Search

Bicky Thapa,1,* Navonil De Sarkar,2– 4,* Subhajit Giri,2,3 Komal Sharma,2– 4 Mingee Kim,5 Deepak Kilari1 1Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 2Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA; 3Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA; 4Data Science Institute, Medical College of Wisconsin, Milwaukee, WI, USA; 5School of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA*These authors Contributed equally to this workCorrespondence: Deepak Kilari, Email dkilari@mcw.eduAbstract: Metastatic castrate-resistant prostate cancer (mCRPC) is associated with poor prognosis. DNA damage response (DDR) genes are commonly altered in mCRPC rendering them as promising therapeutic targets. Poly (ADP ribose) polymerase inhibitors (PARPi) demonstrated antitumor activity in mCRPC patients with DDR gene mutations through synthetic lethality. Multiple clinical trials with PARPi monotherapy exhibited encouraging clinical outcomes in selected patients with mCRPC. More recently, three Phase III randomized clinical trials (RCTs) combining PARPi with androgen receptor signaling inhibitors (ARSIs) demonstrated improved antitumor activity compared to ARSI monotherapy in mCRPC patients as the first-line therapy. Clinical benefit was more pronounced in patients harboring DDR alterations, specifically BRCA1/2. Interestingly, antitumor activity was also observed irrespective of DDR gene mutations, highlighting BRCAness phenotype with androgen receptor blockade resulting in synergistic activity between ARSIs and PARPi. In this review, we discuss the clinical efficacy and safety data of the combination of PARPi plus ARSI in all Phase 3 randomized controlled trials (RCTs), emphasizing strategies for patient selection and highlighting emerging trends based on clinical trial data.Keywords: PARP inhibitors, talazoparib, ARSI, DDR genes, HRD, metastatic CRPC

There remains limited data as to the efficacy of higher doses of elective radiation therapy (RT) to the pelvic lymph nodes for men with very high risk, non-metastatic adenocarcinoma of the prostate. We conducted a prospective phase II study to evaluate the toxicity and efficacy of external beam dose escalation to the pelvic lymph nodes using a simultaneous integrated boost (SIB) to the prostate. We report the long-term clinical outcomes of a prospective phase II clinical trial (NCT02177292) with a median follow up of over 10 years. Patients were eligible with biopsy proven adenocarcinoma of the prostate, a probability of lymph node risk of at least 25%, Karnofsky Performance Scale of at least 70, and no evidence of M1 disease. Acute and late toxicity were prospectively collected at each follow up using CTCAE version 4.0. Pelvic lymph nodes were treated to a dose of 56 Gy over 28 fractions with a simultaneous integrated boost (SIB) to the prostate to a total dose of 70 Gy over 28 fractions using IMRT. Patients were followed every three months for the first two years, every 6 months from years three to five, and annually. All patients received neoadjuvant, concurrent, and adjuvant androgen deprivation therapy for a median of 24 months. Secondary to the time frame of the study accrual, PSMA pet was not available. Descriptive statistics, including mean and inter-quartile ranges for all continuous variables, such as age and PSA and frequencies for all categorical variables were computed. Survival statistics were computed using the Kaplan Meier method. 80 patients were prospectively enrolled with 78 patients deemed eligible after final review. The mean patient age at biopsy was 72 (57-86), mean pre-treatment PSA was 19.01 (2.6-111.5), median T stage was T2c (T1c-T3b), 69.2% (54/78) patients had a Gleason score of 9, 28% had a Gleason score of 8. 84% of patients were classified as NCCN very high risk. At a median follow up of 10.6 years biochemical control was achieved in 92.5% of patients, distant metastasis free survival was 96.2%. Cumulative rates of all grade 2 or higher late toxicity (attributable and non-attributable to RT) was 38%, the majority of patients (62%) had grade 1 or lower toxicity. Nodal RT dose escalation in a modern prospective cohort of NCCN very high-risk prostate cancer resulted in extremely promising 10-year clinical outcomes. Radiation dose intensification to the pelvic nodes warrants further study and consideration for further testing in randomized phase III clinical trials. [ABSTRACT FROM AUTHOR]

