an increased risk of cardiovascular disease and venous thromboembolism. Methods This study aimed to investigate whether patients with stable COPD have a prothrombotic state compared to COPD-free smokers. We conducted an observational study comparing levels of: D-dimers, INR, aPTT, coagulation factors; fibrinogen, FII, FV, FVII, FVIII, FIX, FX and coagulation inhibitors; protein S, proteins C and antithrombin between stable COPD patients and control subjects. Results A total of 103 COPD patients and 42 controls with similar age, sex, current smoking status, comorbidity burden and cardiovascular risk met the inclusion criteria. Compared to controls, COPD patients had higher levels of D-dimers (median (interquartile range): 360 (230–600) ng·mL−1 versus 240 (180–400) ng·mL−1, p=0.001), fibrinogen (mean±sd: 399±82 mg·dL−1 versus 346±65 mg·dL−1, p, Patients with stable COPD exhibit increased levels of key coagulation factors and decreased levels of coagulation inhibitors, namely protein S and antithrombin, compared to COPD-free smokers, indicating a prothrombotic state in stable COPD https://bit.ly/2VmR1PP

Background Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature. Methods This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival. Results Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST. Conclusions AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.

Introduction: During the first COVID-19 wave, a considerable decline in hospital admissions was observed worldwide. Aim: This retrospective cohort study aimed to assess if there were any changes in the number of patients hospitalized for respiratory diseases in Greece during the first CO­VID-19 wave. Methods: In the present study, we evaluated respiratory disease hospitalization rates across 9 tertiary hospitals in Greece during the study period (March–April 2020) and the corresponding period of the 2 previous years (2018–2019) that served as the control periods. Demographic data and discharge diagnosis were documented for every patient. Results: Of the 1,307 patients who were hospitalized during the study period, 444 (35.5%) were males with a mean (±SD) age of 66.1 ± 16.6 years. There was a 47 and 46% reduction in all-cause respiratory morbidity compared to the corresponding periods of 2018 and 2019, respectively. The mean incidence rate for respiratory diseases during the study period was 21.4 admissions per day, and this rate was significantly lower than the rate during the same period in 2018 (40.8 admissions per day; incidence rate ratio [IRR], 0.525; 95% confidence interval [CI], 0.491–0.562; p < 0.001) or the rate during 2019 (39.9 admissions per day; IRR, 0.537; 95% CI, 0.502–0.574; p < 0.001). The greatest reductions (%) in the number of daily admissions in 2020 were observed for sleep apnoea (87% vs. 2018 and 84% vs. 2019) followed by admissions for asthma (76% vs. 2018 and 79% vs. 2019) and chronic obstructive pulmonary disease (60% vs. 2018 and 51% vs. 2019), while the lowest reductions were detected in hospitalizations for pulmonary embolism (6% vs. 2018 and 23% vs. 2019) followed by tuberculosis (25% vs. both 2018 and 2019). Discussion/Conclusion: The significant reduction in respiratory admissions in 2020 raises the reasonable question of whether some patients may have avoided seeking medical attention during the COVID-19 pandemic and suggests an urgent need for transformation of healthcare systems during the pandemic to offer appropriate management of respiratory diseases other than COVID-19.

Purpose: Preclinical studies demonstrated that a DNA vaccine (pTVG-AR, MVI-118) encoding the androgen receptor ligand-binding domain (AR LBD) augmented antigen-specific CD8+ T cells, delayed prostate cancer progression and emergence of castration-resistant disease, and prolonged survival of tumor-bearing mice. This vaccine was evaluated in a multicenter phase I trial. Patients and Methods: Patients with metastatic castration-sensitive prostate cancer (mCSPC) who had recently begun androgen deprivation therapy were randomly assigned to receive pTVG-AR on one of two treatment schedules over one year, and with or without GM-CSF as a vaccine adjuvant. Patients were followed for 18 months. Primary objectives were safety and immune response. Secondary objectives included median time to PSA progression, and 18-month PSA-PFS (PPFS). Results: Forty patients were enrolled at three centers. Twenty-seven patients completed treatment and 18 months of follow-up. Eleven patients (28%) had a PSA progression event before the 18-month time point. No grade 3 or 4 adverse events were observed. Of 30 patients with samples available for immune analysis, 14 (47%) developed Th1-type immunity to the AR LBD, as determined by IFNγ and/or granzyme B ELISPOT. Persistent IFNγ immune responses were observed irrespective of GM-CSF adjuvant. Patients who developed T-cell immunity had a significantly prolonged PPFS compared with patients without immunity (HR = 0.01; 95% CI, 0.0–0.21; P = 0.003). Conclusions: pTVG-AR was safe and immunologically active in patients with mCSPC. Association between immunity and PPFS suggests that treatment may delay the time to castration resistance, consistent with preclinical findings, and will be prospectively evaluated in future trials. See related commentary by Shenderov and Antonarakis, p. 5056

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.

Background: Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory lung disease characterized by airflow limitation that is not completely reversible. The fixed-dose combination of salmeterol and fluticasone propionate (SFC) has been approved as a treatment for COPD patients with a history of recurrent exacerbations and significant symptoms despite regular bronchodilator therapy. In the present study, we evaluated the change in FEV1, mMRC dyspnea score and satisfaction in COPD patients with at least one comorbidity versus those without comorbidities treated with a fixed-dose SFC via the Elpenhaler® device for 12 months. Methods: A 12-month multicenter prospective, observational study (NCT02978703) was designed. Data were collected during the enrollment visit (V0) and six (V1) and twelve months (V2) after the initiation of treatment with Elpenhaler® SFC. The evaluation of the efficacy of the fixed-dose SFC was performed by assessing the change in lung function and dyspnea as expressed by FEV1 and the mMRC dyspnea scale score in COPD patients with and without comorbidities. Results: In total 1016 patients were enrolled, following usual daily clinical practice. A statistically significant improvement was observed in FEV1 in the total study population between visits V0, V1 and V2, with a change from the baseline at V1 0.15 ± 0.22 L and at V2 0.21 ± 0.25 L (p &lt, 0.0001 for both comparisons). This improvement was exhibited regardless of the COPD severity at the baseline, being more noticeable in GOLD 2020 groups B and C. Similarly, a significant improvement was observed in mMRC dyspnea scale values between successive visits (p &lt, 0.0001). In patients without comorbidities, there was a significant improvement in FEV1 of 0.19 ± 0.24 L at V1 and 0.28 ± 0.27 L at V2 (p &lt, 0.0001 for both comparisons), as well as in the mMRC dyspnea score (p &lt, 0.0001). In patients with at least one comorbidity, a corresponding but smaller improvement in FEV1 was observed (0.11 ± 0.34 L at V1 and 0.20 ± 0.42 L at V2, p &lt, 0.0001 for both comparisons and in the mMRC score (p &lt, 0.0001). In the multiple linear regression analysis BMI, GOLD 2020 groups, mMRC and the presence of comorbidities at the baseline were significant factors for the change of FEV1 between V0 and V2. Conclusions: COPD patients treated for twelve months with SFC via the Elpenhaler® device showed significant improvement in lung function and dyspnea at 6 and 12 months, irrespective of the presence of comorbidities.

BackgroundWe previously reported a pilot clinical trial using a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP), given over 12 weeks either concurrently or in sequence with pembrolizumab, in patients with mCRPC. We report here the final analysis of this trial following two additional treatment arms in which patients with mCRPC were treated beyond 12 weeks until progression.MethodsPatients with mCRPC were treated with pTVG-HP and pembrolizumab every 3 weeks (Arm 3, n=20), or pTVG-HP every 2 weeks and pembrolizumab every 4 weeks (Arm 4, n=20). The primary objectives were safety, 6-month PFS, median time to radiographic progression, and objective response rates. Secondary objectives included immunological evaluations.ResultsTreatment was without unexpected toxicity, and only 1 grade 4 event (hyperglycemia) was observed. Immune related adverse events (irAE) > grade 1 included adrenal insufficiency, hepatitis, colitis, thyroid dysfunction, pancreatitis, pneumonitis, and rash, occurring in 42% of patients overall. 10/25 patients with measurable disease experienced any decrease in tumor volume from baseline, with 1 confirmed PR and no CR. 23/66 (35%) experienced any PSA decline from baseline. Overall median TTP was 5.4 months (95% CI; 5.3–8.1 months); median TTP for Arm 3 was 5.3 months compared to 8.0 months for Arm 4. Overall, 41.7% of patients had no radiographic progression at 6 months (29.9% Arm 3, 57.9% Arm 4). Median overall survival was 22.9 months. IFNγ and/or granzyme B immune response to PAP was detected in 2/20 patients in Arm 3 and 6/20 patients in Arm 4. Cytokines associated with immune activation and CD8+ T cell recruitment were augmented in the plasma of patients at weeks 6 and 12. Increased IFNγ in the sera at week 6 trended with prolonged TTP (p=0.010) and overall survival (p=0.025). The development of irAE was associated with a prolonged TTP (HR=0.25, p=0.003).ConclusionsPD-1 pathway inhibitors have demonstrated little clinical activity to date as monotherapies for mCRPC. Our findings demonstrate that combining PD-1 blockade with tumor-targeted T-cell activation using pTVG-HP is safe, can augment tumor-specific T cells, and result in objective changes with longer time to progression than what has been observed in previous trials. The association of progression or survival with increased IFNγ, irAE, and vaccine schedule suggests T cell activation by vaccination is critical to the mechanism of action of this combination. This study suggests this approach should be further evaluated in randomized clinical trials for patients with advanced mCRPC.AcknowledgementsFunding for this trial was from a 2014 Movember Prostate Cancer Foundation Challenge Award and Madison Vaccines, Inc.Trial RegistrationNCT02499835Ethics ApprovalThis trial was reviewed and approved by the University of Wisconsin Human Subjects’ Review Committee (IRB), protocol 2015–0453. All participants provided IRB-approved written informed consent before taking part.

