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Olaparib plus chemotherapy extended PFS in recurrent platinum-sensitive ovarian cancer
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The addition of olaparib to paclitaxel and carboplatin followed by maintenance therapy with olaparib significantly extended PFS compared with chemotherapy alone in women with platinum-sensitive, recurrent, high-grade serous ovarian cancer, according to results of a randomized, open-label phase 2 study.
Patients with BRCA mutations appeared to derive the greatest PFS benefit from the regimen, results of an exploratory analysis showed.
“Despite significant initial response to platinum-based chemotherapies, many patients with ovarian cancer undergo relapse followed by disease progression within 1 year of treatment,” Amit Oza, MD, FRPCPC, senior staff physician and professor of medicine at Princess Margaret Hospital and the University of Toronto, and colleagues wrote. “[This] emphasizes the need for treatments that improve clinical outcomes.”
Olaparib (Lynparza, AstraZeneca), a PARP inhibitor that exploits tumor DNA repair pathway deficiencies to preferentially kill cancer cells, has demonstrated antitumor activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer. The benefits have been observed in patients with or without BRCA1 or BRCA2 mutations.
In the current study, Oza and colleagues assessed the efficacy and safety of olaparib in combination with chemotherapy followed by maintenance therapy with olaparib vs. chemotherapy alone.
The analysis included 162 patients treated at 43 investigational sites in 12 countries between Feb. 12 and July 30, 2010. All patients had received up to three prior courses of platinum-based chemotherapy and were progression free for at least 6 months prior to randomization.
Researchers randomly assigned 81 patients to olaparib 200 mg twice daily on days 1-10 of each 21 day cycle, plus paclitaxel 175 mg/m2 administered via IV on day 1 and carboplatin (area under the curve [AUC] 4 mg/mL per minute) administered via IV on day 1. After four to six cycles of olaparib plus paclitaxel and carboplatin, patients also underwent maintenance therapy with olaparib 400 mg twice daily until progression.
The other 81 patients were assigned chemotherapy alone, which consisted of paclitaxel 175 mg/m2 plus carboplatin (AUC, 6 mg/mL) on day 1 of each 21-day cycle. The patients assigned chemotherapy alone did not undergo maintenance.
PFS served as the primary endpoint.
Results showed patients assigned olaparib plus chemotherapy experienced significantly longer median PFS compared with those assigned chemotherapy alone (12.2 months vs. 9.6 months; HR=0.51; 95% CI, 0.34-0.77).
Patients with BRCA mutations appeared to derive the greatest PFS benefit (HR=0.21; 95% CI, 0.08-0.55) from the combination of olaparib plus chemotherapy.
Adverse events that occurred more frequently in the olaparib plus chemotherapy arm included alopecia (74% vs. 59%), nausea (69% vs. 57%), neutropenia (49% vs. 39%), diarrhea (42% vs. 27%), headache (33% vs. 9%), peripheral neuropathy (31% vs. 19%) and dyspepsia (26% vs. 12%). Most adverse events were mild to moderate, according to researchers.
Grade ≥3 neutropenia (43% vs. 35%) and anemia (9% vs. 7%) occurred more frequently in the olaparib plus chemotherapy arm. Serious adverse events occurred in 15% of patients assigned the combination regimen and 21% of patients assigned chemotherapy alone.
Disclosure: The researchers report research funding/grants from AstraZeneca, Novartis, Roche and Tessaro. They also report advisory board roles with, employment with and stock ownership in AstraZeneca.
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