Context.—: Patients can now immediately review pathology reports via online health portals., Objective.—: To better characterize patient perceptions of pathology report helpfulness and preferences for access of pathology reports via a patient portal., Design.—: Semistructured interviews were conducted with oncology patients with breast, endocrine, gastrointestinal, genitourinary, and thoracic malignancies. Patient demographic information, cancer type, question responses, and thematically grouped comments were statistically analyzed., Results.—: Among 230 patients, there was equal sex distribution (116 of 230, 50.4% female; 114 of 230, 49.6% male). Patients who viewed or had a support member view their reports in the portal (172 of 230; 74.8%) differed from those who did not (58 of 230; 25.2%) only in perception of helpfulness (P < .001) of the report. Difficulty understanding medical terminology was the most frequently cited challenge among both those who found the reports helpful (30 of 160; 18.75%) and not helpful (31 of 46; 67.4%). Most patients (196 of 230; 85.2%) preferred immediate release of results, even if the news was bad, whereas some (34 of 230; 14.7%) would opt out of immediate release for fear of misunderstanding (11 of 34; 32.4%) or receiving distressing information from reading the report (23 of 34; 67.6%)., Conclusions.—: Options for portal flexibility (ie, patient choice of opting for immediate release of some, but not all, results), patient-centered pathology reports, educational materials, clinician preparation of patients, and tailored patient support are strategies that can help more patients benefit from reviewing pathology report information., (© 2024 College of American Pathologists.)

Enfortumab vedotin (EV) is used as monotherapy or combined with pembrolizumab in advanced urothelial carcinoma (aUC), but biomarker data associated with EV outcomes are limited. We identified 170 patients in the UNITE study who received EV monotherapy and had molecular biomarker data available. Outcomes for groups with and without a particular biomarker were compared using logistic regression (unadjusted) for the objective response rate (ORR), and a log-rank test and Cox proportional-hazard models (CPHMs) for progression-free survival (PFS) and overall survival (OS) from EV initiation. Molecular biomarkers were also evaluated in separate multivariable analyses using CPHMs that accounted for clinical characteristics. Median patient age was 70 yr; 78% of the cohort were male and 65% had pure UC histology. Median PFS was shorter for patients with CDKN2A alterations (4.6 vs 6 mo; p = 0.024) and for patients with CDKN2B alterations (4.4 vs 6 mo; p = 0.008). Median OS was longer for patients with high tumor mutational burden (13.6 vs 8.3 mo; p = 0.014). ORR was higher for patients with TSC1 alterations (87% vs 51%; p = 0.018). In multivariable analyses, CDKN2A and CDKN2B alterations were associated with inferior median PFS. This multi-institutional retrospective study of patients with aUC identified potential biomarkers associated with EV monotherapy outcomes that should be further investigated. PATIENT SUMMARY: We investigated genetic changes in urinary tract tumors that might be associated with response to enfortumab vedotin (EV) treatment in patients with advanced disease. Survival after EV treatment was longer for tumors with a higher number of mutations than for tumors with fewer mutations. However, mutations in two genes (CDKN2A and CDKN2B) were associated with worse outcomes after EV treatment. These findings will not affect current clinical practice, but should be investigated further in future studies., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Competing Interests: Disclosure JO: nothing to declare, KS: nothing to declare, ND: nothing relevant to declare, DK: nothing to declare, ESA: reports grants and personal fees from Janssen, Sanofi, Bayer, Bristol Myers Squibb, Curium, Merck, Pfizer, AstraZeneca, Clovis, Constellation; personal fees from Astellas, Amgen, Blue Earth, Exact Sciences, Invitae, Eli Lilly, and Foundation Medicine; grants from Novartis, Celgene, and grants from Orion outside the submitted work; and has a patent for an AR-V7 biomarker technology that has been licensed to Qiagen. Funding: ESA is partially supported by NCI Cancer Center Support Grant grant P30 CA077598 and DOD grant W81XWH-22-2-00.

