Ursula A. Matulonis, MD
Analyses of clinical trials continue to illuminate the role of the PARP inhibitor olaparib (Lynparza) in the treatment of women with ovarian cancer, Ursula A. Matulonis, MD, explained during a plenary session at the 2015 Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer.
Matulonis presented findings from a post-hoc exploratory analysis of interim phase II trial results and a pooled analysis of six clinical trials looking at olaparib monotherapy at time of relapse. Full findings from the phase II investigation led to an accelerated approval from the FDA for olaparib as a treatment for women with BRCA-positive advanced ovarian cancer following three or more prior lines of chemotherapy in December 2014.
In this phase II trial, maintenance monotherapy with 400-mg, twice-daily olaparib led to a significant improvement in progression-free survival versus placebo, especially in patients with a BRCA
mutation (BRCAm); however, no statistically significant increase in overall survival (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 198-patient analysis 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.
Matulonis, medical director of gynecologic oncology at Dana-Farber Cancer Institute, said the findings from the post-hoc analysis might support the initial hypothesis that patients switching treatments due to disease progression may have confounded the beneficial impact of olaparib on OS.
“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.”
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) is a 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). SOLO3 (NCT02282020) is a 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).