Tocilizumab has been repurposed against the 'cytokine storm' in the setting of coronavirus disease 2019 (COVID-19). Our aim was to evaluate the efficacy of tocilizumab in the management of hospitalized COVID-19 patients. We searched MEDLINE, CENTRAL and medRxiv for studies of tocilizumab in hospitalized COVID-19 patients. Primary objective was the effectiveness of tocilizumab on mortality. Secondary objectives included the need for invasive mechanical ventilation (IMV), composite endpoints of mortality or IMV and intensive care unit (ICU) admission or IMV, length of hospitalization and differences in mortality in subgroups (ICU and non-ICU patients and patients receiving or not receiving concomitant corticosteroids). We included 52 studies (nine randomized controlled trials [RCTs] and 43 observational) with a total of 27,004 patients. In both RCTs and observational studies, the use of tocilizumab was associated with a reduction in mortality; 11% in RCTs (risk ratio [RR] 0.89, 95% CI 0.82 to 0.96) and 31% in observational studies (RR 0.69, 95% CI 0.58 to 0.83). The need for IMV was reduced by 19% in RCTs (RR 0.81, 95% CI 0.71 to 0.93), while no significant reduction was observed in observational studies. Both RCTs and observational studies showed a benefit from tocilizumab on the composite endpoint of mortality or IMV. Tocilizumab improved mortality both in ICU and non-ICU patients. Reduction in mortality was evident in observational studies regardless of the use of systemic corticosteroids, while that was not the case in the RCTs. Tocilizumab was associated with lower mortality and other clinically relevant outcomes in hospitalized patients with moderate-to-critical COVID-19.

Background Chronic obstructive pulmonary disease (COPD) is a multifactorial clinical condition, characterized by chronic progressive (or worsening) respiratory symptoms, structural pulmonary abnormalities, and impaired lung function, and is often accompanied by multiple, clinically significant comorbid disorders. In 2017, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) issued a new report on COPD prevention, diagnosis and management, aiming at personalizing the maintenance therapeutic approach of the stable disease, based on the patients’ symptoms and history of exacerbations (ABCD assessment approach). Our objective was to evaluate the implementation of GOLD suggestions in everyday clinical practice in Greece. Methods This was a cross-sectional observational study. Sixty-five different variables (demographics, vital sign measurements, COPD-related medical history parameters, comorbidities, vaccination data, COPD severity based on spirometry measurements, COPD stage based on the ABCD assessment approach, COPD treatments) were collected from 3615 nation-wide COPD patients (Greece). Results The mean age at the time of initial COPD diagnosis was 63.8 (± 10.2). Almost 60% of the subjects were classified into group B, while the remaining patients were falling into groups A (18%) and D (21%), and only a small minority of patients belonged to Group C, according to the ABCD assessment approach. The compliance of respiratory physicians to the GOLD 2017 therapeutic suggestions is problematic, especially when it comes to COPD patients belonging to Group A. Conclusion Our data provide valuable information regarding the demographic and medical profile of COPD patients in Greece, the domains which the revised ABCD assessment approach may show some clinical significance on, and the necessity for medical practitioners dealing with COPD patients to adhere closer to international recommendations for the proper management of the disease.

Smoking has been accounted for numerous adverse effects. We report a direct effect of smoking in a 73-year-old patient, a heavy smoker who presented to the emergency department with a 48-h history of productive cough and fever. Chest x-ray and chest CT revealed right lung infiltrates; however, they were not suggestive of the diagnosis, which was established through flexible bronchoscopy. The specific procedure concurrently contributed to the treatment of the patient.

Summary In Crete, as in the rest of the Ottoman Empire, patients who suffered from hernias and other diseases that required surgery made statements to the court of law that absolved the surgeons of liability in case of death as a result of the operation. These statements also included information about the medical condition concerned, the surgeon, the medical procedure and the fee to be paid. In this article, we discuss such statements of the period 1670–1760 from the town of Kandiye (mod. Heraklion). On one hand, we demonstrate that a critical analysis of the statements reveals a dynamic society, which actively overcomes its ideology of submission to God and religious prejudices when it comes to dealing with health issues. On the other hand, we argue that, as the statements were made before the official court of law, they constitute a facet of the Ottomanisation of Cretan society and its practices.

Brief abstract: Castleman's disease (CD) is an uncommon lymphoproliferative process that can present concurrent to other solid organ malignancy, especially in selected populations. Concomitant CD and renal cell carcinoma (RCC) are challenging in terms of diagnosis and treatment. Assessment of CD involvement is a crucial step in selecting the optimal treatment strategy. Here we report a case of metastatic RCC and concurrent CD treated with surgery and immunotherapy.

Introduction : The Metastatic Renal Cell Carcinoma (MaRCC) Registry provides prospective data on real-world treatment patterns and outcomes in patients with metastatic renal cell carcinoma (mRCC). Methods and Materials : Patients with mRCC and no prior systemic therapy were enrolled at academic and community sites. End of study data collection was in March 2019. Outcomes included overall survival (OS). A survey of treating physicians assessed reasons for treatment initiations and discontinuations. Results : Overall, 376 patients with mRCC initiated first-line therapy; 171 (45.5%) received pazopanib, 75 (19.9%) sunitinib, and 74 (19.7%) participated in a clinical trial. Median (95% confidence interval) OS was longest in the clinical trial group (50.3 [35.8–not reached] months) versus pazopanib (39.0 [29.7–50.9] months) and sunitinib 26.2 [19.9–61.5] months). Non-clear cell RCC (21.5% of patients) was associated with worse median OS than clear cell RCC (18.0 vs 47.3 months). Differences in baseline characteristics, treatment starting dose, and relative dose exposure among treatment groups suggest selection bias. Survey results revealed a de-emphasis on quality of life, toxicity, and patient preference compared with efficacy in treatment selection. Conclusion : The MaRCC Registry gives insights into real-world first-line treatment selection, outcomes, and physician rationale regarding initial treatment selection prior to the immunotherapy era. Differences in outcomes between clinical trial and off-study patients reflect the difficulty in translating trial results to real-world patients, and emphasize the need to broaden clinical trial eligibility. Physician emphasis on efficacy over quality of life and toxicity suggests more data and education are needed regarding these endpoints. MicroAbstract : The Metastatic Renal Cell Carcinoma Registry provides prospective data on real-world treatment patterns and outcomes in patients with metastatic renal cell carcinoma (mRCC). 376 patients with mRCC and no prior systemic therapy were included in this study. This report describes initial real-world treatment patterns. Physician emphasis on efficacy over quality of life and toxicity suggests more data and education are needed.

Introduction: There is evidence for the presence of endothelial dysfunction in patients with COPD. Objectives: We sought to examine potential associations of two important markers of endothelial dysfunction, MAB as well as serum vWf:Ag and vWf:Ac, in patients with COPD. Methods: 103 outpatients with stable COPD and 42 smokers of more than 10-pack-years without airway obstruction (control group) were included. Results: Cardiovascular risk, assessed by HEART score, was not different between the two groups (P=0.061).The presence of MAB was greater in patients with COPD than in the control group: 29% vs. 12% P=0.032.Patients with COPD had significantly higher levels of MAB than controls (mean±SD): 42.17±67.16 vs. 14.17±15.80 mg/g, P=0.001. In the COPD group, the presence of MAB was different among GOLD 2020 ABCD groups (P=0.006), being highest (47%) in group D. Presence of microalbuminuria was greater in patients with CAT score ≥10 (P=0.017) and in patients with FEV1 Conclusions: The present study has found significant associations of MAB, vWf:Ag and vWf:Ac with the new version of ABCD grading system and with COPD patients who have reduced lung function.

