The treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) continues to evolve rapidly. The 2023 update to the AUA/Society of Urologic Oncology guidelines for patients with mCRPC details the treatment options, including chemotherapy (docetaxel, cabazitaxel, or platinum-based therapy), oral hormonal therapies (abiraterone acetate plus prednisone or enzalutamide), radium-223,¹⁷⁷Lu-PSMA-617, or sipuleucel-T.¹ The National Comprehensive Cancer Network guidelines also recommend germline and/or somatic testing to identify genetic mutation(s) and microsatellite instability status, as this may qualify patients for management with novel immunotherapeutic agents.²

Immunotherapy for advanced cancer has led to improvement in survival with several cancers including head and neck cancers, renal cell carcinoma, melanoma, and lung cancer.³ In particular, immune checkpoint inhibitors such as pembrolizumab have shown excellent efficacy and safety through their targeting of PD-1 (programmed death protein 1)/PD-L1 (programmed death ligand-1)⁴ and CTLA-4 (cytotoxic T-lymphocyte–associated antigen 4).⁵ However, the results in mCRPC have been relatively underwhelming, as prostate cancer is recognized as an immunologically “cold” tumor.^6,7 Early trials with ipilimumab in the postchemotherapy and chemotherapy-naïve settings did not show any survival benefit; however, there was some indication that patients on therapy for more than 1 year may have improved survival and longer progression-free survival.^8,9 Pembrolizumab has also been studied in mCRPC as a monotherapy in several trials, notably in KEYNOTE-199. This was a phase 2 study to determine safety and efficacy in 3 groups, all of whom had received docetaxel and at least 1 targeted endocrine therapy: (1) patients with PD-L1–positive disease; (2) patients with PD-L1–negative disease; and (3) patients with bone-predominant disease, regardless of PD-L1 expression.¹⁰ The objective response rate was 5% in cohort 1 and 3% in cohort 2, and median survival was 9.5 months, 7.9 months, and 14.1 months, respectively, with only 5% of patients discontinuing treatment.¹⁰ Several trials using a combination of immune checkpoint inhibitors have shown similar modest improvements in overall survival and progression-free survival including CheckMate 650,¹¹ CheckMate 9KD,¹² and STARVE-PC.¹³

The most significant results appear to be in tumors with high tumor mutational burden, tumors with mutations in genes involved in homologous recombination repair such as BRCA 1 and 2, CHEK2, ATM, those with deficiencies in mismatch repair pathways, and/or high microsatellite instability. These genetic alterations are common in mCRPC and may be particularly sensitive to poly-(adenosine diphosphate-ribose) polymerase inhibition.¹⁴ Early evidence of this activity was reported by Mateo and colleagues in the TOPARP-A trial published in 2015, where they investigated olaparib in men with previously treated mCRPC. Thirty-three percent of patients had a significant response, which was associated with homozygous deletions or mutations in BRCA 1 and 2, ATM, CHEK2, and Fanconi’s anemia genes.¹⁵ This, among several other studies, led to the approval of olaparib and rucaparib as standard therapies for patients with mCRPC who harbor deleterious genetic alterations in the genes of interest.

The first Food and Drug Administration–approved immunotherapy for mCRPC was in 2010 with advent of sipuleucel-T after publication of the IMPACT trial.¹⁶ Sipuleucel-T is an autologous cellular immunotherapy where a patient’s peripheral blood mononuclear cells are activated with a recombinant prostatic acid phosphatase fusion protein before reinfusion. This resulted in a modest 4.1-month improvement in median survival (HR = 0.78); however, subsequent subset analysis showed an even greater improvement (13.1 months) in men who were treated in the lowest quartile of PSA below 22.1 ng/mL.^16,17 Sipuleucel-T remains a recommended therapeutic option for patients with minimally symptomatic or asymptomatic mCRPC.²

Table. Metastatic Castration-Resistant Prostate Cancer Trials in Recruitment in the US

The future for patients with mCRPC remains hopeful, with several clinical trials for immunotherapy on the horizon (Table). Many of these trials utilize a combination approach to address both the immune and hormonal milieus. As oncologists investigate and discover new treatment paradigms, emphases on clinical efficacy and quality of life will be paramount.