AT THE 2016 ASCO ANNUAL MEETING

CHICAGO (FRONTLINE MEDICAL NEWS) Long-term maintenance monotherapy with olaparib following a response to platinum therapy in patients with recurrent high-grade serous ovarian cancer was associated with continued benefit vs. placebo in an updated analysis of the randomized phase II Study 19.

The new survival analysis supports prior Study 19 data showing a significant progression-free survival (PFS) advantage and a delay in time to first and second subsequent therapy in the 136 patients in the study with a BRCA 1/2 mutation who were treated with the approved PARP inhibitor, Dr. Jonathan A. Ledermann reported at the annual meeting of the American Society of Clinical Oncology.

The PFS in the overall study population of 265 patients in that prior analysis was 8.4 months in the olaparib group vs. 4.8 months in the placebo group (hazard ratio, 0.35). The PFS in the BRCA mutation subpopulation was 11.2 and 4.3 months in the groups, respectively (HR, 0.18), reported Dr. Ledermann of University College London.

“Time to first subsequent therapy or death was significantly improved with olaparib. This represents the time that women are free from the next line of chemotherapy,” he said, adding that time to second subsequent therapy or death was also significantly improved with olaparib.

“[These measures] can demonstrate the benefit beyond the next line of chemotherapy, and also help to address the confounding impact of crossover that occurs in many trials,” he explained.

Neither of two prior data analyses, the first with data maturity of 38% and the second with maturity of 58%, showed an improvement in overall survival in Study 19 participants.

In the current analysis, with a data cut-off of Sept. 31, 2015 (an additional 3 years of follow-up since the last analysis), and data maturity of 77%, overall survival was 29.8 and 27.8 months in 136 treatment group patients and 129 placebo group patients, respectively (HR, 0.73). In the BRCA mutation subgroup, the median overall survival was 34.9 months with treatment, vs. 30.2 months with placebo (HR, 0.62). For 118 patients with BRCA wild type, the hazard ratio was 0.83.

The differences did not meet the criteria for statistical significance, as the study was not powered to show a difference in overall survival, but a restricted means analysis to compare mean survival – a “useful additional way of looking at the data, rather than the point-estimated median PFS, particularly as the data mature” – showed a mean overall survival of 40.1 and 34.9 months in the olaparib and placebo patients, respectively (difference of 5.2 months), and 44.3 and 36.9 months in the BRCA mutation subgroup (difference of 7.4 months).

As for the median time to first subsequent therapy in BRCA mutation patients in the current analysis, the benefit of olaparib is maintained, with a 9.4-month difference between the treatment and placebo groups (15.6 vs. 6.2), and this was highly statistically significant (HR, 0.32; data maturity, 82%). For wild-type patients, the difference in the median was 6 months (12.9 vs. 6.9 months; HR, 0.45; maturity, 91%).

The same was true for the time to second subsequent treatment in BRCA mutation patients (22 vs. 15.3 months; HR, 0.41; data maturity, 79%), he said, noting that 23% of placebo patients crossed over to a PARP inhibitor at some point in their treatment.

A separation between the groups was also seen in BRCA wild-type patients (median of 17 vs. 14.7 months; HR, 0.63; data maturity, 90%), “perhaps maintained by those patients taking the drug for a long time,” Dr. Ledermann said.

At a median follow-up of 5.9 years, 15 patients were still receiving olaparib (11%), including 8 BRCA mutation patients and 7 BRCA wild-type patients. One patient was still receiving placebo.

“So 13% were on the drug for at least 5 years, 15% in the BRCA mutation subgroup were on it for at least 5 years, and 12% of patients with the BRCA wild type were on the drug for at least 5 years,” Dr. Ledermann said, noting that this represents “unprecedented long-term exposure to olaparib.”

Olaparib is a potent oral PARP inhibitor that traps PARP at sites of DNA damage, which blocks base-excision repair and leads to the collapse of DNA replication forks and the accumulation of DNA double-strand breaks, Dr. Ledermann explained, noting that the agent induces synthetic lethality in tumors with deficient hemologous recombination repair, which is most often seen with BRCA 1/2 mutations.

In Study 19, patients received 400 mg of olaparib twice daily or placebo after response to platinum-based therapy. BRCA mutation status was known for 254/265 patients (96%) from germline or tumor tests.

No new safety signals were observed with the longer follow-up, and the frequency of common adverse events, including nausea, fatigue, vomiting, and anemia was consistent with that seen in the overall population, with most adverse events initially reported during the first 2 years, he said.

The greatest benefits, in terms of overall survival and time to first and second subsequent treatment, were seen in patients with BRCA mutation, he concluded.

This study was sponsored by AstraZeneca. Dr. Ledermann reported that he has participated in advisory boards and lecture symposia and received institutional and personal fees from AstraZeneca, personal fees from Roche and Pfizer, and institutional fees from Clovis Oncology and Merck.

sworcester@frontlinemedcom.com

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