INTRODUCTION AND OBJECTIVE:The addition of docetaxel to androgen deprivation therapy (ADT) significantly improves progression-free survival and overall survival compared to ADT alone in men with me...

We report a case of rapid evolution of polycystic liver disease in a 76-year-old patient with metastatic renal cell carcinoma who underwent treatment with numerous antineoplastic agents. The aim was to identify a causative etiology for these hepatic cysts of unclear origin. The cystic lesions of the patient were ultimately innumerable and developed rapidly, more than tripling the total liver volume from complete absence over the course of 24 months. The hepatic lesions continued to grow despite an otherwise moderate tumor response. Prior to patient death, the patient remained relatively asymptomatic from the cyst burden and was without signs of grossly metastatic disease. This rapid development of polycystic liver disease most likely represents a previously unseen medication side-effect of cabozantinib or pazopanib. It is important to identify adverse effects of novel antineoplastic agents in this time of oncological medical discovery.

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory disease with multisystemic manifestations. Studies either held on stable disease patients or during exacerbations have demonstrated that COPD is strongly related to venous thromboembolism and cardiovascular events. The aim of the present review of the literature was to provide an in-depth overview regarding the alterations of coagulation factors and prothrombotic changes generated in patients with stable COPD and during COPD exacerbations.

Androgen deprivation therapy (ADT) has been conventional treatment of newly diagnosed metastatic prostate cancer for more than 70 years. However, all patients eventually become castration-resistant and a significant proportion of life span is spent in the castration-resistant state. Prospective randomized control trials have incorporated early chemotherapy along with ADT based on the hypothesis that a significant level of resistance to ADT already exists in newly diagnosed metastatic prostate cancer and ADT exhibits synergistic antitumor activity with taxanes. In this chapter we discuss the changing landscape of management of newly diagnosed metastatic prostate cancer patients based on recently published landmark randomized trials.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These guidelines are developed by a multidisciplinary panel of leading experts from NCCN Member Institutions consisting of medical oncologists, hematologists and hematologic oncologists, radiation oncologists, urologists, and pathologists. The NCCN Guidelines are in continuous evolution and are updated annually or sometimes more often, if new high-quality clinical data become available in the interim.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non–clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.

4503 Background: Transurethral resection of bladder tumor (TURBT) plus systemic therapy has been known for decades to achieve durable bladder-intact survival in a subset of patients with MIBC but efforts to advance this paradigm have been complicated by (a) lack of prospective studies exclusively testing cisplatin-based neoadjuvant chemotherapy, (b) lack of rigorous methods to define clinical complete response (cCR) and its association with long term outcomes and (c) limited understanding of the role of “salvage” cystectomy. Methods: Eligible patients were cisplatin-eligible with cT2-T4aN0M0 urothelial bladder cancer. Patients received 4 cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging including urine cytology, MRI/CT of the bladder, cystoscopy and bladder/prostatic urethral biopsies. Patients achieving a cCR (normal cytology, imaging, and cT0/Ta) were eligible to proceed without cystectomy and receive nivolumab q2 weeks x 8 followed by surveillance; otherwise, patients underwent cystectomy. Coprimary endpoints included (1) cCR rate and (2) ability of cCR to predict 2-year metastasis-free survival (MFS). The key secondary endpoint was the impact of genomic alterations in baseline TURBT (TMB, ERCC2, FANCC, RB1, ATM) on performance of cCR for predicting MFS. The cCR rate coprimary endpoint, and interim analysis of 1-year outcomes, are reported. Results: Between 8/2018-11/2020, 76 patients were enrolled at 7 sites (male 79%, median age 69; cT2 = 56%, cT3 = 32%, cT4 = 12%) and 64 (84%) have completed post-cycle 4 restaging; 31/64 achieved a cCR (48%; 95% CI 36%, 61%). The median follow-up of cCR patients is 13.7 months (range, 2.5-24 months). One cCR patient opted for immediate cystectomy (pTaN0M0). Outcomes for the entire cohort are summarized in the table below. Local recurrence has occurred in 8/31 cCR patients and 6 underwent cystectomy (pT0N0 = 1, pTaN0 = 1, pTisN0 =1, pT2N0 = 2, pT4N1 = 1). TMB ≥ 10 mut/Mb (p=0.02) or mutant ERCC2 (p=0.02) were associated with cCR or pT0. Conclusions: TURBT + gemcitabine, cisplatin, plus nivolumab achieves stringently defined cCR in a large subset of patients with MIBC. 1-year bladder intact survival is possible though the durability of responses, and role of genomic biomarkers in management algorithms, requires longer follow-up. Clinical trial information: NCT03558087. [Table: see text]

TPS5098 Background: Radiation therapy (RT) to the prostate bed and pelvic nodes with short-term androgen deprivation therapy (STAD) is considered a standard of care (SOC) salvage therapy (ST) paradigm for prostate cancer (PC) patients (pts) with post-prostatectomy (RP) biochemical recurrence (BCR). Fluciclovine-PET/CT imaging is FDA-approved in this setting, with improved accuracy for detection of metastases not identified with conventional imaging (CIM). Given PET's greater sensitivity and specificity, its findings are increasingly but variably applied to justify modification or omission of SOC therapies without high-level evidence of clinical benefit. PET may help identify candidates for local or systemic treatment intensification of the otherwise non-tailored SOC approach. Improved systemic control and disease detection with molecular imaging have led to increasing use of focally ablative metastasis-directed RT, to delay or enhance systemic therapy through increased local control. There is also interest in earlier use of systemic therapy; apalutamide (Apa) is a nonsteroidal antiandrogen with established efficacy in improving overall and radiographic progression-free survival (PFS) for non-metastatic castration-resistant and metastatic castration-sensitive PC. This study will evaluate whether pts with PET-detected lesions benefit from such local or systemic treatment intensification approaches. Methods: PC pts with post-RP BCR (PSA>0.5ng/mL; >0.2ng/mL if within 12 mos of RP) and no metastases on CIM who are candidates for SOC ST (RT to prostate bed and pelvic nodes with STAD) are eligible. Prior to study registration, pts undergo SOC baseline PET (18F-fluciclovine but PSMA radiotracers permitted pending commercial availability). Based on institutional clinical interpretation of the SOC PET, pts will be placed in Cohort 1 (PET-negative) or 2 (PET-positive for extra-pelvic metastases). Cohort 1 will be randomized to SOC ST +/- Apa for 6 months and Cohort 2 will be randomized to SOC ST and Apa +/- metastasis-directed RT to PET-positive lesions. The primary endpoint is PFS, defined as time from randomization to radiographic progression on CIM, symptomatic disease or death. Primary objectives are to evaluate whether addition of Apa to SOC ST and addition of metastasis-directed RT to SOC ST and Apa could prolong PFS in Cohorts 1 and 2, respectively. For Cohort 1, 480 pts will be randomized with 85% power to distinguish 5-year PFS rate of 90% (Apa arm) vs. 80% (SOC arm) using one-sided stratified log-rank test with type I error of 0.025. For Cohort 2, 324 pts will be randomized with 85% power to distinguish 5-year PFS rate of 76.5% in the experimental arm from 61.5% in the control arm. Secondary endpoints include overall and event-free survival, toxicity, and PET progression. Clinical trial information: NCT04423211.

