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BackgroundThe large registry, PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED)(NCT01306890), evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).MethodsPROCEED enrolled patients with mCRPC receiving 3 biweekly sipuleucel-T infusions. Assessments included overall survival (OS), serious adverse events (SAEs), cerebrovascular events (CVEs), and anticancer interventions (ACIs). Follow-up was for ≥3 years or until death or study withdrawal.ResultsIn 2011-2017, 1976 patients were followed for 46.6 months (median). The median age was 72 years, and the baseline median prostate-specific antigen level was 15.0 ng/mL; 86.7% were white, and 11.6% were African American. Among the patients, 1902 had 1 or more sipuleucel-T infusions. The median OS was 30.7 months (95% confidence interval [CI], 28.6-32.2 months). Known prognostic factors were independently associated with OS in a multivariable analysis. Among the 1255 patients who died, 964 (76.8%) died of prostate cancer (PC) progression. The median time from the first infusion to PC death was 42.7 months (95% CI, 39.4-46.2 months). The incidence of sipuleucel-T-related SAEs was 3.9%. The incidence of CVEs was 2.8%, and the rate per 100 person-years was 1.2 (95% CI, 0.9-1.6). The CVE incidence among 11,972 patients with mCRPC from the Surveillance, Epidemiology, and End Results-Medicare database was 2.8%; the rate per 100 person-years was 1.5 (95% CI, 1.4-1.7). One or more ACIs (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium 223) were received by 77.1% of the patients after sipuleucel-T; 32.5% and 17.4% of the patients experienced 1- and 2-year treatment-free intervals, respectively.ConclusionsPROCEED provides contemporary survival data for sipuleucel-T-treated men in a real-world setting of new life-prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel-T. The safety and tolerability of sipuleucel-T in PROCEED were consistent with previous findings.

PURPOSE: 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. [ABSTRACT FROM AUTHOR]

Androgen-receptor signaling inhibitors (ARSI) such abiraterone and enzalutamide have significantly improved clinical outcomes in patients with metastatic castrate-resistant prostate cancer (mCRPC). However, patients with genomic alterations in androgen receptor (AR) and its enhancer region do not respond well and acquire resistance to these inhibitors. We previously developed a cell-free DNA (cfDNA) liquid biopsy assay (EnhanceAR-Seq) that can detect alterations in AR locus including the upstream enhancer. Here, we applied this assay to detect AR/enhancer alterations in mCRPC patients prior to the administration of first-line AR-directed therapy and correlated with survival. We applied EnhanceAR-Seq to plasma cfDNA isolated from 94 mCRPC patients enrolled independently from Washington University in St. Louis (n = 51) and Tulane University (n = 43). Plasma samples were collected prior to initiation of AR-targeted therapy (n = 60) and during treatment (n = 34). EnhanceAR-Seq detected AR/enhancer alterations in 31% of all plasma samples analyzed. Presence of AR/enhancer alterations was highly prognostic for worse survival (PFS p = 0.0002; OS: p = 0.04). In subset analysis, AR/enhancer alterations detected in 37% of samples collected prior to first-line ARSI treatment correlated significantly with worse PFS (p = 0.02; HR = 2.23) and worse OS trending toward significance (p = 0.10). Furthermore, AR/enhancer alterations detected in 21% of samples collected during AR-directed therapy was also associated with worse PFS (p = 0.0005) and OS (p = 0.02). AR/enhancer alterations detected in pre-treatment and on-treatment plasma cfDNA predicted worse survival in mCRPC patients, which has important diagnostic and therapeutic implications. [ABSTRACT FROM AUTHOR]