PARP Inhibitor Olaparib and Its Combination Therapy in Metastatic Castration-resistant Prostate Cancer: A Systematic Review and Network Meta-analysis

TL;DR

Olaparib combined with abiraterone improves survival for BRCA-mutated prostate cancer, while olaparib alone works for other gene mutations.

Contribution

Identifies optimal olaparib-based treatment strategies for mCRPC based on genetic subtypes using a network meta-analysis.

Findings

Olaparib plus abiraterone significantly improves PFS and OS in BRCA-mutated mCRPC.

Olaparib monotherapy is sufficient for HRR/BRCA wild-type mCRPC.

Combination therapy benefits are consistent across prostate-specific antigen subgroups.

Abstract

For BRCA mutated–type metastatic castration-resistant prostate cancer (mCRPC), olaparib + abiraterone significantly improves progression-free or overall survival. In patients with HRR mutated-type/BRCA wild-type mCRPC, olaparib monotherapy suffices. Molecular subtyping is essential for optimal treatment selection.

Olaparib is one of the earliest approved treatment options for metastatic castration-resistant prostate cancer (mCRPC). This systematic review and network meta-analysis aimed to determine the optimal olaparib strategy for treating mCRPC.

The Cochrane, Embase, PubMed, and Web of Science databases were searched comprehensively using “mCRPC” and “olaparib” as keywords. Study quality was appraised with the National Institutes of Health tools. Data were analyzed in R version 4.4.1. The primary endpoints included progression-free (PFS) and overall (OS) survival. The secondary endpoints included adverse events and severe adverse events (grade ≥3). Effect sizes were reported as hazard ratios (HRs) and risk ratios, with 95% credibility intervals (CrIs).

Nine studies from seven clinical trials involving 2355 patients were identified. For homologous recombination repair–mutated mCRPC, combination therapies did not demonstrate significant benefits compared with olaparib alone. However, for BRCA-mutated mCRPC, olaparib combined with abiraterone improved PFS (HR = 0.61, 95% CrI = 0.41–0.91) and OS (HR = 0.41, 95% CrI = 0.21–0.80) significantly. These significant advantages of olaparib combined with abiraterone were also observed in patients from different prostate-specific antigen subgroups.

These findings suggest that olaparib combined with abiraterone offers substantial benefits in BRCA mutated type (BRCAmt) mCRPC patients. For those with BRCA wild type homologous recombination repair–mutated mCRPC, olaparib monotherapy is effective.

We reviewed the published studies comparing different treatment options using the drug olaparib (alone or combined with other therapies) for advanced prostate cancer that has spread and no longer responds to standard hormone therapy (metastatic castration-resistant prostate cancer). We found evidence that the effectiveness of olaparib depends significantly on specific genetic features of the cancer. For patients whose cancer has changes in the BRCA genes, the combination of olaparib and the drug abiraterone was more effective in delaying cancer growth and improving survival than olaparib alone. For patients with changes in other related DNA repair genes (but not BRCA), olaparib alone was an effective treatment. This information may assist doctors and patients in choosing the most suitable treatment based on the cancer’s genetic characteristics.

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