Activity of Platinum Chemotherapy in Men With Prostate Cancer With and Without DNA Damage Repair Mutations

Alterations in genes involved in homologous recombination repair can be seen in 20-30 % of patients with metastatic castration-resistant prostate cancer. Mutations in homologous recombination repair genes may predict clinical benefit to platinum-based chemotherapy. This real-world retrospective study evaluated the efficacy of platinum chemotherapy in 24 men with metastatic castration-resistant prostate cancer with and without homologous recombination repair alterations. Findings did not reveal a difference in anti-tumor activity from platinum chemotherapy in patients with a pathogenic homologous recombination repair alteration compared to patients without an alteration. Platinum therapy may be active in advanced prostate cancer regardless of homologous recombination repair status warranting further research into identifying factors that may predict response to platinum therapy. Introduction: Alterations in homologous recombination repair (HRR) genes occur in 20%-30% of men with metastatic castration-resistant prostate cancer (mCRPC) which may increase sensitivity to platinum chemotherapy. Specifically, exceptional responses to platinum chemotherapy have been reported among patients with BRCA mutations. This study aimed to evaluate the efficacy of platinum chemotherapy in patients with mCRPC with and without HRR. Patient and Methods: In this retrospective, multi-institution series, we analyzed patients with mCRPC to assess response to platinum-containing chemotherapy based on HRR alteration status. Outcome measures were prostate specific antigen (PSA)50 response rate (percentage of patients achieving at least a 50% decline in PSA from baseline), overall survival (OS) and progression-free survival (PFS). Results: From 1999 to 2020, 24 patients with mCRPC who received platinum chemotherapy were included with 7 patients analyzable for PSA outcomes. HRR alterations were found in 19 out of 24 patients (79.2%) with mutations recognized in 11 different HRR genes. Patients with a HRR alteration achieved a PSA50 response rate of 20% (1 out of 5) after platinum chemotherapy compared to 50% (1 out of 2) in patients without a HRR mutation. No difference in OS or PSA PFS was detected among patients with BRCA1/2 mutations compared to HRR alterations other than BRCA1/2 and patients without HRR alterations. Conclusion: In patients with mCRPC, we did not find a statistical difference in anti-tumor activity after receiving platinum chemotherapy among patients harboring a pathogenic HRR alterations compared to patients without a HRR alteration. Additionally, we were unable to detect an association between BRCA1/2 mutation status and response to platinum chemotherapy. Platinum chemotherapy, however, had clinically meaningful activity in a subset of patients regardless of HRR alteration status. Additional studies are warranted using genomic data to predict sensitivity to platinum chemotherapy.