Addition of olaparib to maintenance bevacizumab significantly improves PFS in ovarian cancer
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BARCELONA, Spain — The addition of olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy and bevacizumab significantly improved PFS among women with advanced ovarian cancer, according to results of the randomized phase 3 PAOLA-1/ENGOT-ov25 study presented at European Society for Medical Oncology Congress.
The PFS benefit appeared particularly substantial among women with BRCA mutations and those with homologous recombination deficiency-positive disease, researchers noted.
“Bevacizumab increased response rates, PFS, and OS in some subgroups, so it is a standard-of-care for most patients with newly advanced ovarian cancer,” Isabelle L. Ray-Coquard, MD, PhD, medical oncologist in the medical oncology department and Institute for Clinical Science at Centre Leon Berard in France and professor of medical oncology at University Claude Bernard Lyon I, said during her presentation. “This is the first randomized trial to explore the efficacy and safety of the combination of olaparib and bevacizumab [for] patients with newly-advanced ovarian cancer.”
The study by Ray-Coquard and colleagues included 806 women with stage III or stage IV high-grade serous or endometrioid ovarian, fallopian tube or primary peritoneal cancer who were in clinical complete or partial response after receiving standard platinum-based chemotherapy in combination with bevacizumab (Avastin, Genentech).
Researchers randomly assigned the women 2:1 to maintenance bevacizumab with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza, AstraZeneca; n = 537) or with placebo (n = 269).
Researchers administered olaparib at 300 mg orally for up to 24 months and bevacizumab at 15 mg/kg for 15 months.
PFS in the intent-to-treat population served as the study’s primary endpoint.
Median follow-up was 24 months in the olaparib group and 22.7 months in the placebo group.
Results showed significantly longer median PFS in the olaparib group compared with the placebo group (22.1 months vs. 16.6 months; HR = 0.59; 95% CI, 0.49-0.72).
Among patients with BRCA-mutated tumors, median PFS was 37.2 months in the olaparib group vs. 21.7 months in the placebo group (HR = 0.31; 95% CI, 0.2-0.47). Among women without BRCA mutations, median PFS was 18.9 months in the olaparib group vs. 16 months in the placebo group (HR = 0.71; 95% CI, 0.58-0.88).
Women with homologous recombination deficiency (HRD)-positive disease had median PFS of 37.2 months with olaparib vs. 17.7 months with placebo (HR = 0.33; 95% CI, 0.25-0.45). Women with HRD-positive status without BRCA mutations had median PFS of 28.1 months with olaparib and 16.6 months with placebo group. Women with HRD-negative or unknown status had median PFS of 16.9 months with olaparib and 16 months with placebo.
“It is interesting to note that PFS in the combination arm is longer than what was seen in the SOLO-1 trial, which is probably due to the use of bevacizumab,” Ray-Coquard said.
Grade 3 or higher adverse events occurred among 57% of women in the olaparib group and 51% of patients in the placebo group. More than half of the women in the olaparib group (54%) had dose interruptions because of adverse events, compared with 24% in the placebo group.
“[This study] population is representative of the majority of patients with advanced ovarian cancer [because] patient selection was not restricted by surgical outcome or BRCA mutation status,” Ray-Coquard said. “I can also tell you that the safety profile of olaparib in combination with bevacizumab was generally consistent with previous trials and the addition of olaparib did not have an impact on bevacizumab tolerability and quality-of-life.”– by John DeRosier
Reference:
Ray-Coquard IL, et al. Abstract LBA2_PR. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.
Disclosures: Arcagy, AstraZeneca and Roche funded this study. Ray-Coquard reports consultant roles with and honoraria from AstraZeneca, Clovis Oncology, Pharma Mar and Tesaro; travel expenses from AstraZeneca and Roche; research funding from Merck Sharpe & Dohme; and a consultant role with Pfizer. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Susana Banerjee, PhD, MA, MBBS, FRCP
Ovarian cancer is the eighth most common cancer in the world, with 295,000 women diagnosed and over 185,000 deaths each year. The majority of women relapse, with 5-year survival of 20% for stage III disease and 5% for stage IV disease.
PARP inhibitors have revolutionized the treatment landscape of ovarian cancer. Olaparib, niraparib (Zejula, Tesaro/GlaxoSmithKline) and rucaparib (Rubraca, Clovis Oncology) are approved for recurrent ovarian cancer and have been shown to increase PFS. But if we are really going to have a chance to improve OS and get more women cured, we are going to have to bring these drugs into the first-line setting.
The SOLO-1 trial presented at ESMO last year and published in The New England Journal of Medicine showed that women with BRCA mutations who took maintenance olaparib after chemotherapy had increased PFS.
The key question for me as a clinician and a trialist is: How can we improve on the results of the standard of care that we have had so far? Can more women benefit from a PARP inhibitor in the first-line setting beyond those with BRCA mutations? We are seeing now in this study that that is indeed possible.
The next main question is: If patients without BRCA mutations can benefit like those with BRCA mutations, how can we best select those who are going to benefit for the longest time? That brings in the concept of HRD-deficiency.
Another question is whether we can improve outcomes by combining treatments.
We know now [from this trial and two others presented at ESMO] that we can use PARP inhibitors in the first-line setting for women who don’t have BRCA mutations.
We know the women who will get the most benefits moving forward from this combination are those with BRCA mutations and HRD positivity. Going forward, we will need to look at patients who don’t have HRD deficiency.
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