Comprehensive Genomic Profiling of Cell-Free DNA in Men With Advanced Prostate Cancer: Differences in Genomic Landscape Based on Race.

Advanced prostate cancer (aPC) in Black men was reported to present with aggressive features and to be associated with poor prognosis. Herein, we compared the cell-free DNA (cfDNA) genomic landscape of aPC in Black vs White men. Patients (pts) with aPC from 6 academic institutions and available cfDNA comprehensive genomic profiling (CGP) were included. Association between mutated genes and race was evaluated using Barnard's test and a Probabilistic Graphical Model (PGM) machine learning approach. Analysis included 743 aPC pts (217 Black, 526 White) with available cfDNA CGP. The frequency of alterations in the androgen receptor gene was significantly higher in Black vs White men (55.3% vs 35% respectively, P < .001). Additionally, alterations in EGFR, MYC, FGFR1, and CTNNB1 were present at higher frequencies in Black men. PGM analysis and Barnard's test were concordant. Findings from the largest cohort of Black men with aPC undergoing cfDNA CGP may guide further drug development in these men.

Radium-223 plus Enzalutamide Versus Enzalutamide in Metastatic Castration-Refractory Prostate Cancer: Final Safety and Efficacy Results.

LESSONS LEARNED: Long-term safety of radium-223 with enzalutamide was confirmed in this clinical trial. PSA-PFS2 was prolonged with the combination compared with enzalutamide alone. BACKGROUND: Previously, we showed the combination of radium-223 and enzalutamide to be safe and associated with improved efficacy based on a concomitant decline in serum bone metabolism markers compared with enzalutamide alone in a phase II trial of men with metastatic castration-resistant prostate cancer (mCRPC) [1]. METHODS: Secondary endpoints were not included in our initial report, and we include them herein, after a median follow-up of 22 months. These objectives included long-term safety, prostate-specific antigen (PSA)-progression-free survival (PFS), and radiographic progression-free survival; PSA-PFS2 (time from start of protocol therapy to PSA progression on subsequent therapy); time to next therapy (TTNT); and overall survival (OS). Survival analysis and log-rank tests were performed using the R statistical package v.4.0.2 (https://www.r-project.org). Statistical significance was defined as p < .05. RESULTS: Of 47 patients (median age, 68 years), 35 received the combination and 12 enzalutamide alone. After a median follow-up of 22 months, final safety results did not show any increase in fractures or other adverse events in the combination arm. PSA-PFS2 was significantly improved, and other efficacy parameters were numerically improved in the combination over the enzalutamide arm. CONCLUSION: The combination of enzalutamide and radium-223 was found to be safe and associated with promising efficacy in men with mCRPC. These hypothesis-generating results portend well for the ongoing phase III PEACE III trial in this setting.

Comparative Effectiveness of Immune Checkpoint Inhibitors in Patients with Platinum Refractory Advanced Urothelial Carcinoma.

PURPOSE: Five programmed cell death protein 1 or its ligand (L1) inhibitors are approved for treatment of platinum refractory, locally advanced/unresectable or metastatic urothelial carcinoma. However, their comparative effectiveness is unknown. We compared time to initiation of third therapy or death, and overall survival with different programmed cell death protein 1/L1 inhibitors in patients with platinum refractory metastatic urothelial carcinoma. MATERIALS AND METHODS: Patient-level data were extracted from a real-world de-identified database. Comparative effectiveness was inferred via Cox proportional hazards model, weighted by matching weights. Each patient's propensity for each treatment was modeled via random forest, based on potential drivers of treatment selection. A propensity score for each therapy was used to calculate a matching weight, targeting the same estimand as 1:1 matching of treatment groups with balance among potential confounders. Eligibility criteria included diagnosis of metastatic urothelial carcinoma, receipt of first line treatment with a platinum based chemotherapy, followed by initiation of single agent programmed cell death protein 1/L1 inhibitor after disease progression from August 1, 2016 through May 1, 2019. RESULTS: Overall, 609 patients were eligible for analysis. Median time to initiation of third therapy or death with atezolizumab, nivolumab and pembrolizumab was 4.2, 5.3 and 4.5 months, respectively, and median overall survival was 6.4, 8.0 and 8.3 months, respectively. Matching weighted analyses did not show strong evidence of differences among programmed cell death protein 1/L1 inhibitors in terms of time to initiation of third therapy or death and overall survival. CONCLUSIONS: In this large real-world cohort, effectiveness in terms of time to initiation of third therapy or death and overall survival with programmed cell death protein 1/L1 inhibitors in patients with platinum refractory locally advanced/unresectable or metastatic urothelial carcinoma was similar.

