OBJECTIVES: Mutations in DNA damage repair genes have been associated with poorer prognosis in patients with mCRPC. We conducted a systematic review to assess multiple outcomes including efficacy/safety of therapies for mCRPC patients with DDRm after treatment with novel hormonal therapy (NHT) and taxane-based chemotherapy.

METHODS: We searched Ovid MEDLINE^®, Embase^®, and Evidence-Based Medicine Reviews from January 2009-December 2019, key conferences 2015-2020, bibliographies of existing systematic reviews, and ClinicalTrials.gov through March 2020 to identify phase 2/3 clinical trials including adult patients with mCRPC and DDRm who progressed on ≥1 NHT and received 1-2 taxane(s) for metastatic disease. Multiple outcomes were summarized.

RESULTS: Of 8612 citations identified, 42 citations were eligible, which represented 7 clinical trials enrolling 779 DDRm patients. Six phase 2 non-comparative trials were identified. Treatments included PARP inhibitors (PARPi) (olaparib, rucaparib, talazoparib, niraparib) and pembrolizumab monotherapies. One phase 3 randomized trial was identified investigating olaparib vs NHT. Three trials (talazoparib, niraparib, rucaparib) have only published interim results. Median follow-up of all trials ranged from 6.4-17.6 months. Most common DDR gene mutations were BRCA1/2 (33%-62%), ATM (20%-33%), and CDK12 (10%-26%). Objective response rates ranged from 16%-88% among PARPi and was 7% for pembrolizumab. Among PARPi, median radiographic progression-free survival and overall survival ranged from 5.3-9.8 months and 10.1-15.8 months, respectively, and grade 3/4 anemia was the most frequent adverse event (AE), affecting 16%-37% of DDRm patients. Fatigue AE (all grades) accounted for 15% of pembrolizumab intention-to-treat patients. Additional ongoing trials are being monitored to determine latest published results and study eligibility.

CONCLUSIONS: Drugs that target the DDR pathway in mCRPC have reported safety and efficacy results in a post-NHT, post-chemotherapy setting. Further head-to-head clinical trials, indirect treatment comparisons and/or real-world observational studies may be required to assess comparative efficacy across these drugs to aid physician-patient treatment decision.