74 Background: Understanding the lethal nature of high risk prostate cancer, there is a need for the development of multimodal therapies. Prior studies have confirmed a survival benefit with the addition of docetaxel to androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (HSPC). We conducted a Phase II trial enrolling men with very high risk localized, locally advanced or oligometastatic prostate cancer (PC) to examine resistance and response to neoadjuvant chemohormonal therapy. This analysis aims to identify the preoperative predictors of biochemical recurrence (BCR). Methods: UW17009 is an IRB-approved open-label, single-arm trial that recruited 26 men with newly diagnosed advanced PC. Patients received ADT and docetaxel for 3 months followed by prostatectomy. The primary endpoint was pathologic complete response rate. A secondary clinical objective was the rate of PSA recurrence 12 months after surgery. The pre-trial PSAs, age, cancer grade, stage, percent tumor involvement of the initial biopsy, metastatic disease on conventional and 18F-DCFPyL PSMA (DCFPyL) PET/CT and MRI imaging, completion of chemohormonal therapy and PSA nadirs following chemohormonal therapy were assessed in relationship to biochemical recurrence. One way ANOVA was used to evaluate differences among continuous values: age, PSA at diagnosis, percent tumor involvement, and PSA nadir after chemo ADT. Fisher’s exact tests were used to evaluate the differences among categorical variables: stage at diagnosis, positive bone scan, and positive PSMA PET. Results: 26 patients were enrolled and underwent neoadjuvant treatment, radical prostatectomy (RP) and lymph node dissection. The median age was 62 (IQR 58-66), mean PSA at diagnosis was 32.8 ng/dl and 88.4% had Gleason 9 cancer. At study initiation, 12/26 patients had metastatic disease detected by DCFPyL-based PSMA PET. Final pathology demonstrated 81%(21/26) had ≥ pT3 and 73%(19/26) patients had negative margins. Positive lymph nodes were found in 10/26(38.5%) patients on final pathology. At week 6 after surgery, 91%(24/26) had undetectable PSA. At a mean follow up of 12.1 months(5.2-21.4), the biochemical recurrence rate is 58%(15/26). Features associated with BCR include stage, % tumor involvement, and positive PSMA PET scan. All patients with positive margins and 9/10 patients with positive nodes at final pathology developed BCR at a mean follow up of 12 months. Conclusions: In this neoadjuvant cohort, stage T2c, elevated PSA, positive pre-operative PSMA PET/CT, and PSA nadir > 1 following chemohormonal therapy predict biochemical recurrence. Clinically, and in the short term, neoadjuvant chemohormonal therapy prior to definitive surgery for very high risk localized and/or oligometastatic PC generates local tumor control with a high rate of negative surgical margins.

TPS267 Background: Radiation therapy (RT) to the prostate bed and pelvic nodes with short-term androgen deprivation therapy (STAD) is considered a standard of care (SOC) salvage therapy (ST) paradigm for prostate cancer (PC) patients (pts) with post-prostatectomy (RP) biochemical recurrence (BCR). Fluciclovine-PET/CT imaging is FDA-approved in this setting, with improved accuracy for detection of metastases (mets) not identified with conventional imaging (CIM). Given greater sensitivity and specificity of PET, its findings are being increasingly but variably applied to justify modification or omission of SOC therapies without high-level evidence of clinical benefit. PET may help identify candidates for local or systemic treatment intensification of otherwise non-tailored SOC. Earlier detection of mets with molecular imaging has led to increasing use of focally ablative met-directed RT, to delay or enhance systemic therapy through better local control. There is also interest in earlier use of advanced systemic therapy; apalutamide (Apa) is a nonsteroidal antiandrogen with established efficacy in improving overall and radiographic progression-free survival (PFS) for non-metastatic castrate-resistant and metastatic castration-sensitive PC, and potential activity for low-volume mets. This study will evaluate whether pts with PET-detected lesions benefit from such local or systemic treatment intensification approaches. Methods: PC pts with post-RP BCR (PSA>0.5ng/mL; >0.2 if RP within 12 mos), and negative CIM who are candidates for SOC ST (RT to prostate bed and pelvic nodes + STAD) and undergo SOC baseline PET are eligible. The study will initially use 18F-fluciclovine but permit additional radiotracers based on FDA approval and availability. Based on institutional clinical interpretation of the SOC PET, pts will be placed in Cohort 1 (PET-negative) or 2 (PET-positive for extra-pelvic mets). Cohort 1 will be randomized to SOC ST +/- Apa for 6 months and Cohort 2 will be randomized to SOC ST and Apa +/- met-directed RT to PET-positive lesions. The primary endpoint is PFS, defined as time from randomization to radiographic progression on CIM, symptomatic disease or death. Primary objectives are to evaluate whether addition of Apa to SOC ST and addition of met-directed RT to SOC ST and Apa could prolong PFS in Cohorts 1 and 2, respectively. For Cohort 1, 480 pts will be randomized with 85% power to distinguish 5-year PFS rate of 90% (Apa arm) vs. 80% (SOC arm) using one-sided stratified logrank test with type I error of 0.025. For Cohort 2, 324 pts will be randomized with 85% power to distinguish 5-year PFS rate of 76.5% in experimental arm from 61.5% in control arm. Secondary endpoints include overall and event-free survival, toxicity, and PET progression. Trial was activated on October 8, 2020; NCT04423211. Acknowledgement: This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180794, U10CA180820, U10CA180868, U10CA180888, U10CA180821, UG1CA233196, UG1CA233253, UG1CA233277, UG1CA233328, and UG1CA233330. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. government. Clinical trial information: NCT 04423211.

36 Background: Interest has arisen in the use of prostate specific membrane antigen (PSMA) PET/CT imaging to detect prostate cancer at metastatic sites using different tracers. Here, we examined the ability of 18F-DCFPyL (DCFPyL) PSMA-based PET imaging to detect nodal disease in comparison to conventional imaging in a cohort of men with locally advanced or oligometastatic prostate cancer (PC). Methods: UW17009 is an IRB-approved open-label, single-arm trial that enrolled 26 patients with newly diagnosed advanced PC. Patients received androgen deprivation therapy and docetaxel for 3 months followed by radical prostatectomy (RP) and pelvic lymph node dissection (PLND). Exploratory interventions include PSMA PET/CT and MRI imaging as a method for determining treatment response and heterogeneity in primary PC and metastatic lesions performed before and after chemohormonal therapy. Prior to randomization, patients received DCFPyL PET/CT and PET/MR imaging as well as CTs and Bone Scans. A mean dose of 7.86 mCi DCFPyL was administered. Whole-body PET/CT images were acquired starting at approximately 60 minutes after radiotracer injection followed by dedicated pelvic PET/MR and whole-body PET/MR. PET imaging findings were compared to conventional dedicated CT imaging and were correlated to the results of final pathologic examination of each pelvic nodal dissection. Results: 26 patients underwent conventional and exploratory imaging with subsequent neoadjuvant treatment, RP and PLND. The mean diagnostic PSA was 32.1 ng/dl and 88.5% had Gleason 9 PCa. Using conventional imaging, pelvic nodal disease was identified in 6/26 patients. Pelvic lymph node uptake was identified in 12/26 patients using DCFPyL-based PSMA PET. Initial correlation of the pathologic specimens with pretreatment PSMA PET imaging revealed pelvic nodal metastatic PC in 10/12(83%) patients. On a per-lymph node packet basis (6 per patient), there were 156 evaluable regions, including 65 from patients with positive nodes. PSMA detected 14 packets that were positive for PC and 102 packets that were negative on imaging and final pathology. PC was missed in 5 packets. The mean tumor size in the missed nodes was 2.3 mm(range 1-4 mm). Calculated sensitivity was 73.7%(95% CI [48.8, 90.8]), 85.7 % specificity(95% CI[78.1, 91.4]), and 95.3 % negative predictive value(95% CI[90.5, 97.7]). Conclusions: In comparison to conventional imaging, in this cohort, DCFPyL PSMA-based PET imaging identified nodal positive disease at twice the rate and when evaluating on a per-packet basis, there was high negative predictive value. Ongoing analysis of post-chemohormonal therapy PET imaging may provide more information regarding tumor response in this cohort.

34 Background: Management of BCR PCa requires accurate assessment of location and extent of recurrent disease. FACBC has been shown to be a sensitive modality for detection and localization of recurrent disease but treatment guidelines are based on the findings of conventional (conv) imaging, including computed tomography, magnetic resonance imaging, or bone scintigraphy, and little is known about how prior treatment impacts FACBC findings and concordance with conv scans. Methods: This single-center retrospective study included 137 patients (pts) who had FACBC for BCR at the University of Wisconsin-Madison from 10/2017-10/2019. Clinical, pathological, imaging, and treatment data were collected by chart review. Pts were classified by type of primary treatment for localized PCa, either radical prostatectomy (RP) or radiation therapy (RT). Findings of conv scans performed within 4 weeks prior or any time after FACBC were collected. Results: 105 pts had RP and 32 pts had RT as their primary PCa treatment. Gleason score and PSA at diagnosis were similar between groups. Median PSA at time of FACBC was higher in the RT compared to RP group (3.3 vs 0.7 ng/dL) and median time from initial diagnosis to FACBC was longer (70 vs 55 months). Frequency of (+) FACBC findings was higher in the RT group (66% vs 47%); only 3% of pts in the RT group had a (-) FACBC compared to 29% in the RP group. The rate of (+) lesions in the prostate/prostate bed was higher in the RT group (41% vs 22%), while the rate of (+) lesions in pelvic nodes and distant sites was similar between groups. Of 69 pts who also had conv imaging, 61% had concordant conv imaging findings. In the RT group, conv and FACBC findings were similar in 47% of pts and not similar in 28%. In the RP group, conv and FACBC findings were similar in 26% of pts and not similar in 17%. Management after FACBC is listed in table. Median time from FACBC to first (+) conv scans was 6 (range: 0-18) and 5 (range: 0-17) months for RT and RP groups, respectively. Conclusions: In this large retrospective cohort, pts treated with initial RT had a longer median time from diagnosis to FACBC and higher median PSA at the time of FACBC compared to the RP group. RT patients had a higher rate of (+) FACBC findings but were more likely to continue on observation. The median time from FACBC to first (+) conv scan was 5-6 months, supporting the role of FACBC in earlier detection of recurrent disease in both groups of patients. Further analysis of concordance between FACBC and conv imaging is in process. [Table: see text]