Background and Objective: Advances in non-clear cell renal cell carcinoma (RCC) have lagged behind clear cell RCC due to the heterogeneity and relative rarity of the disease. However, more advanced molecular and genetic testing has allowed us to gain a more detailed and nuanced appreciation of these malignancies. This has laid the foundation for the identification of the distinct mutational and molecular patterns such as succinate dehydrogenase (SDH)-deficient RCC, fumarate hydratase (FH)-deficient RCC, and translocation RCC, so that clinicians can create a more personalized approach to their clinical management. Particularly for the rare non-papillary RCC variant histologies, clinical trial representation is lacking. In the discussed studies, no histology enrolled more than 29 patients of any particular RCC aside from Papillary. As such, evidence-based management decisions can be challenging to make for this patient population., Methods: We have collected the most up-to-date available evidence to describe the pathophysiology, molecular, and pathologic characteristics of the more commonly seen non-clear cell RCC variants, including papillary, chromophobe, translocation, FH-deficient, as well as a group of "unclassified" RCCs. Additionally, we provide an overview of the available evidence from recent clinical trials for non-clear cell RCC and current treatment paradigms., Key Content and Findings: The diagnostic approach for renal malignancies is rapidly changing, favoring a more molecular and genetically based approach. These techniques will allow for a more detailed understanding of the clinical behavior of these cancers. Most data for non-clear cell RCC are from single-arm phase 2 clinical trials. The clinical response to vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) varies greatly by histology., Conclusions: Molecularly targeted therapy as monotherapy or when combined with immunotherapy have efficacy in non-clear cell RCC, though there are differences in treatment response by histology., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-737/coif). D.K. has received grants from Exelixis and Genentech, consulting fees from Exelixis, Janssen, Pfizer, Eisai, and honoraria from Janssen, Aveo, MJH Life Science, and Astellas. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Puerto Rican (PR) Hispanic/Latino (H/L) men are an understudied population that has the highest prostate cancer (PCa) specific mortality among other Hispanic populations. Little information is known about the higher mortality in PR H/L men. It is thought that epigenetic changes in key genes may play a critical role in aggressive tumors. We aimed to identify key 5-hydroxymethylcytosine (5hmC) changes in PR H/L men with aggressive PCa. We performed sequencing analysis using the 5hmC-enriched DNA from 22 prostate tumors and 24 adjacent normal FFPE samples. We identified 808 differentially methylated genes (DMGs) in tumors compared to adjacent normal tissues (FDR<0.05, log2FC>|0.4|). Pathway analysis of DMGs demonstrated that DNA repair pathway was most upregulated in tumors. Since 5hmC abundance positively correlates with gene expression levels, we further investigated 808 DMGs in TCGA PCa gene expression data. Further, we identified 59 DMGs (80.1%, FDR<0.05, ΔGE (gene expression) >|1|) with significant gene expression changes in the same direction. Additionally, we identified 111 aggressiveness-related DMGs, of which, two hypomethylated genes ( CCDC122 , NUDT15 ) and four hypermethylated genes ( PVT1 , RPL30 , TRMT12 , UBR5 ) were found to be altered at transcriptomic level in a concordant manner in PR H/L PCa patients (N=86). The aberrant 5hmC (N=55) and GE (N=497) changes in these six genes were also associated with progression-free survival in the mixed PCa population. In conclusion, our study identified 59 DMGs showing concordant epigenetic and transcriptomic changes in tumor tissues and 111 DMGs showing association with aggressive PCa among PR H/L men.

Background: Currently, no biomarkers are available to identify resistance to androgen-deprivation therapies (ADT) in men with hormone-naive prostate cancer. Since 5-hydroxymethylcytosines (5hmC) in gene body are associated with gene activation, in this study, we evaluated whether 5hmC signatures in cell-free DNA (cfDNA) predicts early resistance to ADT., Results: We collected a total of 139 serial plasma samples from 55 prostate cancer patients receiving ADT at three time points including baseline (prior to initiating ADT, N=55), 3-month (after initiating ADT, N=55), and disease progression (N=15) within 24 months or 24-month if no progression was detected (N=14). To quantify 5hmC abundance across the genome, we used selective chemical labeling sequencing and mapped sequence reads to individual genes. Differential methylation analysis in baseline samples identified significant 5hmC difference in 1,642 of 23,433 genes between patients with and without progression (false discovery rate, FDR<0.1). Patients with disease progression showed significant 5hmC enrichments in multiple hallmark gene sets with androgen responses as top enriched gene set (FDR=1.19E-13). Interestingly, this enrichment was driven by a subgroup of patients featuring a significant 5hmC hypermethylation in the gene sets involving AR , FOXA1 and GRHL2 . To quantify overall activities of these gene sets, we developed a gene set activity scoring algorithm and observed significant association of high activity scores with poor progression-free survival (P<0.05). Longitudinal analysis showed that the high activity scores were significantly reduced after 3-months of initiating ADT (P<0.0001) but returned to higher levels when the disease was progressed (P<0.05)., Conclusions: This study demonstrates that 5hmC-based activity scores from gene sets involved in AR , FOXA1 and GRHL2 may be used as biomarkers to determine early treatment resistance, monitor disease progression, and potentially identify patients who would benefit from upfront treatment intensification.

