Olaparib Shows Promise as Long-term Maintenance Therapy in Relapsed Serous Ovarian Cancer in Final Study 19 Analysis

Charlie Gourley, MB ChB, PhD

The PARP inhibitor olaparib (Lynparza) provides clinically significant, long-term treatment benefits in patients with platinum-sensitive relapsed serous ovarian cancer, according to the protocol-specified final overall survival (OS) analysis of the phase II Study 19 trial presented during the 2017 ASCO Annual Meeting.

In Study 19 (n = 265), olaparib maintenance monotherapy significantly improved progression-free survival (PFS) compared with placebo in patients with platinum-sensitive relapsed serous ovarian cancer (hazard ratio [HR], 0.35, 95% CI, 0.25-0.49).¹The greatest benefits were seen in patients with aBRCAmutation.

At the final data cutoff of May 9, 2016, the median OS follow-up was 78 months at a data maturity of 79%. Fifteen patients (11%) were still receiving olaparib after being on treatment for 6 or more years, including 8 patients withBRCAmutations. OneBRCA-mutated patient was still receiving placebo.

Lead author Charlie Gourley, MB ChB, PhD, chair of medical oncology and honorary consultant in medical oncology, University of Edinburgh Cancer Research UK Centre, emphasized the durability of the response, especially among theBRCA-mutated andBRCAwild-type patients. “This 6+ year response is unprecedented in the relapsed ovarian cancer setting,” he said in an interview withTargeted Oncology. “What’s more, once a patient made it to 4 years without relapse, we saw very little drop-off.”

Gourley did offer a caveat regarding the current data. “This final OS analysis was protocol-specified but not designed to show a statistically significant difference between treatment arms,” he said. “The current OS analysis should therefore be considered descriptive, withPvalues deemed nominal.” OS was analyzed using a Cox proportional hazards model.

Study 19 assessed patients with platinum-sensitive, recurrent high-grade serous ovarian cancer. They had received 2 or more prior regimens of platinum-based chemotherapy and experienced complete response (CR) or partial response (PR) to their most recent regimen. In a double-blind, 1:1 randomization, half the patients received olaparib 400 mg capsules twice daily as maintenance therapy (n = 136) and half received placebo capsules twice daily until disease progression (n = 129).

The full analysis set included all 136 patients on olaparib and demonstrated an overall median OS of 29.8 months. Of the 129 patients on placebo, 112 (86.8%) experienced an OS event. The median OS was 27.8 months with placebo. The HR was 0.73 (95% CI, 0.55-0.95).

TheBRCA-mutated patient data were at 73% maturity at cutoff. Among the olaparib patients (n = 74), 7 were on treatment at data cutoff and 8 had been on treatment for 6 or more years. Forty-nine patients (66.2%) had experienced OS events, and the median OS was 34.9 months. The placebo group (n = 62) contained 1 patient who was on treatment at data cutoff and had been on treatment for 6 or more years. Fifty patients (80.6%) experienced an OS event and the median OS was 30.2 months. The HR for theBRCA-mutated group was 0.62 (95% CI, 0.42-0.93).

TheBRCAwild-type patient data had reached 86% maturity at cutoff. The olaparib group (n = 57) included 7 patients on treatment at cutoff and who had been on treatment more than 6 years. Forty-five patients (78.9%) experienced an OS event and the median OS was 24.5 months. There were no patients in this group who were still on treatment; 57 (93.4%) had experienced an OS event. Their median OS was 26.6 months. TheBRCAwild-type group’s HR was 0.84 (95% CI, 0.57-1.25).

Of the 15 patients who received olaparib for 6+ years, 9 had aBRCAmutation; 3 of these had a somaticBRCAmutation. Five patients wereBRCAwild-type. One was found to have aRAD51Bmutation. Some patients had no homologous recombination repair (HRR) mutations and 1 patient tested negative for HRD results. One patient with germlineBRCAwild-type had no available tumor test results.

“That means that at least one-third of the patients deriving substantial long-term benefit from olaparib hadBRCAwild-type status,” said Gourley. “Patients who had both a negative tumor test result for mutations in HRR-associated genes and a negative Myriad HRD score were found within this group.”

No new safety issues or changes in olaparib’s tolerability profile were seen from previously reported studies.²

References:

1. Gourley C, Friedlander M, Matalonis U et al. Clinically significant long-term maintenance treatment with olaparib in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (PSR SOC).J Clin Oncol35, 2017 (suppl; abstr 5533).
2. Ledermann JA, Harter P, Gourley C, et al. Overall survival (OS) in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (PSR SOC) receiving olaparib maintenance monotherapy: An interim analysis.J Clin Oncol34, 2016 (suppl; abstr 5501).