PURPOSE: The standard of care for metastatic castration-resistant prostate cancer (mCRPC) after second-generation androgen receptor pathway inhibitor (ARPI) therapy is still docetaxel. The randomized, double-blind, phase III KEYNOTE-921 trial (Clinicaltrials.gov identifier: NCT03834506 ) evaluated the efficacy and safety of pembrolizumab or placebo plus docetaxel for previously treated mCRPC. METHODS: Adults with mCRPC who progressed after androgen-deprivation therapy and one ARPI were randomly assigned 1:1 to pembrolizumab or placebo plus docetaxel with concomitant prednisone. Dual primary end points were radiographic progression-free survival (rPFS) by blinded independent central review per Prostate Cancer Working Group 3–modified RECIST 1.1 and overall survival (OS). Safety was a secondary end point. RESULTS: Between May 30, 2019, and June 17, 2021, 515 participants were randomly assigned to pembrolizumab plus docetaxel and 515 to placebo plus docetaxel. Median time from random assignment to data cutoff date (June 20, 2022) at final analysis (FA) was 22.7 months (range, 12.1-36.7). At first interim analysis (data cutoff date: September 27, 2021), median rPFS was 8.6 months (95% CI, 8.3 to 10.2) with pembrolizumab plus docetaxel versus 8.3 months (95% CI, 8.2 to 8.5) with placebo plus docetaxel (hazard ratio [HR], 0.85 [95% CI, 0.71 to 1.01]; P = .03). At FA, median OS was 19.6 months (95% CI, 18.2 to 20.9) versus 19.0 months (95% CI, 17.9 to 20.9), respectively (HR, 0.92 [95% CI, 0.78 to 1.09]; P = .17). Grade ≥3 treatment-related adverse events occurred in 43.2% of participants who received pembrolizumab plus docetaxel and 36.6% of participants who received placebo plus docetaxel. Two and seven participants, respectively, died due to a treatment-related adverse event. Pneumonitis was the most common immune-mediated adverse event (7.0% v 3.1%). CONCLUSION: The addition of pembrolizumab to docetaxel did not significantly improve efficacy outcomes for participants with previously treated mCRPC. The current standard of care remains unchanged.

Established first- and second-line standard-of-care treatment options (abiraterone, enzalutamide, taxane chemotherapy) are available for patients with metastatic castration-resistant prostate cancer (mCRPC), but almost all patients experience subsequent disease progression. The randomized, double-blind, phase III KEYNOTE-641 study evaluated pembrolizumab plus enzalutamide versus placebo plus enzalutamide in participants with chemotherapy-naive mCRPC. Eligible participants were males aged ≥18 years with confirmed mCRPC and no prior chemotherapy except docetaxel in the hormone-sensitive setting. Prior abiraterone treatment was permitted. Participants were randomly assigned 1:1 to receive pembrolizumab 200 mg or placebo intravenously once every 3 weeks for ≤35 cycles plus enzalutamide 160 mg orally daily. Dual primary end points were overall survival (OS) and radiographic progression-free survival (rPFS) per Prostate Cancer Clinical Trials Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review. Safety was a secondary end point. Between 21 August 2019, and 10 June 2022, 1244 participants were randomly assigned to pembrolizumab plus enzalutamide (n = 621) or placebo plus enzalutamide (n = 623). At the data cut-off date (12 December 2022), median follow-up was 27.6 months (range, 6.1-39.8 months). Primary end points of OS [median, 24.7 versus 27.3 months; hazard ratio (HR) 1.04, 95% confidence interval (CI) 0.88-1.22, P = 0.66] and rPFS (median, 10.4 versus 9.0 months; HR 0.98, 95% CI 0.84-1.14, P = 0.41) with pembrolizumab plus enzalutamide versus placebo plus enzalutamide were not met. The prespecified boundary for futility for OS was crossed, and the study was stopped. Grade ≥3 treatment-related adverse events occurred in 192 of 615 participants (31.2%) with one or more doses of pembrolizumab plus enzalutamide and in 67 of 620 participants (10.8%) with one or more doses of placebo plus enzalutamide. Seventy-one (11.5%) and 21 (3.4%) participants, respectively, discontinued study treatment due to treatment-related adverse events. Adding pembrolizumab to enzalutamide did not improve efficacy outcomes for participants with chemotherapy-naive mCRPC. Additional toxicity was observed with the combination regimen.

The androgen signaling pathway is the cornerstone in the treatment of high risk or advanced prostate cancer patients. However, in recent years, different mechanisms of resistance have been defined in this field, limiting the efficacy of the currently approved antiandrogen drugs. Different therapeutic approaches are under research to assess the role of combination therapies against escape signaling pathways or the development of novel antiandrogen drugs to try to solve the primary or acquired resistance against androgen dependent or independent pathways. The present review aims to summarize the current state of androgen inhibition in the therapeutic algorithm of patients with advanced prostate cancer and the mechanisms of resistance to those available drugs. In addition, this review conducted a comprehensive overview of the main present and future research approaches in the field of androgen receptor inhibition to overcome these resistances and the potential new drugs under research coming into this setting.

Despite treatment advances, most patients with metastatic hormone-sensitive prostate cancer (mHSPC) experience disease progression to castration-resistant disease within 5 years. The placebo-controlled, double-blind, phase III KEYNOTE-991 study evaluated the efficacy and safety of adding pembrolizumab to enzalutamide and androgen deprivation therapy (ADT) in participants with mHSPC. Eligible participants were aged ≥18 years with next-generation hormonal agent-naive mHSPC. Participants were randomly assigned (1 : 1) to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for ≤35 cycles, with oral enzalutamide 160 mg and continuous ADT. Primary endpoints were radiographic progression-free survival (rPFS) and overall survival (OS). Safety was a secondary endpoint. Between 2 March 2020 and 9 August 2021, 626 participants were randomly assigned to receive pembrolizumab plus enzalutamide and ADT and 625 participants to receive placebo plus enzalutamide and ADT. At the first interim analysis, the median follow-up was 21.1 months (range 14.8-32.0 months). rPFS was not superior with pembrolizumab versus placebo [median not reached in both arms; hazard ratio (HR) 1.20, 95% confidence interval (CI) 0.96-1.49, P = 0.9467]. Median OS was not reached in either arm (HR 1.16, 95% CI 0.88-1.53; not formally statistically tested as per the multiplicity strategy). Grade ≥3 adverse events (AEs) and serious AEs (SAEs) were reported in 61.9% versus 38.1% and 40.3% versus 23.2% of participants in the pembrolizumab versus the placebo arm, respectively. Any-grade rash occurred at a higher frequency with pembrolizumab (25.1%) versus placebo (9.3%). KEYNOTE-991 did not meet its primary endpoint and was stopped for futility. The addition of pembrolizumab to enzalutamide and ADT was associated with higher frequencies of grade ≥3 AEs and SAEs than with placebo. Rash was identified as an additional safety signal with pembrolizumab plus enzalutamide and ADT.