Intensifying Salvage Therapy in Prostate-specific Antigen Recurrent Prostate Cancer After Radical Prostatectomy with Apalutamide, Salvage Radiation, and Docetaxel: The Phase 2 STARTAR Trial.

BACKGROUND AND OBJECTIVE: Androgen deprivation therapy (ADT) with salvage radiation therapy (RT) improves survival for patients with prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP) for prostate cancer (PC), but many patients suffer further relapse. This study aims to determine the benefit of the combination of ADT, apalutamide, salvage RT, and docetaxel for high-risk PSA recurrent PC. METHODS: STARTAR is a multicenter, investigator-initiated phase 2 trial of men with PSA recurrent PC after RP. The key inclusion criteria included M0 by computed tomography/bone scan, Gleason 7 with either T3/positive margin/N1 disease or Gleason 8-10 prostate adenocarcinoma, PSA relapse (0.2-4 ng/ml) <4 yr after RP, and fewer than four positive resected lymph nodes. Patients received ADT with apalutamide for 9 mo, RT starting week 8, and then six cycles of docetaxel. The primary endpoint was 36-mo progression-free survival (PFS) with testosterone recovery and compared against the prior STREAM trial. KEY FINDINGS AND LIMITATIONS: We enrolled 39 men, including those with Gleason 8-10 (46%), pN1 (23%); the median PSA was 0.58 ng/ml. The median follow-up was 37 mo. All patients achieved undetectable PSA nadir. At 24 and 36 mo, PFS rates were 84% and 71%, respectively, which improved significantly over 3-yr 47% historic PFS and 54% enzalutamide/ADT/RT (STREAM) PFS rates (p = 0.004 and p = 0.039, respectively). Common any-grade adverse events included 98% hot flashes, 88% fatigue, 77% alopecia, 53% rash (10% G3), and 5% febrile neutropenia. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this phase 2 trial of ADT, apalutamide, salvage RT, and six cycles of docetaxel for high-risk PSA recurrence, the 3-yr PFS rate improved to 71%, indicating feasible and efficacious treatment intensification, with durable remissions beyond historic data. PATIENT SUMMARY: Prostate cancer recurrence after surgical removal of the tumor occurs often, and current treatment options to limit recurrence after surgery are only partially effective. In this study, we found that the addition of an androgen receptor inhibitor and docetaxel chemotherapy to standard postsurgery radiation therapy and androgen deprivation therapy significantly improved progression-free survival at 3 yr after treatment. These results suggest that intensification of treatment after surgery can provide long-term benefit to a subset of patients with high-risk prostate cancer.

Emerging racial disparities among Medicare beneficiaries and Veterans with metastatic castration-sensitive prostate cancer.

BACKGROUND: Previous studies have shown that Black men receive worse prostate cancer care than White men. This has not been explored in metastatic castration-sensitive prostate cancer (mCSPC) in the current treatment era. METHODS: We evaluated treatment intensification (TI) and overall survival (OS) in Medicare (2015-2018) and Veterans Health Administration (VHA; 2015-2019) patients with mCSPC, classifying first-line mCSPC treatment as androgen deprivation therapy (ADT) + novel hormonal therapy; ADT + docetaxel; ADT + first-generation nonsteroidal antiandrogen; or ADT alone. RESULTS: We analyzed 2226 Black and 16,071 White Medicare, and 1020 Black and 2364 White VHA patients. TI was significantly lower for Black vs White Medicare patients overall (adjusted odds ratio [OR] 0.68; 95% confidence interval [CI] 0.58-0.81) and without Medicaid (adjusted OR 0.70; 95% CI 0.57-0.87). Medicaid patients had less TI irrespective of race. OS was worse for Black vs White Medicare patients overall (adjusted hazard ratio [HR] 1.20; 95% CI 1.09-1.31) and without Medicaid (adjusted HR 1.13; 95% CI 1.01-1.27). OS was worse in Medicaid vs without Medicaid, with no significant OS difference between races. TI was significantly lower for Black vs White VHA patients (adjusted OR 0.75; 95% CI 0.61-0.92), with no significant OS difference between races. CONCLUSIONS: Guideline-recommended TI was low for all patients with mCSPC, with less TI in Black patients in both Medicare and the VHA. Black race was associated with worse OS in Medicare but not the VHA. Medicaid patients had less TI and worse OS than those without Medicaid, suggesting poverty and race are associated with care and outcomes.

NCCN Guidelines® Insights: Prostate Cancer, Version 3.2024.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

Toward Informed Selection and Interpretation of Clinical Genomic Tests in Prostate Cancer.

Clinical genomic testing of patient germline, tumor tissue, or plasma cell-free DNA can enable a personalized approach to cancer management and treatment. In prostate cancer (PCa), broad genotyping tests are now widely used to identify germline and/or somatic alterations in BRCA2 and other DNA damage repair genes. Alterations in these genes can confer cancer sensitivity to poly (ADP-ribose) polymerase inhibitors, are linked with poor prognosis, and can have potential hereditary cancer implications for family members. However, there is huge variability in genomic tests and reporting standards, meaning that for successful implementation of testing in clinical practice, end users must carefully select the most appropriate test for a given patient and critically interpret the results. In this white paper, we outline key pre- and post-test considerations for choosing a genomic test and evaluating reported variants, specifically for patients with advanced PCa. Test choice must be based on clinical context and disease state, availability and suitability of tumor tissue, and the genes and regions that are covered by the test. We describe strategies to recognize false positives or negatives in test results, including frameworks to assess low tumor fraction, subclonal alterations, clonal hematopoiesis, and pathogenic versus nonpathogenic variants. We assume that improved understanding among health care professionals and researchers of the nuances associated with genomic testing will ultimately lead to optimal patient care and clinical decision making.