Background: Even though cytoreductive nephrectomy (CN) was once the standard of care for patients with advanced renal cell carcinoma (RCC), its role in treatment has not been well analyzed or defined in the era of immunotherapy (IO)., Materials and Methods: This study analyzed pathological outcomes in patients with advanced or metastatic RCC who received IO prior to CN. This was a multi-institutional, retrospective study of patients with advanced or metastatic RCC. Patients were required to receive IO monotherapy or combination therapy prior to radical or partial CN. The primary endpoint assessed surgical pathologic outcomes, including American Joint Committee on Cancer (AJCC) staging and frequency of downstaging, at the time of surgery. Pathologic outcomes were correlated to clinical variables using a Wald-chi squared test from Cox regression in a multi-variable analysis. Secondary outcomes included objective response rate (ORR) defined by response evaluation criteria in solid tumors (RECIST) version 1.1 and progression-free survival (PFS), which were estimated using the Kaplan-Meier method with reported 95% CIs., Results: Fifty-two patients from 9 sites were included. Most patients were male (65%), 81% had clear cell histology, 11% had sarcomatoid differentiation. Overall, 44% of patients experienced pathologic downstaging, and 13% had a complete pathologic response. The ORR immediately prior to nephrectomy was stable disease in 29% of patients, partial response in 63%, progressive disease in 4%, and 4% unknown. Median follow-up for the entire cohort was 25.3 months and median PFS was 3.5 years (95% CI, 2.1-4.9)., Conclusions: IO-based interventions prior to CN in patients with advanced or metastatic RCC demonstrates efficacy, with a small fraction of patients showing a complete response. Additional prospective studies are warranted to investigate the role of CN in the modern IO-era., (© The Author(s) 2023. Published by Oxford University Press.)

Background: KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study evaluating pembrolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC). Results from cohorts 4 (C4) and 5 (C5) are presented., Methods: Eligible patients had not received chemotherapy for mCRPC and had responded to enzalutamide prior to developing resistance as defined by Prostate Cancer Clinical Trials Working Group 3 guidelines. Patients with RECIST-measurable disease were enrolled in C4, and patients with bone-only or bone-predominant disease were enrolled in C5. All patients received pembrolizumab 200 mg every 3 weeks for ≤35 cycles with ongoing enzalutamide until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate (ORR) per RECIST v1.1 by blinded independent central review in C4. Secondary end points included disease control rate (DCR), overall survival, and safety in each cohort and both cohorts combined., Results: A total of 126 patients were treated (C4, n = 81; C5, n = 45). Median age was 72 years (range 43-92), and 87.3% had received ≥6 months of enzalutamide prior to study entry. Confirmed ORR was 12.3% (95% CI 6.1-21.5%) for C4. Median duration of response in C4 was 8.1 months (range, 2.5+ to 15.2), and 5 of these patients experienced an objective response lasting ≥6 months. DCR was 53.1% (95% CI 41.7-64.3%) in C4 and 51.1% (95% CI 35.8-66.3%) in C5. Median overall survival was 17.6 months (95% CI 14.0-22.6) in C4 and 20.8 months (95% CI 14.1-28.9) in C5. Grade ≥3 treatment-related adverse events occurred in 35 patients (27.8%); 2 patients in C4 died from immune-related adverse events (myasthenic syndrome and Guillain-Barré syndrome)., Conclusions: The addition of pembrolizumab to ongoing enzalutamide treatment in patients with mCRPC that progressed on enzalutamide after initial response demonstrated modest antitumor activity with a manageable safety profile., Clinical Trial Registry and Id: ClinicalTrials.gov, NCT02787005., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: Outcomes data for DNA-damaging therapeutics for men with prostate cancer (PC) and non- BRCA1/2 homologous recombination repair (HRR) mutations are limited. We evaluated outcomes by HRR alteration in men with PC treated with poly(ADP-ribose)polymerase inhibitors (PARPi) and/or platinum chemotherapy., Methods: Retrospective data from the PROMISE consortium were used. Clinical outcomes differences were assessed between patients with BRCA1 / 2 mutations (cohort A) and those with HRR mutations without direct BRCA complex interaction (cohort B: ATM , CDK12 , CHEK1 , CHEK2 , and FANCL ). Outcomes in patients with HRR mutations with direct BRCA complex interaction were also explored (cohort C: RAD51B/C/D , RAD54L2 , BARD1 , GEN1 , PALB2 , FANCA , and BRIP1 )., Results: One hundred and forty-six patients received PARPi (cohort A: 94, cohort B: 45, cohort C: 7) and 104 received platinum chemotherapy (cohort A: 48, cohort B: 44, cohort C: 10). PSA50 response rate to PARPi was higher in cohort A (61%) than cohort B (5%), P < .001. Median clinical/radiographic progression-free survival (crPFS) with PARPi in cohort A was significantly longer than in cohort B: 15.9 versus 8.7 months, P = .005. PSA50 response rate to platinum therapy was higher in cohort A (62%) than in cohort B (32%), P = .024, although crPFS was not significantly different. PSA50 response rate to PARPi and platinum was 40% and 32%, respectively, in cohort C. In multivariable analysis, cohort A had significantly improved overall survival and crPFS compared with cohort B with PARPi but not platinum chemotherapy., Conclusion: Patients with BRCA1/2 -mutated PC had significantly improved outcomes to PARPi but not platinum chemotherapy compared with those with HRR mutations without direct BRCA complex interaction.