5005 Background: Nivo + Ipi is an established first-line treatment (tx) for advanced RCC. We hypothesized that the addition of CTLA-4 blockade may not be required for all patients (pts). Furthermore, the optimal duration of Nivo maintenance in responding pts is unknown. In this phase II response-adaptive trial, we investigate the sequential addition of 2 doses of Ipi to induce response in Nivo non-responders (NR) and duration of Nivo in responding pts (NCT03203473). Methods: We enrolled pts with advanced RCC with no prior checkpoint inhibitor exposure. All pts received Nivo alone with subsequent arm allocation based on RECISTv1.1 response within 6 months (mos) of tx. Pts with a confirmed partial response (PR) or complete response (CR) within 6 months (mos) discontinued Nivo and were observed (Arm A). Arm A pts reinitiated Nivo if they developed progressive disease (PD); Ipi was added to Nivo if PD persisted or recurred. Pts with stable disease (SD) or PD after no more than 6 mos of Nivo alone received 2 doses of Ipi (Arm B). The primary endpoints were the proportion with PR/CR at 1-year (yr) after Nivo discontinuation (Arm A) and proportion of Nivo NR who convert to PR/CR after adding Ipi (Arm B). Results: 83 pts initiated tx of whom 99% had ECOG 0-1, 96% clear cell RCC, 51% tx-naïve, and 69% IMDC intermediate/poor risk. Median follow-up was 17.0 mos. 15 pts were not allocated to an arm [7 withdrew for PD, 7 withdrew for toxicity, 1 still on tx with unconfirmed PR (uPR)]. At 6 mos, induction Nivo resulted in a confirmed PR in 11% of pts (n=9/83): 12% (n=5/42) tx-naïve, 10% (4/41) prior tx, 8% (n=1/13) favorable risk, 11% (n=8/70) intermediate/poor risk (Table). 11 pts (13%: 9 PR, 1 uPR, 1 SD) were allocated to Arm A, of whom 5 (45%, 90% CI 20-73%) remained off Nivo at ≥ 1 yr. Of 57 pts (69%) allocated to Arm B, 2 pts converted to a PR (4%, 90% CI 1-11%), both of whom had prior tx and PD as best response to Nivo alone. Grade 3-4 treatment related adverse events (TrAE) occurred in 7% (n=6/83) on induction Nivo and in 23% (n=13/57) on Arm B (Nivo + Ipi). Conclusions: We cannot currently recommend a strategy of Nivo followed by response-based addition of Ipi due to the absence of CR and low PR/CR conversion rate (4%). Though a subset of pts treated with Nivo alone can maintain durable responses off tx at 1-yr, early Nivo discontinuation in the absence of toxicity cannot currently be recommended. Investigation into biomarkers to guide tx is ongoing. Clinical trial information: NCT03203473 . [Table: see text]

TPS273 Background: Radical prostatectomy (RP) and radiation therapy (RT) are the gold standard, curative intent treatment for pts with presumed organ-confined PCa. However, about one third of these pts will have progressive or metastatic disease at 10 years (yr). Pts with PSA recurrence without radiographic evidence of metastatic (m) PCa (stage M0) will ultimately develop radiographically apparent mPCa within a median of 8 yr. Pts with rapid PSA doubling time (DT) have a markedly shorter time to mPCa and death. Utilizing an immunotherapeutic approach could utilize the sensitivity and specificity of the immune system to treat microscopic disease and potentially avoid or postpone androgen deprivation therapy (ADT) and its unwanted side effects. Methods: In this single arm, two-stage phase II trial, a total of 21-41 PCa pts with PSA only progression (4 rising PSA with final PSA ≥ 2 ng/mL) after initial RP for presumed organ-confined disease who have no radiographic evidence of mPCa in conventional imaging (CT and bone scan) will be enrolled. Pts with small cell or other variant PCa, or history of ADT other than concurrent with RT are excluded. All pts will be treated with pTVG-HP 100 μg intradermally (id) and Nivo 240 mg IV every (Q) 2 weeks (w) x6, and then pTVG-HP 100 μg id and Nivo 480 mg IV Q4w x9 beginning w12 on study. Pts with PSA on w4 > PSA on day 1 will additionally receive rhGM-CSF 208 μg id, as a vaccine adjuvant, Q2w x4 beginning w4 on study. Pts will be treated until progression or up to a total of 1 yr. Response will be monitored by CT and bone scan Q6 months or as clinically indicated. Primary endpoints are safety and tolerability of this combination and PSA complete response rate (PSA < 0.2 ng/mL). Key secondary endpoints are 2-yr metastasis-free survival, median radiographic progression-free survival, PSA response rate (≤50% of baseline), and changes in PSA DT. Elicited antigen-specific T-cell and/or IgG response and its correlation with PSA response will be explored. Bone mets not detected by conventional imaging and their association with response will be evaluated by Quantitative Total Bone Imaging (QTBI) by NaF PET/CT. Updated enrollment will be presented. Clinical trial information: NCT03600350.

334 Background: Previous studies have shown that addition of docetaxel to androgen deprivation therapy (ADT) significantly improves progression-free survival (PFS) and overall survival (OS) in men with metastatic hormone-sensitive PC. Removal of the primary may also improve outcomes by reducing tumor self-seeding. We are conducting a phase II trial in men with PC to examine the feasibility of NAC, response using PSMA PET/MRI imaging and molecular mechanisms of resistance. Methods: This is an open-label, single-arm trial. Thirty patients with newly diagnosed very high risk localized, locally advanced or oligometastatic PC will receive ADT/docetaxel for three cycles before prostatectomy. The primary endpoint is rate of complete pathologic response. Key secondary objectives include PSA recurrence at month 12 after surgery. Exploratory objectives include tumor response and response heterogeneity in primary and metastatic tumors before and after treatment assessed by PSMA PET/MRI and evaluation of gene expression signatures in cancer cells, prostate stroma, bone marrow microenvironment and circulating tumor cells. Results: To date, 26 of 30 patients have enrolled and completed treatment. Mean age was 61 and mean PSA at time of diagnosis was 32.1 ng/dl. All patients had multi-focal prostate cancer with 23/26 patients with Gleason Grade Group 5. Metastatic disease by conventional imaging was identified in 6/26 patients (5 in lymph nodes [LN] and bone, 1 in LN only). Treatment was overall well tolerated. All patients had multi-focal primary prostate cancer detected on PSMA PET/MRI. All patients had a decline in PSMA PET SUVmax in at least one intraprostatic lesion. Two patients had an increase in SUVmax in at least one intraprostatic lesion that correlated with a resistant tumor focus on histopathology. Conclusions: NAC prior to surgery generates high rates of local tumor control with a heterogeneous response between foci. Primary resistance, identified by increasing PSMA PET SUVmax, is uncommon, however incomplete responses were observed in nearly all patients, suggesting that more cycles of treatment would improve response. PSMA PET/MRI can be used to monitor response and resistance in PC. Clinical trial information: NCT03358563.

TPS251 Background: In patients with mCRPC, androgen receptor (AR) pathway inhibitors such as enzalutamide or abiraterone acetate are often used as first-line systemic therapy. After progression on either of these inhibitors, the likelihood of response to the other is significantly lower than in the first-line setting. Multiple resistance mechanisms have been identified, including the emergence of AR splice variants. Trop2 is a cell-surface antigen that is expressed in > 70% of prostate cancers and is enriched in mCRPC expressing AR splice variants. Sacituzumab govitecan (SG; IMMU-132) is a novel antibody drug conjugate composed of humanized anti-Trop2 antibody conjugated to SN-38 payload by hydrolyzable linker. SG has potential to be an effective therapy after progression on initial AR pathway inhibitors to meet this significant unmet clinical need. Methods: This is a single-arm, open-label, multicenter phase 2 trial (NCT03725761) to determine the efficacy and safety of SG. The primary endpoint is PSA response rate (≥50% PSA decline at or within 9 weeks of starting treatment); secondary endpoints include rPFS and overall survival. 55 subjects with mCRPC who have progressed on second-generation AR-directed therapy in either the hormone sensitive or CRPC setting will be included. Fresh or archived metastatic site biopsy is required. Subjects will be treated with SG IV at 10 mg/kg on Day 1 and Day 8 of 21-day cycles until disease progression. Subjects who receive ≥1 SG dose and have ≥1 PSA post-dose assessment will be included in final efficacy analysis. Circulating tumor cell biomarker studies will be performed throughout treatment and at progression to investigate potential mechanisms of response/resistance to SG. Tumor biopsies at baseline and after 3 therapy cycles will evaluate genomic alterations that predict treatment response. Subjects who remain progression free will undergo repeated evaluations of extent of disease every 9 weeks. The trial is actively accruing. Managed by: Prostate Cancer Clinical Trials Consortium; Funding: Immunomedics; Support: Prostate Cancer Foundation. Clinical trial information: NCT03725761.

