Stanley B. Kaye, MD, of Royal Marsden Hospital in London, the invited discussant, commented, “The trial of olaparib was important, showing clear superiority of olaparib with an impressive hazard ratio that was not restricted to BRCA-mutated patients.…There is a role for taking this drug forward as potential maintenance.”
He noted that homologous repair deficiency is a common molecular defect, and pointed out that olaparib had already been shown in an earlier trial to be active in a proportion of patients in whom BRCA status was negative. Therefore, drugs that capitalize on this could be worthy candidates in unselected populations. “The majority of patients in whom BRCA status was unknown or negative responded to olaparib,” he noted.
As to whether a single-agent PARP inhibitor or combination approach would be preferable, Dr. Kaye emphasized that a PARP inhibitor/chemotherapy combination, while synergistic, could be myelotoxic.
What We Know and Don’t Know
Emphasizing “what we know now” about PARP inhibitors as single agents, he observed that olaparib has significant clinical activity in both BRCA-mutated and sporadic ovarian cancer, with a favorable toxicity profile and the potential as maintenance therapy.
As for “what we still need to know,” he named long-term toxicity, impact on subsequent chemotherapy and overall survival, nature of a reliable biomarker, and potential for combination with other maintenance approaches, such as bevacizumab (Avastin).
PARP inhibitors and chemotherapy in combination have also proven feasible though this usually increases myelosuppression. The combination may also increase efficacy in platinum-sensitive disease, although the impact on progression-free and overall survival in randomized trials remains unclear. Optimal dose and schedule, biomarkers, and differences in the potential of the different PARP inhibitors should be explored, he said. ■
Financial Disclosure: Dr. Kaye is a member of advisory boards for AstraZeneca and Merck.