In breast, ovarian, and pancreatic cancer, deficiencies in genes related to homologous recombination repair (HRR), including BRCA1/2 and ATM, are known to be associated with increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. According to preliminary results from the ongoing phase III PROfound trial, prostate cancer can now be added to this list. In a recent press release, AstraZeneca announced that the PARP inhibitor olaparib was associated with a significant improvement in radiographic progression-free survival (PFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) with BRCA1/2 or ATM mutations, successfully achieving the trial’s primary endpoint. The study compared olaparib to either abiraterone or enzalutamide in patients who had progressed on prior abiraterone or enzalutamide treatment. These data follow on the heels of those from the phase II TOPARP-B trial, which showed that olaparib had activity in heavily pretreated mCRPC with defects in DNA damage repair. Full data from PROfound are expected to be presented at an upcoming medical conference, where more details will be available. Additional studies, such as the phase III PROpel trial, evaluating olaparib in combination with androgen inhibitors in the first-line mCRPC setting, will evaluate further positioning of olaparib within the treatment continuum.
High Altitude: The demonstration of a PFS benefit with olaparib in HRR-mutated mCRPC is an important step forward for HRR mutations as a biomarker. Mutations in HRR genes such as BRCA1/2 and ATM are found in numerous tumor types. These CRPC data suggest that HRR mutations could be a pan-tumor or even a tumor-agnostic biomarker. Tumor-agnostic markers have been used successfully twice now, with high levels of microsatellite instability (MSI-H) serving as a biomarker for pembrolizumab, and presence of NTRK gene fusions guiding use of TRK inhibitors. As personalized precision medicine continues to evolve, it is likely that additional mutation-/marker-specific agents will be developed to target underlying hallmarks of cancer.
Ground Level: Metastatic CRPC remains a therapeutic challenge. Having an additional oral therapy is a welcome advance for patients, oncologists, and urologists alike.