Low-dose Paclitaxel with Pembrolizumab Enhances Clinical and Immunologic Responses in Platinum-refractory Urothelial Carcinoma.

PURPOSE: Single-agent checkpoint inhibition is effective in a minority of patients with platinum-refractory urothelial carcinoma; therefore, the efficacy of combining low-dose paclitaxel with pembrolizumab was tested. MATERIALS AND METHODS: This was a prospective, single-arm phase II trial with key inclusion criteria of imaging progression within 12 months of platinum therapy and Eastern Cooperative Oncology Group ≤1. Treatment was pembrolizumab 200 mg day 1 and paclitaxel 80 mg/m2 days 1 and 8 of a 21-day cycle for up to eight cycles unless progression or unacceptable adverse events (AE). The primary endpoint was overall response rate (ORR) with overall survival (OS), 6-month progression-free survival (PFS), and safety as key secondary endpoints. Change in circulating immune cell populations, plasma, and urinary miRs were evaluated. RESULTS: Twenty-seven patients were treated between April 2016 and June 2020, with median follow-up of 12.4 months. Baseline median age was 68 years, with 81% men and 78% non-Hispanic White. ORR was 33% by intention to treat and 36% in imaging-evaluable patients with three complete responses. Six-month PFS rate was 48.1% [95% confidence interval (CI): 28.7-65.2] and median OS 12.4 months (95% CI: 8.7 months to not reached). Common ≥ grade 2 possibly-related AEs were anemia, lymphopenia, hyperglycemia, and fatigue; grade 3/4 AEs occurred in 56%, including two immune-mediated AEs (pneumonitis and nephritis). Responding patients had a higher percentage of circulating CD4+IFNγ+ T cells. Levels of some miRs, including plasma miR 181 and miR 223, varied in responders compared with nonresponders. CONCLUSIONS: The addition of low-dose paclitaxel to pembrolizumab is active and safe in platinum-refractory urothelial carcinoma. SIGNIFICANCE: We found that combining pembrolizumab with low-dose paclitaxel may be effective in patients with urothelial carcinoma progressing on platinum chemotherapy, with favorable safety profiles.

Marital Status, Living Arrangement, and Survival among Individuals with Advanced Prostate Cancer in the International Registry for Men with Advanced Prostate Cancer.

BACKGROUND: Studies have shown improved survival among individuals with cancer with higher levels of social support. Few studies have investigated social support and overall survival (OS) in individuals with advanced prostate cancer in an international cohort. We investigated the associations of marital status and living arrangements with OS among individuals with advanced prostate cancer in the International Registry for Men with Advanced Prostate Cancer (IRONMAN). METHODS: IRONMAN is enrolling participants diagnosed with advanced prostate cancer (metastatic hormone-sensitive prostate cancer, mHSPC; castration-resistant prostate cancer, CRPC) from 16 countries. Participants in this analysis were recruited between July 2017 and January 2023. Adjusting for demographics and tumor characteristics, the associations were estimated using Cox regression and stratified by disease state (mHSPC, CRPC), age (<70, ≥70 years), and continent of enrollment (North America, Europe, Other). RESULTS: We included 2,119 participants with advanced prostate cancer, of whom 427 died during up to 5 years of follow-up (median 6 months). Two-thirds had mHSPC. Most were married/in a civil partnership (79%) and 6% were widowed. Very few married participants were living alone (1%), while most unmarried participants were living alone (70%). Married participants had better OS than unmarried participants [adjusted HR: 1.44; 95% confidence interval (CI): 1.02-2.02]. Widowed participants had the worst survival compared with married individuals (adjusted HR: 1.89; 95% CI: 1.22-2.94). CONCLUSIONS: Among those with advanced prostate cancer, unmarried and widowed participants had worse OS compared with married participants. IMPACT: This research highlighted the importance of social support in OS within this vulnerable population.

Genomic classifiers and prognosis of localized prostate cancer: a systematic review.

BACKGROUND: Refinement of the risk classification for localized prostate cancer is warranted to aid in clinical decision making. A systematic analysis was undertaken to evaluate the prognostic ability of three genomic classifiers, Decipher, GPS, and Prolaris, for biochemical recurrence, development of metastases and prostate cancer-specific mortality in patients with localized prostate cancer. METHODS: Data sources: MEDLINE, Embase, and Web of Science were queried for reports published from January 2010 to April 2022. STUDY SELECTION: prospective or retrospective studies reporting prognosis for patients with localized prostate cancer. DATA EXTRACTION: relevant data were extracted into a customized database by one researcher with a second overreading. Risk of bias was assessed using a validated tool for prognostic studies, Quality in Prognosis Studies (QUIPS). Disagreements were resolved by consensus or by input from a third reviewer. We assessed the certainty of evidence by GRADE incorporating adaptation for prognostic studies. RESULTS: Data synthesis: a total of 39 studies (37 retrospective) involving over 10,000 patients were identified. Twenty-two assessed Decipher, 5 GPS, and 14 Prolaris. Thirty-four studies included patients who underwent prostatectomy. Based on very low to low certainty of evidence, each of the three genomic classifiers modestly improved upon the prognostic ability for biochemical recurrence, development of metastases, and prostate cancer-specific mortality compared to standard clinical risk-classification schemes. LIMITATIONS: downgrading of confidence in the evidence stemmed largely from bias due to the retrospective nature of the studies, heterogeneity in treatment received, and era in which patients were treated (i.e., prior to the 2000s). CONCLUSIONS: Genomic classifiers provide a small but consistent improvement upon the prognostic ability of clinical classification schemes, which may be helpful when treatment decisions are uncertain. However, evidence from current management-era data and of the predictive ability of these tests is needed.