Prostate cancer is a disease characterized by high genomic instability. Prostate cancers with deleterious aberrations in DNA damage repair (DDR) genes, including homologous recombination repair (HRR), such as mutations in BRCA1/2 and ATM, are associated with response to poly(adenosine diphosphate–ribose) polymerase (PARP) inhibition. The US Food and Drug Administration (FDA) has approved PARP inhibitors as monotherapy for the treatment of previously treated patients with HRR gene-mutated (olaparib) and BRCA mutation-associated (rucaparib) metastatic castration-resistant prostate cancer (mCRPC). Despite the advances with PARP inhibitors as monotherapy, primary and secondary resistances are seen, and evidence suggests that PARP inhibitors should be reserved for mCRPC with BRCA1, BRCA2, or ATM mutations. Now, clinical trials are evaluating PARP inhibitors in combination with other treatments such as androgen pathway inhibitors which may expand the clinical use of PARP inhibitors. When PARP inhibition is combined with novel hormonal therapies, a treatment benefit may be observed regardless of the HRR deficiency status.
This educational activity will review emerging clinical evidence and potentially practice-changing advancements in the treatment of mCRPC with PARP inhibitor combination treatment strategies, especially those that include combinations with androgen receptor targeted agents, to improve understanding of the evolving treatment and management of mCRPC.