Background: Aberrant Wnt signaling has been implicated in prostate cancer tumorigenesis and metastasis in preclinical models but the impact of genetic alterations in Wnt signaling genes in men with advanced prostate cancer is unknown., Methods: We utilized the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) clinical-genomic database for this retrospective analysis. Patients with activating mutations in CTNNB1 or RSPO2 or inactivating mutations in APC, RNF43, or ZNRF3 were defined as Wnt-altered, while those lacking such alterations were defined as Wnt non-altered. We compared patient characteristics and clinical outcomes as well as co-occurring genetic alterations according to Wnt alteration status., Results: Of the 1498 patients included, 193 (12.9%) were Wnt-altered. These men had a statistically significant 2-fold increased prevalence of liver and lung metastases as compared with Wnt non-altered patients at the time of initial diagnosis, (4.66% v 2.15% ; 6.22% v 3.07%), first metastatic disease diagnosis (10.88% v 5.29%; 13.99% v 6.21%), and CRPC development (11.40% v 6.36%; 12.95% v 5.29%). Wnt alterations were associated with more co-occurring alterations in RB1 (10.4% v 6.2%), AR (38.9% vs 25.7%), SPOP (13.5% vs 4.1%), FOXA1 (6.7% vs 2.8%), and PIK3CA (10.9% vs 5.1%). We found no significant differences in overall survival or other clinical outcomes from initial diagnosis, first metastatic disease, diagnosis of CRPC, or with AR inhibition for mCRPC between the Wnt groups., Conclusions: Wnt-altered patients with prostate cancer have a higher prevalence of visceral metastases and are enriched in RB1, AR, SPOP, FOXA1, and PIK3CA alterations. Despite these associations, Wnt alterations were not associated with worse survival or treatment outcomes in men with advanced prostate cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: There are limited data available on the real-world patterns of molecular testing in men with advanced prostate cancer. We thus sought to evaluate next-generation sequencing (NGS) testing in the United States, focused on single versus serial NGS testing, the different disease states of testing (hormone-sensitive v castration-resistant, metastatic vs nonmetastatic), tissue versus plasma circulating tumor DNA (ctDNA) assays, and how often actionable data were found on each NGS test., Methods: The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort clinical-genomic database was used for this retrospective analysis, including 1,597 patients across 15 institutions. Actionable NGS data were defined as including somatic alterations in homologous recombination repair genes, mismatch repair deficiency, microsatellite instability (MSI-high), or a high tumor mutational burden ≥10 mut/MB., Results: Serial NGS testing (two or more NGS tests with specimens collected more than 60 days apart) was performed in 9% (n = 144) of patients with a median of 182 days in between test results. For the second NGS test and beyond, 82.1% (225 of 274) of tests were from ctDNA assays and 76.1% (217 of 285) were collected in the metastatic castration-resistant setting. New actionable data were found on 11.1% (16 of 144) of second NGS tests, with 3.5% (5 of 144) of tests detecting a new BRCA2 alteration or MSI-high. A targeted therapy (poly (ADP-ribose) polymerase inhibitor or immunotherapy) was given after an actionable result on the second NGS test in 31.3% (5 of 16) of patients., Conclusion: Repeat somatic NGS testing in men with prostate cancer is infrequently performed in practice and can identify new actionable alterations not present with initial testing, suggesting the utility of repeat molecular profiling with tissue or blood of men with metastatic castration-resistant prostate cancer to guide therapy choices.