Additional Trial Analyses Add to Understanding of Olaparib's Role in Ovarian Cancer

Ursula Matulonis, MD

Ursula Matulonis, MD

Two newly reported studies are providing more insight into the efficacy and safety profile of the PARP inhibitor olaparib in ovarian cancer. A post-hoc exploratory analysis of interim phase II trial results continued to find no significant difference in overall survival (OS) with the drug, while in a separate study involving a pooled analysis of six clinical trials, taking olaparib monotherapy at time of relapse showed median responses lasting nearly 8 months.

The data were presented March 28, 2015 at the 2015 Society of Gynecologic Oncology’s (SGO) Annual Meeting on Women’s Cancer.

Olaparib (Lynparza) received an accelerated approval from the FDA December 19, 2014 for the treatment of women with BRCA-positive advanced ovarian cancer following three or more prior lines of chemotherapy. In the phase II trial leading up to the FDA approval, maintenance monotherapy with 400-mg, twice-daily olaparib led to a significant improvement in progression-free survival versus placebo, especially in patients with aBRCAmutation (BRCAm); however, no statistically significant increase in OS was seen in either the overall or the BRCAm populations.

Investigators hypothesized that with 12% of patients in the placebo arm receiving a PARP inhibitor after disease progression, this may have confounded the results. In the post-hoc analysis involving 198 patients reported at SGO, all patients from trial sites where at least one patient received post-progression treatment with a PARP inhibitor were excluded.

This resulted in a change in the OS hazard ratio (HR) in BRCA-positive patients at a 95% confidence interval as follows: OS HR all sites = 0.73 (0.45-1.17); PARP inhibitor sites excluded = 0.52 (0.28-0.97). Due to small sample sizes and data immaturity (currently 58%), further analysis will follow when the data mature.

Lead author Ursula A. Matulonis, MD, said the findings from the post-hoc analysis may support the initial hypothesis that the beneficial impact of olaparib on OS may have been confounded by patients switching treatments due to disease progression.

“This analysis showed that placebo patients had longer treatment with a subsequent PARP inhibitor than with placebo,” she said at the conference. “Despite the later use of a PARP inhibitor in the course of their disease, patients still received benefit.” Matulonis is medical director of gynecologic oncology at Dana-Farber Cancer Institute.

In the pooled analysis of 300 women with relapsed ovarian, peritoneal, or fallopian tube cancer, all patients had received olaparib 400-mg capsules twice daily as monotherapy in one of six prospective clinical trials. The analysis used germline BRCAm status and patient outcomes data based on definitions from the original trials and assessed objective response rate (ORR) using RECIST criteria and duration of response (DoR) based on CT/MRI imaging at baseline.

Median DoR was 7.4 months in the overall study population and 7.8 months in patients who received ≥3 prior chemotherapy regimens; ORR was 36% and 31%, respectively.

Adverse events (AEs) were recorded throughout the six trials and graded by NCI CTCAE. AEs of any grade were seen in more than 25% of patients, ranging from 26% with abdominal pain (n = 79) to up to 65% with nausea (n = 196). Grade 3 or 4 AEs ranged from 1% with diarrhea (n = 4) to 14% with anemia (n = 43).

Serious AEs (SAEs) were reported in 30% of patients overall and 34% of those who had received three or more lines of chemotherapy. Causally related SAEs occurred in 10% of patients. Eight patients had an AE that led to death, but none was considered causally related to olaparib. Olaparib’s overall tolerability profile was similar in patients with and without the germline BRCA mutation.

“It’s important to note that adverse events were generally low grade and manageable without olaparib discontinuation,” lead author Matulonis said. “And duration of response was not reduced in patients who had received three or more prior lines of chemotherapy. Further, olaparib treatment benefits were observed in all patient subgroups.”

Phase III studies of the agent in patients with ovarian cancer and a germline BRCAm are ongoing. SOLO1 (NCT01844986) is a randomized, double-blind, placebo-controlled trial in patients who are in response following first-line platinum-based chemotherapy; SOLO2 (NCT01874353): randomized, double-blind, placebo-controlled trial in patients with platinum-sensitive relapsed disease who are in response following platinum-based therapy (having completed ≥2 lines of platinum-based therapy); and SOLO3 (NCT02282020), a randomized, open-label trial of olaparib versus single-agent chemotherapy (physician’s choice) in patients with platinum-sensitive relapsed disease (who have completed ≥2 lines of platinum-based therapy).

References

Matulonis UA, Harter P, Gourley C et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer and a BRCA mutation: overall survival adjusted for post-progression PARP inhibitor therapy. Presented at: 2015 Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer; March 28-31, 2015; Chicago, IL. Abstract 13.

Matulonis UA, Penson RT, Domchek SM, et al. Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multi-study sub-analysis. Presented at: 2015 Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer; March 28-31, 2015; Chicago, IL. Abstract 14.