Maintenance Olaparib Resurrected for Phase III Program

The first patient has been enrolled in a phase III clinical program investigating treatment with olaparib for patients with BRCA-mutated ovarian cancer, marking another step in the revived development of an agent once relegated to the sidelines.

AstraZeneca, the company developing the agent, said the PARP inhibitor would be investigated as a maintenance therapy for patients with ovarian cancer in two separate studies. In the SOLO 1 study, olaparib will be explored as a monotherapy following first-line platinum-based chemotherapy. In SOLO 2, the agent will be explored for patients with relapsed, platinum-sensitive, high-grade disease following at least two lines of platinum-based chemotherapy.

A companion diagnostic for the detection of BRCA mutations in tumors of patients participating in the program will be provided through a nonexclusive global collaboration agreement between AstraZeneca and Myriad Genetics, Inc. In August, the FDA approved an Investigational Device Exemption for Myriad’s BRACAnalysis test for use in the trials.

Olaparib’s Rocky Past

“Our hope is that the phase III development program for olaparib will result in a new treatment option for patients suffering from BRCA-mutated ovarian and breast cancers, accompanied by a diagnostic to help physicians identify the patients for whom the therapy might be most appropriate,” said Ruth March, vice president and head of Personalized Healthcare and Biomarkers at AstraZeneca. Olaparib has experienced several twists and turns throughout its clinical development. Promising results for the agent were reported at the 2011 ASCO Annual Meeting, based on impressive early phase II results, only to have clinical development discontinued later that year. As a result of the enrollment of the first patient in the phase III trial, AstraZeneca said it would reverse $285 million in pretax impairment charges that the company assessed to its research and development expenses when the program was terminated.

The decision to discontinue the treatment was based on an interim analysis suggesting that the progression-free survival (PFS) advantage would not translate into an overall survival (OS) benefit. Furthermore, attempts at identifying an appropriate dose were not successful.

In March 2012, the data from this interim analysis were published in The New England Journal of Medicine showing an improvement in median PFS of 8.4 months with olaparib compared with 4.8 months with placebo (HR = 0.35; 95% CI, 0.25 - .049; P < .001) but no significant difference for OS. However, a preplanned subgroup analysis of a small portion of patients (36.6%) with BRCA mutations identified at the time showed a clear advantage for olaparib, causing renewed interest.

Based on this subgroup analysis, BRCA status was retrospectively identified for patients in the phase II trial. In total, germline BRCA mutations were identified in 96 patients. When including somatic tumor mutations, 136 of the 265 patients (51%) were identified as positive for a BRCA mutation. Altogether, BRCA status was identified for 96% of trial participants.

Results from this study, presented at the 2013 ASCO Annual Meeting, suggested a greater clinical benefit in the BRCA-mutant population, but an OS analysis was confounded. For those with the mutation, PFS was 11.2 months compared with 4.3 months, for olaparib and placebo, respectively (HR = 0.18; 95% CI, 0.11-0.31; P < .00001).

The OS findings between patients with germline BRCA mutations and wild-type BRCA were similar. Trial authors believe this similarity was due in part to 35% of patients with germline mutations on the placebo arm receiving a subsequent PARP inhibitor. However, when looking at all types of BRCA mutations, the OS was 34.9 months with olaparib compared with 31.9 months for placebo (HR = 0.74; 95% CI, 0.46-1.19).

Jonathan A. Ledermann, MD

In relation to the presentation of these results in June, the lead author of the retrospective analysis, Jonathan A. Ledermann, MD, said, "The statistically significant seven month difference in progression-free survival in the subgroup of patients with a BRCA mutation supports the hypothesis that a personalized therapeutic approach based on BRCA mutation status could preferentially benefit this patient population. This warrants further investigation of olaparib in a phase III clinical trial.” Ledermann is a professor of Medical Oncology in the UCL Cancer Institute at University College London.

In the phase II trial, the dose of olaparib was 400 mg twice daily (BID); however, there was difficulty identifying whether this was the correct dose. For the phase III development program, olaparib will be administered at 300 mg BID.

“This is a significant milestone for olaparib, and further evidence of AstraZeneca’s commitment to invest in distinctive science in our core therapy areas, with a particular focus on high unmet need. We feel olaparib has real potential to significantly improve treatment decisions for this group of patients who currently have limited options, and to become the next important product in our growing oncology portfolio,” Antoine Yver, vice president and head of Oncology in AstraZeneca’s Global Medicines Development unit, said in a statement.

The SOLO 1 study will be conducted in collaboration with the Gynecologic Oncology Group, and hopes to enroll 344 women with newly diagnosed stage III/IV BRCA1/2-mutant ovarian cancer. SOLO 2 hopes to enroll 264 patients with relapsed high-grade serous ovarian cancer with a mutation in BRCA1/2 following at least two previous lines of treatment. This trial will be conducted in collaboration with the European Network of Gynaecological Oncology Trial Groups. The primary endpoint of both studies is PFS by RECIST criteria. OS will remain a secondary endpoint, as was the case in earlier phase II trials.