A Living Interactive Systematic Review and Meta-Analysis assessing Efficacy of PARP inhibitors in Metastatic Castration Resistant Prostate Cancer
The therapeutic landscape of metastatic castration resistant prostate cancer (mCRPC) is rapidly changing. DDR deficiencies can confer dependence on the DNA repair enzyme PARP, rendering tumors exquisitely sensitive to PARP inhibition in individuals with homologous recombination repair (HRR) deficiency. This biological rationale has already led to FDA approvals for the PARP inhibitors (PARPi) olaparib and rucaparib in molecularly defined mCRPC patient subsets. While olaparib gained broad approval encompassing BRCA1/2, ATM, and 12 other DDR genes, rucaparib’s indication remains restricted to BRCA1/2 mutant mCRPC. Recently, three phase III clinical trials (PROpel, TALAPRO-2, MAGNITUDE have investigated PARPi and androgen pathway inhibitor (API) combinations for first line (treatment-naïve) mCRPC patients. Both PROpel and TALAPRO-2 demonstrated improved progression-free survival (PFS) in overall patient population with greater magnitude of benefit observed in HRR-deficient subgroup of patients. Conversely, the PFS benefit in the MAGNITUDE trial was only limited to HRR-positive (HRR-deficient) patients and was not observed in HRR-negative (HRR-proficient) population. This provides a compelling rationale to examine evidence in totality and conduct a comprehensive review of available data. We have initiated a living and interactive systematic review in this space to provide most contemporary evidence as soon as new information becomes available