Systematic Review of Treatments in Metastatic Castration-Resistant Prostate Cancer (mCRPC) with DNA Damage Repair Gene Mutation (DDRm)


Samjoo I1, Craigie S1, Gupta K1, Bartlett M2, Cameron C3, Fox K4, Quek RGW5
1EVERSANA, Burlington, ON, Canada, 2EVERSANA, SYDNEY, NS, Canada, 3CRG-EVERSANA, Sydney, NS, Canada, 4Strategic Healthcare Solutions, LLC, Aiken, SC, USA, 5Pfizer Inc., San Francisco, CA, USA

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 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.

Conference/Value in Health Info

2020-11, ISPOR Europe 2020, Milan, Italy

Value in Health, Volume 23, Issue S2 (December 2020)




Clinical Outcomes

Topic Subcategory

Comparative Effectiveness or Efficacy


Biologics and Biosimilars, Drugs, Oncology, Urinary/Kidney Disorders

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