Research in context
Evidence before this study
Olaparib is a poly(ADP-ribose) polymerase (PARP) inhibitor that is approved in ovarian and breast cancer indications. Other PARP inhibitors in clinical development include niraparib, pamiparib, rucaparib, talazoparib, and veliparib. Abiraterone is an androgen synthesis inhibitor, which is the standard of care for metastatic castration-resistant prostate cancer. We searched PubMed and the databases of the American Society of Clinical Oncology and European Society for Medical Oncology for journal publications and meeting abstracts published between Jan 1, 2012, and March 1, 2018, using the search terms “poly(ADP-ribose) polymerase” or “PARP” and “inhibitor” or “inhibition” and “prostate cancer”. No language restrictions were applied. In a previous phase 2 study, the efficacy of olaparib monotherapy in patients with advanced prostate cancer was almost exclusively limited to patients with a homologous recombination repair mutation. A phase 2 trial of veliparib in combination with abiraterone in patients with metastatic castration-resistant prostate cancer found no significant efficacy benefit with this combination treatment when compared with abiraterone alone.
Added value of this study
To our knowledge, our data are the first to show a significant improvement in radiographic progression-free survival (rPFS) for men with metastatic castrate-resistant prostate cancer treated with the combination of a PARP inhibitor and androgen synthesis inhibitor compared with an androgen synthesis inhibitor alone. Additionally, and in contrast to the results of previous studies of olaparib monotherapy for this indication, the rPFS benefit was observed for patients with metastatic castration-resistant prostate cancer given olaparib and abiraterone, regardless of homologous recombination repair mutation status, which has not previously been reported. In our study, more patients treated with olaparib and abiraterone had grade 3 or worse adverse events and serious adverse events than those treated with abiraterone alone; however, the increased duration of exposure in the olaparib and abiraterone group suggests that this tolerability risk might be offset by the observed efficacy benefit. No detriment to health-related quality of life was recorded with the combination compared with abiraterone alone.
Implications of all the available evidence
The significant improvement in rPFS observed in patients with metastatic castration-resistant prostate cancer treated with olaparib plus abiraterone compared with abiraterone alone suggests that these patients, who were not selected on the basis of biomarker criteria, might benefit from the combination treatment irrespective of homologous recombination repair mutation status. This result, which suggests that the treatment could provide clinical benefit for a broader patient population, is consistent with preclinical data that indicate a synergy between olaparib and drugs inhibiting androgen synthesis or function, potentially caused by PARP inhibition of androgen-receptor-dependent transcription or creation of a phenotype similar to that of the BRCAness phenotype that is susceptible to PARP inhibition. Larger studies are needed to confirm the results of this trial; however, our data suggest that the combination of olaparib and abiraterone has the potential to provide additional and practice-changing therapeutic options for men with metastatic castration-resistant prostate cancer.