Conference Coverage

PAOLA-1/ENGOT-ov25 trial: PARP inhibitor for maintenance improves PFS in advanced ovarian cancer



– Adding olaparib to bevacizumab as maintenance after first-line platinum-based chemotherapy for advanced ovarian cancer provided a significant and clinically meaningful progression-free survival (PFS) benefit in the phase 3 PAOLA-1/ENGOT-ov25 trial.

Dr. Isabelle Ray-Coquard, a medical oncologist at Centre Léon Bérard, and a professor of medical oncology at the University Claude Bernard, Lyon, France.

Dr. Isabelle Ray-Coquard

The benefit was particularly pronounced in patients with a tumor BRCA mutation (tBRCAm), and in those with homologous recombination deficiency (HRD)–positive disease, Isabelle Ray-Coquard, MD, PhD, reported at the European Society for Medical Oncology Congress.

Investigator-assessed median PFS was 22.1 months in 537 patients randomized to receive the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor olaparib plus bevacizumab maintenance, compared with 16.6 months in 269 patients who received placebo plus bevacizumab in the randomized, double-blind trial.

The difference was statistically significant (hazard ratio, 0.59; P = .0001), said Dr. Ray-Coquard, a medical oncologist at Centre Léon Bérard and a professor of medical oncology at the Université Claude Bernard, Lyon, France.

In patients with tBRCAm, the median PFS in the olaparib and placebo arms, respectively, was 37.2 vs. 21.7 months (HR, 0.31); in HRD-positive patients – inclusive of those with tBRCAm – median PFS was 37.2 vs. 17.7 months, respectively; and in HRD-positive patients without tBRCAm, median PFS was 28.1 and 16.6 months, respectively (HR, 0.43), she said.

“So PAOLA-1 met its primary endpoint of a statistically significant improvement in PFS in the [intent-to-treat] population, in favor of the olaparib arm,” Dr. Ray-Coquard said. “What does that mean? For advanced ovarian cancer ... a benefit of a median time of nearly 30 months without relapse.”

The findings of the subgroup analysis showing an even stronger association between combination olaparib and bevacizumab and improved PFS in patients with tBRCAm are similar to those reported from the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer, she noted.

“It is interesting to note that our PFS in the control arm is longer than [that seen] in the SOLO1 trial, which is probably due to the use of bevacizumab” in PAOLA-1, she said.

Additionally, a “new population of patients was identified: HRD-positive [patients] without BRCA mutation,” who experienced a PFS improvement of almost 1 year with olaparib versus placebo, Dr. Ray-Coquard noted.

Patients enrolled in the international trial – the first randomized trial to explore the efficacy and safety of maintenance olaparib plus bevacizumab in this setting and in patients with or without tBRCAm – had newly diagnosed stage III-IV, high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; had undergone upfront or interval surgery; had received platinum-taxane–based chemotherapy; and had received at least three cycles of bevacizumab. They were randomized 2:1 to receive maintenance therapy with 300-mg olaparib tablets given twice daily for up to 24 months along with bevacizumab at a dose of 15 mg/kg on day 1 every 3 weeks for 15 months (including when combined with platinum-based chemotherapy), or placebo plus bevacizumab.

The current standard of care for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone for maintenance.

Patient characteristics in the two arms were well balanced, Dr. Ray-Coquard said. “The PAOLA-1 population is representative of the majority of patients with advanced ovarian cancer, as the patient selection was not restricted by surgical outcome or BRCA mutation,” she commented, adding that the safety profile of the olaparib-bevacizumab combination was generally consistent with that seen in previous trials.

The addition of olaparib did not appear to affect bevacizumab tolerability or quality of life, she noted.

Dr. Susana Banerjee, Consultant Medical Oncologist and Research Lead for the Gynecology Unit of The Royal Marsden Hospital - NHS Foundation Trust, London, U.K.

Dr. Susana Banerjee

During a press briefing at the congress, Susan Banerjee, MBBS, PhD, who reported the SOLO1 results at the 2018 ESMO Congress, said that “PARP inhibitors have revolutionized the treatment landscape in ovarian cancer,” and have been approved in the recurrent ovarian cancer setting.

“But if we’re really going to have a chance to increase overall survival, and hopefully [have] more women cured, we need to bring these treatments into the first-line setting,” said Dr. Banerjee, consultant medical oncologist and research lead for the gynecology unit of the Royal Marsden Hospital, NHS Foundation Trust, London.

Given these and other recent findings, answers to the key question of how to improve outcomes in the first-line setting – and in patients beyond those with BRCA mutations – are emerging and showing that more women with ovarian cancer can benefit from PARP inhibitors.

“We know now ... that we can use PARP inhibitors in the first-line setting, beyond women with BRCA mutations,” Dr. Banerjee said. “The key question, really, is ‘What about patients that don’t have HRD deficiency? We do know that patients with BRCA mutations and who are HRD-positive have the greatest benefit with either a PARP inhibitor alone or, indeed, in combination with bevacizumab.”

In an ESMO press release about the PAOLA-1 and other related data presented at the congress, Ana Oaknin, MD, of Vall D’Hebron Institute of Oncology in Barcelona, stated that “the main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low.”

Combination olaparib and bevacizumab for first-line maintenance therapy “should become a new standard of care for patients with advanced ovarian cancer,” she said, noting that, while the PAOLA-1/ENGOT-ov25 trial did not include patients with no response to first-line chemotherapy (who comprise a small group of ovarian cancer patients), the trial is “a significant step forward in treatment for these women.”

In the context of other positive trial findings, including those from SOLO1 and other studies of PARP inhibition in this setting, the results represent a milestone, Dr. Oaknin said. “After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival, and hopefully we will improve long-term outcome.”

As for the “next priority for research in this field, Dr. Oaknin said that strategies are needed to improve the current 45% 5-year overall survival rate for ovarian cancer. “I think the next approach is to incorporate immunotherapy as part of first-line therapy; ongoing trials are expected to report in 2-3 years,” she commented.

The PAOLA-1/ENGOT-ov25 trial was funded by ARCAGY Research, AstraZeneca, and Roche. Dr. Ray-Coquard reported relationships with AstraZeneca, Clovis Oncology, Tesaro, Pharma Mar, Roche, and Genmab, including receiving honoraria, travel/accommodations/expenses, and/or research grant funding, and/or serving as an advisor or consultant. Dr. Banerjee is a lecturer and/or advisory board member for AstraZeneca, Clovis, Gamamabs, Merck Serono, Pharmamar, Seattle Genetics, Roche, and Tesaro, and has received a travel grant from Nucana. Dr. Oaknin reported having no disclosures.

SOURCE: Ray-Coquard I et al. ESMO 2019, Abstract LBA2. Ann Oncol. 19;30:suppl 9.

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