Background Androgen deprivation therapy plus docetaxel (D-ADT) increases overall survival (OS) in men with high-volume, metastatic hormone-sensitive prostate cancer (mHSPC). Although the vast majority of men initially respond to D-ADT, most will progress and develop castration-resistant prostate cancer (CRPC). Little is known about the optimal treatment sequence for men with progressive disease on D-ADT. Patient and methods Retrospective analysis of consecutive mHSPC patients treated with ≥3 cycles of D-ADT at Cleveland Clinic and University of Wisconsin-Madison was undertaken. The primary end-points included radiographic progression free survival (rPFS) and OS with first-line treatment for metastatic CRPC (mCRPC). Results Final analysis included 136 patients, median age 65 (range 35-86), 77% GS ≥ 8, and 79% with high-volume disease who received ≥3 cycles of docetaxel. Undetectable PSA values at 12 and 24 months were observed in 32% and 25% of patients, respectively. Median time to CRPC (biochemical, clinical, or radiographic) was 19.6 months (16.6-22.6). Sixty patients (44%) received ≥1 treatment for CRPC: 48 patients (80%) received a second-generation hormonal therapy (sHT). Among these, 22 received abiraterone acetate, 20 enzalutamide, and six a novel CYP-17 inhibitor on trial (ASN-001). Five patients (8%) received sipuleucel-T; four (7%) radium-223, five (8%) chemotherapy (two carboplatin-based, two single agent cabazitaxel, one single agent docetaxel) and three other. Patients receiving sHT as the first treatment for mCRPC had a median rPFS of 9.0 months (95%CI, 6.9-11.2) compared with 3.0 months (95%CI, 1.5-4.5) for patients who received a non-sHT (P = 0.024). The choice of first therapy for mCRPC was independent of GS (P = 0.909), visceral disease (P = 0.690) and time to CRPC (P = 0.844). Longer OS correlated with time to CRPC (P = 0.010) and first treatment for CRPC with sHT (P = 0.005). Conclusions For patients with progressive disease on D-ADT, subsequent treatment with a sHT is associated with a longer rPFS and OS.

Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m2 for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio [HR], 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.

The prostate cancer disease continuum is best conceptualized as a series of clinical states starting from localized disease (which is curable, in some) and often progressing to biochemically-recurrent disease, to non-metastatic or metastatic castration-resistant disease, and finally to lethal prostate cancer (1). Accordingly, a major decrease in the recurrence rate or death from prostate cancer after primary definitive therapy could potentially be achieved with more effective adjuvant therapies. For patients with localized prostate cancer, treatment options for definite therapy include surgery or radiation, with approximately one-third of these men experiencing disease recurrence (2).

Over the last 10 years, the progress in our understanding of the molecular basis of RCC has led to the development of targeted therapies with significant improvement in patient outcomes. To date, targeting the vascular endothelial growth factor receptor (VEGFR) has been shown to lead to improved clinical outcomes in metastatic RCC. Currently, four VEGFR tyrosine kinase inhibitors (TKIs) have been approved by the Food and Drug Administration (FDA) for the treatment of metastatic RCC: sunitinib, sorafenib, axitinib, and pazopanib. Here, we summarize the clinical data of efficacy, safety, and tolerability of those agents in patients with metastatic RCC.

Malignant melanoma involving the respiratory tract is nearly always metastatic in origin, and primary tumors are extremely rare. Published data on primary pulmonary malignant melanomas are limited. Up to now 40 relevant cases have been reported in the English literature. Herein, we report a case of a 56-year-old female patient who presented with intracranial metastases due to primary pulmonary melanoma. She underwent bronchoscopy and died 5 months after the initial diagnosis despite the administered biochemotherapy and subsequent immunotherapy. To establish the diagnosis of primary pulmonary malignant melanoma, any extrapulmonary origin was excluded by detailed examination and radiographic imaging. Moreover, an extensive review of the literature regarding this rare entity has been performed.

Background We report secondary and exploratory analysis with 18F-NaF PET/CT and CTCs to determine how tumour burden and RNA expression of androgen receptor (AR) splice variants and neuroendocrine (NE) features predict duration of treatment (DoTx) with ENZA. Methods Men with progressive mCRPC with ≥ 2 lesions on bone scintigraphy were enrolled and treated with ENZA 160 mg daily at 3 US sites. 18F-NaF PET/CT scans were obtained at baseline (BL) (PET1), week 13 (PET2), and at the time of PSA progression (per PCWG2 criteria), standard radiographic or clinical progression, or at 2 years without progression (PET3) using QTBI. CTCs were obtained at BL and at PET3. PSA decline and DoTx were compared with BL QTBI, CTC metrics, and change in QTBI. Results 23 men (median age, 72 years [range, 51-93]; median PSA, 20.5 ng/mL [range, 3.9-133.6]) were enrolled; 22 of which completed planned imaging. The mean number of bone lesions on PET1 was 58 (range 9-168), with a median total standardized uptake value (SUVtotal) of 3886.5 (range 506.7-22852.8). DoTx ranged from 1.4 to 31.8+ mo. In general, SUV metrics decreased while on ENZA (PET2) and increased by PET3. Change in lesion heterogeneity (PET1 to PET3) was the most significant predictor of time to PSA progression (hazard ratio, 3.88; 95% confidence interval, 1.24-12.1). ARV7/9 was found in CTCs in 3/20 men and NE features were found in 4/20 men at BL and in 4/19 and in 11/19 men, respectively, at PET3. Conclusions Although PSA response with ENZA is high, DoTx is variable. SUVtotal at BL did not correlate with DoTx; however, decrease in SUVtotal/mean was associated with increased DoTx, with less heterogeneity correlating with a longer time to PSA progression. ARV7/9 or NE expression in CTCs did not predict lack of benefit from ENZA; however, at the time of progression, the observed increase in ARV7/9 and NE expression are consistent with tumor evolution to more aggressive phenotypes. While BL heterogeneity may be prognostic, it may not predict response or DoTx. Assessing response heterogeneity may predict response duration, thus, should be explored as a possible surrogate of benefit in future studies. Clinical trial identification NCT02384382. Editorial acknowledgement Medical writing and editorial assistance funded by Pfizer Inc. and Astellas Pharma, Inc. was provided by Stephanie Vadasz, PhD, and Michele Salernitano from Ashfield Healthcare Communications. Legal entity responsible for the study Pfizer Inc. and Astellas Pharma, Inc. Funding Pfizer Inc. and Astellas Pharma, Inc. Disclosure G. Liu: Leadership role, Shareholder / Stockholder / Stock options, Employee: AIQ Solutions; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Novartis; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): TRACON Pharma; Research grant / Funding (self), Research grant / Funding (institution): Madison Vaccines Inc.; Research grant / Funding (self), Research grant / Funding (institution): Pfizer Inc. C.E. Kyriakopoulos: Advisory / Consultancy, Travel / Accommodation / Expenses: Exelixis; Speaker Bureau / Expert testimony: The France Foundation; Research grant / Funding (self), Research grant / Funding (institution): Sanofi. J.M. Lang: Shareholder / Stockholder / Stock options, Licensing / Royalties, I am listed on the patent on a technology for rare cell capture and analysis. This technology has been licensed by Salus Discovery, LLC though no commercial products are available: Salus Discovery; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Pfizer Inc.; Research grant / Funding (institution): Novartis. E.I. Heath: Advisory / Consultancy, Research grant / Funding (institution): Agensys; Honoraria (self), Speaker Bureau / Expert testimony: Sanofi; Honoraria (self): Bayer; Honoraria (self), Research grant / Funding (institution): Dendreon; Honoraria (self), Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Tokai Pharmaceuticals; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Inovio Pharmaceuticals; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Zenith Epigenetics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Esanik; Research grant / Funding (institution): Oncolys BioPharma; Research grant / Funding (institution): CureMeta; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): eFFECTOR Therapeutics; Research grant / Funding (institution): Fortis. S. Perlman: Research grant / Funding (institution): GE Healthcare Progenics; Advisory / Consultancy: Pfizer Inc. T. Mayer: Advisory / Consultancy: Beacon Biosciences/ICON Medical; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Research grant / Funding (institution): Sotio; Research grant / Funding (institution): Merck; Research grant / Funding (self): Pfizer Inc. K. Modelska: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Employee: Pfizer Inc. A. Porcari: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Employee: Pfizer Inc. W. Duggan: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Employee: Pfizer Inc. R. Jeraj: Licensing / Royalties, Patents: Wisconsin Alumni Research Foundation; Shareholder / Stockholder / Stock options: AIQ Solutions; Research grant / Funding (institution): GE Healthcare. All other authors have declared no conflicts of interest.