Radical trachelectomy and adjuvant vaginal brachytherapy to preserve fertility in pediatric cervical adenocarcinoma.

PURPOSE: This case report describes the use of a trachelectomy and adjuvant vaginal brachytherapy for pediatric clear cell adenocarcinoma as definitive fertility-sparing treatment. METHODS AND MATERIALS: A previously healthy 8-year-old female presented with abdominal cramping and heavy vaginal bleeding. Diagnostic imaging revealed a 3.5 cm circumscribed cervical mass, with subsequent biopsy revealing clear cell adenocarcinoma. Fertility preserving treatment was requested. RESULTS: The patient underwent a radical trachelectomy, with final pathology demonstrating a close radial margin. Due to close margin, adjuvant radiotherapy with a vaginal cylinder was delivered to a total dose of 18 Gray in three fractions prescribed to a depth of 5 mm from the vaginal surface using iridium-192. With 2 years of follow-up, the patient continues to do well with no evidence of recurrence or late toxicity from treatment. CONCLUSIONS: Pediatric clear cell adenocarcinoma of the cervix is a rare occurrence that lacks clinical trials to guide effective treatment. Adjuvant vaginal brachytherapy following trachelectomy in a pediatric patient with clear cell adenocarcinoma of the cervix is feasible and well-tolerated.

Current management of metastatic castration-sensitive prostate cancer.

Prostate cancer affects one in nine men and once metastatic is incurable. The treatment for metastatic castration-sensitive prostate cancer (mCSPC) has evolved rapidly over the last decade with the addition of upfront intensification with novel hormonal therapies (abiraterone, enzalutamide, apalutamide) or docetaxel in addition to androgen deprivation therapy. In this review, we discuss the phase III studies that lead to the approval of these upfront intensification therapies. We also review the recent approval of relugolix, the first oral, gonadotropin-releasing hormone antagonist for patients with advanced prostate cancer. A comparison of various agents is made and variables that can help in treatment selection are reviewed. We also summarize our current understanding of the role of germline and somatic alterations in the mCSPC setting. Finally, we review the ongoing clinical trials which can change the current treatment paradigm.

Development of PARP inhibitor combinations for castration resistant prostate cancer unselected for homologous recombination repair mutations.

Genetic instability is a hallmark of cancer and, with the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors, is a targetable feature of many tumors. Currently, two PARP inhibitors, olaparib and rucaparib, have received approval as monotherapy by the Food and Drug Administration for the treatment of men with castration resistant prostate cancer with selected mutations involving the homologous recombination (HR) pathway. However, it is currently debated whether an HR mutation is a prerequisite for response or if patients with HR-proficient mCRPC may also benefit from their use when combined with other targeted or immunotherapeutic agents. Several large phase III trials of PARP inhibitors with novel androgen axis inhibitors in groups of unselected patients are underway. Additionally, there are several early phase trials combining PARP inhibitors with radioligands or immunecheckpoint inhibitors. Here we discuss the currently ongoing or recently concluded trials of PARP inhibitor based combinatorial therapies in unselected patients with mCRPC, the rationale behind these trials, and how these may impact the treatment paradigm in men with mCRPC.

Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer.

Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration-approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied. METHODS: We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with BRCA1/2-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among BRCA1- versus BRCA2-altered mCRPC. RESULTS: A total of 123 patients (13 BRCA1 and 110 BRCA2) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. BRCA1 patients were more likely to have metastatic disease at presentation (69% v 37%; P = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% v 46%; P = .78) in both groups. BRCA1 patients had more monoallelic (56% v 41%; P = .49) and concurrent TP53 (55% v 36%; P = .32) mutations. PSA50 responses in BRCA1- versus BRCA2-altered patients were 23% versus 63%, respectively (P = .01). BRCA2 patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; P = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; P = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; P = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent TP53 mutation were associated with PARP inhibitor sensitivity. CONCLUSION: PARP inhibitor efficacy is diminished in BRCA1- versus BRCA2-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent TP53 alterations in the BRCA1 group.