Lack of Justification for Delaying Regulatory Approval of Olaparib in Ovarian Cancer

The recent vote of the FDA Oncologic Drugs Advisory Committee against recommending the approval of olaparib as a maintenance therapy strategy following the attainment of a second response to platinum-based therapy in either known BRCA mutation-positive or high-grade serous ovarian cancer raises a number of serious questions worthy of both scientific and societal discussion. These include both the level of evidence that should be mandated prior to FDA approval of a new antineoplastic agent and the individual roles of the drug regulatory agency (and its advisory committees) versus that of the individual cancer patient (in consultation with her or his own physician and personal advisors) in the determination of when it is appropriate to consider the administration of such a drug based on the appropropriateness of the end point used and the magnitude of the benefit. The intent of this commentary is not to attempt to explain the thought processes of the committee, other than to say they apparently were not convinced that the existing data demonstrated sufficient evidence of clinical benefit.1 Rather, what follows is a brief discussion of the data, which (in the opinion of this commentator) should unquestionably have resulted in a positive vote at the meeting and subsequent FDA approval of olaparib in this setting. Olaparib in Ovarian Cancer The theoretical rationale and extensive experimental data supporting the use of PARP (polyadenosine 5’ diphosphosphoribose polymerase) inhibitors in BRCA mutation-positive or highgrade serous tumors has been reported elsewhere and will not be discussed in detail here.2-5 In brief, tumors with homologous recombination defects (eg, BRCA mutations) have been shown to be effectively killed by inhibitors of PARP in preclinical studies. Similarly, PARP inhibition in the absence of such defects is inadequate to result in sufficient tumor cell kill. Of interest, high-grade serous ovarian cancers with wild-type BRCA have been shown to possess a molecular signature that appears similar to that observed in the presence of documented BRCA mutations (so-called, “BRCA-ness”). 3 This observation is the major justification for examining the clinical utility of PARP inhibition in patients with high-grade serous ovarian cancers in the absence of specific evidence of a BRCA abnormality. Olaparib has been shown to be an active inhibitor of PARP-1, PARP-2, and PARP-3 in experimental model systems. It is well absorbed when taken orally and is removed from the body in both the urine and feces. In the initial phase 1 study of olaparib conducted among patients with several BRCA-mutant tumor types (ovary, breast, prostate), 9 patients achieved a partial response. This study was subsequently expanded to include a total of 50 patients with a germline BRCA mutation, with a total objective response rate (RECIST or CA-125 response criteria) of 40%. A difference in the response rate between the platinum-sensitive (69%), platinum-resistant (45%), and platinum-refractory (23%) populations was observed in this trial. These data support the hypothesis that defective homologous recombination pathways are relevant to both sensitivity of platinum agents and PARP inhibitors (such as olaparib). Subsequent phase 2 trials further confirmed the clinical activity of olaparib in ovarian cancer. One study revealed an overall response rate of 33% when the drug was administered at a dosage of 400 mg twice daily, while a response rate of only 13% was noted when the agent was delivered at 100 mg twice daily.8 A second study that included 65 patients revealed a 41% response Abstract