Background Preclinical studies have demonstrated that a DNA vaccine encoding the androgen receptor ligand-binding domain (AR LBD) can elicit CD8+ T cells specific for the AR LBD, delay disease progression and prolong survival of prostate tumor-bearing animals. Vaccination of tumor-bearing mice treated with androgen deprivation (AD) led to a delay in the emergence of castration-resistant disease. This same DNA vaccine (pTVG-AR, MVI-118) was evaluated in a phase I clinical trial in men with metastatic prostate cancer (mPC) on AD therapy. Methods 40 patients with mPC, within 6 months of beginning standard AD therapy, were randomly assigned to receive pTVG-AR on one of two different treatment schedules, and with or without GM-CSF used as an adjuvant. Ten total vaccinations were given over 1 year, and patients were followed for 18 months. The primary objectives were safety and immune activity. Secondary objectives were to evaluate different schedules, the requirement for GM-CSF, and whether treatment was associated with PSA progression-free survival (PSA PFS). Results Between 2015 and 2017, 40 patients were enrolled at 3 centers. 27 patients completed treatment and 18 months of follow-up. Eleven patients (28%) had a PSA progression event. No grade 3 or 4 adverse events were observed. Samples from 30 patients were available for immune analysis. 14/30 (47%) developed Th1 biased immunity to the AR LBD as determined by IFNγ or granzyme B ELISPOT that was detectable at least twice after beginning treatment. Differences in immune responses were observed with different schedules, but not with GM-CSF adjuvant. Patients who developed immunity had a significantly prolonged PSA PFS compared to patients without immunity (HR = 0.18, 95% CI: 0.04-0.92, p = 0.040). Conclusions This trial showed that pTVG-AR was safe and immunologically active in patients with mPC, and identified a preferred schedule of administration. Association between immunity and PSA PFS suggests treatment may delay the time to castration resistance, similar to observations in preclinical studies. Future studies will evaluate pTVG-AR in earlier stages of disease, and in combination with other agents. Clinical trial identification NCT02411786. Legal entity responsible for the study Douglas McNeel. Funding Madison Vaccines, Inc. Disclosure D.G. McNeel: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: Madison Vaccines Inc; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Merck. R. Lesniewski: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Madison Vaccines Inc. B. Olson: Licensing / Royalties: Madison Vaccines Inc. C. Kyriakopoulos: Research grant / Funding (institution): Madison Vaccines Inc. All other authors have declared no conflicts of interest.

5036 Background: 18F-NaF PET/CT provides spatial and quantitative information on osteoblastic activity in men with bone mCRPC; thus, it can be used to assess interlesional response heterogeneity, a critical clinical issue. Here we assess the proportion of men treated with ENZA with responding lesions by 18F-NaF PET/CT at the time of prostate-specific antigen (PSA), standard radiographic, or clinical progression. Methods: Men with progressive mCRPC with ≥ 2 lesions on bone scintigraphy were enrolled and treated with ENZA 160 mg daily at 3 US sites. 18F-NaF PET/CT scans were obtained at baseline (PET1), week 13 (PET2), and at the time of PSA progression (increase of ≥ 25% and ≥ 2.0 ng/mL above nadir), standard radiographic or clinical progression, or at 2 years without progression (PET3) using Quantitative Total Bone Imaging (QTBI). The primary endpoint was the proportion of men with ≥ 1 responding bone lesion (defined as a lesion with a total NaF standardized uptake value [SUV] less than baseline) on PET3. Evaluable men had scans at PET1 and PET3. Results: A total of 23 men (median age, 72 years [range, 51-93]; median PSA, 20.5 ng/mL [range, 3.9-133.6]) were enrolled. The study met its primary objective; 22 of 22 (100%) evaluable men had ≥ 1 responding bone lesion on QTBI at PET3. Total disease burden changed from a mean baseline SUV of 5700 (range, 507-22,850) to 5590 (range, 213-17,090) at PET2 and 6020 (range, 118-16,650) at PET3. The proportion of progressive lesions increased from a mean 7.8% (range, 0-29) at PET2 to 9.4% (range, 0-32) at PET3. Conclusions: Although PSA response with ENZA is high, many men experience a mixed response to treatment. While overall functional disease burden improves during treatment, an eventual increase in global burden is seen at the time of progression as measured by 18F-NaF PET/CT. At the primary endpoint analysis the proportion of progressing lesions is low, supporting both the hypothesis that a substantial number of lesions continue to benefit from treatment and the concept of treating beyond progression and selectively targeting nonresponding lesions while keeping patients on ENZA. Clinical trial information: NCT02384382.

e16517 Background: The combination of PCUR-101 (a synthetic form of the plant-derived medicinal agent, plumbagin) and surgical castration caused regression of androgen dependent tumors in mice. These promising pre-clinical results led to this first-in-human study of PCUR-101 in combination with androgen deprivation therapy (ADT) in men with metastatic, castrate resistant PCa (mCRPC). Methods: The goal of this phase I multicenter trial was to determine the safety profile, maximum tolerated dose (MTD), recommended phase II dose, clinical activity, and pharmacokinetic (PK) parameters of PCUR-101. A 3 + 3 dose escalation design was employed. Patients (pts) in cohorts of 3 were treated with escalating doses of PCUR-101 (50 mg – 200 mg) orally once daily continuously. Cycles were 28 days. Exploratory correlates of IL-6 and urine polyamines were also included. Results: 12 pts (median age 75 [range 63-86]) with mCRPC on ADT were treated in the dose escalation cohorts. No DLTs were observed during treatment and the MTD was not reached. The most frequent adverse events (AEs) included diarrhea (11 pts; all grade 1 or 2), nausea (7 pts; all grade 1 or 2), vomiting (4 pts; all grade 1 or 2) and constipation (3 pts; all grade 1 or 2). No objective responses were observed but 1 pt had PSA decrease by > 50%. Pts remained on study treatment for a median of 10 weeks (range 3-32 weeks). 5 pts, with stable disease, remain on active treatment. PK data could not be fully evaluated due to issues with the PK assay. Analyses of IL-6 and putrescine levels in pt samples indicate that, as compared to no treatment, PCUR-101 treatment in each cycle was associated with decreases in their levels. Reasons for treatment discontinuation included disease progression (n = 4), adverse event (n = 1; nausea and vomiting), subject withdrawal (n = 1), and investigator or sponsor decision (n = 1). After treating 12 pts, the sponsor decided to stop the trial in order to reformulate the study drug to allow for higher dosing and to redevelop the PK assay. Conclusions: At the doses evaluated, PCUR-101 combined with ADT was seen to be safe and may prolong disease stability in men with mCRPC. A second phase I study is planned using a new drug formulation and PK assay. Clinical trial information: NCT03137758.

TPS5094 Background: The E3805 CHAARTED trial showed a significant survival benefit from early treatment with docetaxel in patients (pts) with high-volume metastatic hormone-sensitive prostate cancer (HSPC). However, eventually all these patient will develop castration-resistant disease (CRPC) and it is currently unknown what is the optimal treatment in that setting. We hypothesize that treatment with a second round of chemohormonal therapy –this time in the CRPC setting- will improve outcomes. Methods: This is a prospective randomized phase II open label trial led by ECOG-ACRIN. Pts (N = 210) with metastatic CRPC who have previously received docetaxel for HSPC will be randomized to 2 treatment arms (1:1): abiraterone/prednisone plus cabazitaxel for up to 6 cycles versus abiraterone/prednisone alone. Stratification factors include ECOG performance status, time from initiation of ADT to development of CRPC and visceral versus bone only metastases. The primary objective is to evaluate the efficacy of abiraterone/prednisone plus cabazitaxel versus abiraterone/prednisone alone. The primary endpoint of the trial is progression-free survival (PFS), defined clinically or radiographically. Secondary endpoints include PSA response, radiographic response, time to PSA progression, overall survival and safety. Exploratory objectives include response assessment based on AR-V7 status as well as by NaF PET/CT imaging. Key inclusion criteria include: metastatic CRPC, prior treatment with at least 3 cycles of docetaxel for metastatic HSPC, no prior treatment for CRPC (radium-223 or sipuleucel-T excluded), ECOG performance status of 0-2 and peripheral neuropathy of less than 2. The study was activated on 02/08/2018. As of 01/21/2019, 28/210 pts have been enrolled. Support: CA180820, CA180794, CA180799, CA180802; and Genzyme Corporation, a subsidiary of Sanofi S.A. Clinical trial information: NCT03419234.

Ever since the critical role of androgen deprivation therapy for the treatment of metastatic prostate cancer was established, several trials aimed to show an improved outcome with the early introduction of chemotherapy in metastatic disease. Until recently, all these trials-including the GETUG-AFU 15 trial-failed to confirm an improvement in survival. The recently published CHAARTED and STAMPEDE trials showed a striking benefit and changed the standard of care for patients with newly diagnosed metastatic prostate cancer. We summarize the evidence that emerged from these trials that support the use of combined chemohormonal therapy in metastatic hormone-sensitive prostate cancer.

BACKGROUND: A phase 1/2a dose escalation study of APC-100 (2,2,5,7,8-Pentamethyl-6-chromanol) was conducted to determine maximum tolerated dose (MTD), recommended phase 2 dose, toxicities and efficacy in men with castrate-resistant prostate cancer (CRPC). METHODS: This open label phase 1/2a study utilizes a time-to-event reassessment method (TITE-CRM) design. Patients in cohorts of 3 were treated with escalating doses of APC-100 (900 mg-2400 mg) orally once daily continuously. Cycles were 28 days. RESULTS: Twenty patients with CRPC were enrolled in the dose escalation cohort. One possible DLT (elevated ALT) was seen at dose level 1. No other DLTs were seen and no dose reductions were required. Most frequent AEs included nausea (grade 1 in 6 patients) and elevated transaminases (grade 1–3 in 5 patients). After enrolment of 20 patients the MTD was not reached, however the maximal feasible dose was exceeded due to the number of capsules ingested. Five of the 20 patients had stable disease as their best response. The median progression free survival (PFS) for the cohort was 2.8 months (range 1–8). CONCLUSIONS: APC-100 is a novel agent with dual mechanism of action functioning both as potent antioxidant as well as antiandrogen. No detectable APC-100 was found in the plasma at dose level 5 (2100 mg) and it was felt that maximal feasibility was nearly reached. APC-100 is being reformulated as a tablet to allow further dose escalation. Once a recommended phase 2 dose is established, future studies in prostate cancer chemoprevention should be conducted.

TPS4600Background: CheckMate 025 established NIVO as a standard of care (SOC) option for advanced clear cell RCC (ccRCC) after prior antiangiogenic therapy. The combination of IPI plus NIVO is anti...

305 Background: D-ADT increases overall survival (OS) in men with mHSPC. All patients (pts) however progress and develop castration-resistant prostate cancer (CRPC). Little is known about response to subsequent therapy and outcomes in this setting. Methods: Retrospective analysis of consecutive mHSPC pts treated with ≥3 cycles of D-ADT at Cleveland Clinic and University of Wisconsin-Madison. We aimed to describe baseline, progression characteristics, treatment choices, sequence and outcome of subsequent therapy. Results: A total of 146 mHSPC pts were treated with D-ADT (6% 1-2 cycles; 94% ≥3 cycles). Final analysis included 136 pts, median age 65 (range 35-86), 65% GS≥8, 79% high-volume disease. Median number of D cycles was 6 (1-6). PSA declined to “0” at 12 and 24 months in 32% and 25% of pts, respectively. Median time to CRPC (biochemical, clinical or radiographic) was 19.6 months (95% CI, 16.6-22.6). 57 pts (42%) received ≥1 subsequent treatment after CRPC [46 hormonal therapy (HT) (21 abiraterone acetate, 19 enzalutamide, 6 ASN-001); 4 Sipuleucel-T; 4 radium-223, 5 chemotherapy (2 carboplatin-based, 2 cabazitaxel, 1 D); 3 temsirolimus/bevacizumab]. Treatment response was independent from time to CRPC (≥12 months, p = 0.264). Pts receiving HT as the first subsequent treatment had a median rPFS of 13.3 months (95% CI, 10.1-16.5) compared with 3.1 months (95% CI, 0-15.8) for non-HT (p = 0.332). Treatment choice was independent of GS (p = 0.513), visceral disease (p = 0.374) and time to CRPC (p = 0.500). Most CRPC pts treated with ≥2 lines of therapy received one HT (n = 21) followed by a different HT (43%), chemo (38%), radium-223 (14%) or olaparib (10%). 57% of pts were alive at 2 years. Longer OS correlated with time to CRPC (p = 0.010) and first subsequent treatment with HT (p = 0.009) but not with visceral disease (p = 0.258), GS (p = 0.599) or sequence of therapies received (HT/HT vs HT/non-HT, p = 0.836). Conclusions: Prior D-ADT did not preclude subsequent treatment response in CRPC pts, independent of time to CRPC. The choice of first-line treatment for CRPC may impact survival in favor of those who start HT.

BACKGROUND: Sarcomatoid renal cell carcinoma is associated with poor prognosis. Data regarding outcome in the targeted therapy era are lacking. PATIENTS AND METHODS: Clinical, prognostic, and treatment parameters in metastatic renal cell carcinoma patients with and without sarcomatoid histology treated with targeted therapy were retrospectively analyzed. RESULTS: Two thousand two hundred eighty-six patients were identified (sRCC: n = 230 and non-sRCC: n = 2056). sRCC patients had significantly worse IMDC prognostic criteria compared with non-sRCC (11% vs. 19% favorable risk; 49% vs. 57% intermediate risk, and 40% vs. 24% poor risk; P < .0001). Time from original diagnosis to relapse (excluding synchronous metastatic disease) was shorter in the sRCC group (18.8 vs. 42.9 months; P < .0001). There was no significant difference in the incidence of central nervous system metastases (6%-8%) or underlying clear cell histology (87%-88%). More than 93% of patients received VEGF inhibitors as first-line therapy; objective response was less common in sRCC whereas primary refractory disease was more common (21% vs. 26% and 43% vs. 21%; P < .0001, for both). sRCC patients had significantly less use of second- (P = .018) and third-line (P < .0001) systemic therapy. The median progression-free survival (PFS)/overall survival (OS) was 4.5/10.4 months in sRCC patients and 7.8/22.5 months in non-sRCC patients (P < .0001 for both). Sarcomatoid histology was associated with a significantly worse PFS and OS after adjusting for individual IMDC risk factors in multivariable analysis (hazard ratio, 1.5; P < .0001 for both). CONCLUSION: Patients with sRCC have a shorter time to relapse, worse baseline prognostic criteria, and worse clinical outcome with targeted therapy. Additional insight into the biology of sRCC is needed to develop alternative therapeutics.

IntroductionThis study aims to make an indirect comparison between enzalutamide and abiraterone acetate for mCRPC post-docetaxel.MethodsA search for published phase 3 trials was performed with PubMed. Indirect comparisons of enzalutamide (AFFIRM) to abiraterone acetate (COU-AA-301) on outcomes overall survival (OS), time to prostate-specific-antigen (PSA) progression, radiographic progression-free survival (PFS), and PSA response were constructed in the context of log-linear regression models.ResultsThere was no statistically significant difference in OS (hazard ratio (HR) 0.85, 95% CI 0.68–1.07). However, there was some evidence that enzalutamide may outperform abiraterone acetate with respect to secondary outcomes: time to PSA progression (HR 0.40, 95% CI 0.30–0.53), radiographic PFS (HR 0.61, 95% CI 0.50–0.74), and PSA response rates (RRs) (OR 10.69, 95% CI 3.92–29.20).ConclusionWhile there was no statistically significant difference in OS, enzalutamide may be advantageous for secondary endpoints. Findings of this indirect comparison serve to be hypothesis-generating for future head-to-head trials.

e16097Background: In the past decade, 8 regimens were approved for metastatic renal cell carcinoma (mRCC) leading to a quickly changing clinical landscape. Trials addressing treatment (tx) efficacy...

e16084Background: Metastatic renal cell carcinoma (mRCC) is a heterogeneous disease, often presenting with an indolent course. Our prior retrospective work indicates many patients (pts) may not rec...