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PARIS -- Olaparib (Lynparza) maintenance therapy appears to offer a long-term overall survival (OS) benefit for women with ovarian cancer, according to two phase III studies presented at the European Society for Medical Oncology (ESMO) annual congress.

At 7 years in the , 67% of patients with advanced BRCA-mutated ovarian cancer treated with the PARP inhibitor maintenance therapy were still alive versus 46% of those assigned to placebo (HR 0.55, 95% CI 0.40-0.76, P=0.0004), reported Paul DiSilvestro, MD, of Women and Infants Hospital in Providence, Rhode Island.

"A clinically meaningful benefit," if not a statistically significant one, he said (a P value below 0.0001 was needed to declare the latter). "This despite 44% of patients in the placebo group receiving subsequent PARP inhibitor therapy."

"These 7-year results provide further confirmation that the benefit of maintenance olaparib extends well beyond its 2-year treatment cap," said DiSilvestro, adding that the findings "support the use of maintenance olaparib to achieve long-term remission in women with newly diagnosed advanced ovarian cancer and a BRCA mutation."

Results from SOLO-1 were published concurrently in the .

"Perhaps this is really cure we are seeing," said ESMO discussant Jonathan Ledermann, MD, of UCL Cancer Institute at University College London, noting that the median OS for BRCA-mutated ovarian cancer had not been reached. "We will have to wait for the full maturity to be absolutely certain of that."

In the second study (), which involved women with newly diagnosed advanced ovarian cancer, no significant OS benefit was seen in the overall study population when olaparib was added to bevacizumab (Avastin) maintenance, reported Isabelle Ray-Coquard, MD, PhD, of Centre Léon Bérard in Lyon, France, and the GINECO group.

But a "meaningfully" improved OS was observed in the subset with homologous recombination deficiency (HRD)-positive disease. In this group, 5-year OS rates were 65.5% with added olaparib versus 48.4% with bevacizumab alone (HR 0.62, 95% CI 0.45-0.85).

"These data confirm the addition of olaparib to bevacizumab as a standard of care for HRD-positive patients in this setting, and the importance of precision medicine and biomarker testing to guide treatment decision," said Ray-Coquard.

Ledermann said it remains to be seen what the added value of bevacizumab is, or whether PARP inhibitors alone are sufficient.

"What we can conclude," he added, referring to both SOLO-1 and PAOLA-1, "is that this survival data confirm the value of biomarker-directed first-line therapy with maintenance PARP inhibitors -- here with olaparib -- in the treatment of ovarian cancer."

SOLO-1

This double-blind phase III trial randomly assigned 391 patients with newly diagnosed, advanced BRCA-mutant ovarian cancer in a 2:1 fashion to either maintenance olaparib or placebo for up to 2 years. Patients needed to be in clinical response to platinum-based chemotherapy to enroll.

Median duration of treatment was 24.6 months with olaparib and 13.9 months with placebo, with a median follow-up of more than 87 months for the two arms.

Median time from randomization to first subsequent therapy or death -- evaluated as a proxy for progression-free survival (PFS) -- was 64.0 months with olaparib compared with 15.1 months with placebo (HR 0.37, 95% CI 0.28-0.48). At data cutoff, 45.3% of women in the olaparib arm had yet to receive a subsequent therapy compared with 20.6% of women in the placebo arm.

"For most women in this trial, survival meant survival without subsequent therapy," DiSilvestro observed.

Time to the second subsequent therapy also favored maintenance olaparib (median 93.2 vs 40.7 months with placebo), "indicating a continuing benefit beyond the first subsequent therapy," DiSilvestro said.

No new safety signals were observed, he said, with nausea and vomiting, fatigue, and anemia remaining the most common adverse events (AEs). Anemia and neutropenia were the most common grade ≥3 AEs.

One new case of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) was reported in the olaparib group since the primary data cutoff 4 years ago, resulting in a total of four cases (1.5%) at 7 years versus one case (0.8%) in the placebo group.

"New primary malignancies remain well-balanced, with breast cancer being the primary one in this at-risk population," DiSilvestro said.

Data maturity for OS was 38.1% in this analysis, and DiSilvestro pointed out that the final OS analysis for SOLO-1 is planned to be conducted once 60% of events have occurred. "It may be many years before we reach that final analysis," he said.

Ledermann pointed out that it will be important to determine why 55% of patients on olaparib who required subsequent treatment became resistant to the therapy.

PAOLA-1

This phase III study included 537 patients assigned to olaparib plus bevacizumab and 269 who were assigned to receive placebo plus bevacizumab.

With a follow-up of 62 months, the median OS in the intent-to-treat population was 56.5 months in the olaparib arm versus 51.6 months in the placebo arm (HR 0.92, 95% CI 0.76-1.12), with 5-year OS rates of 47.3% and 41.5%, respectively.

In a subset analysis of patients who harbored a BRCA mutation, the 5-year OS rates were 73.2% and 53.8% in the olaparib and placebo groups, respectively (HR 0.60, 95% CI 0.39-0.93).

An analysis of HRD-positive patients that excluded the BRCA-positive patients favored olaparib, with 5-year OS rates of 54.7% versus 44.2% with placebo (HR 0.71, 95% CI 0.45-1.13), while no benefit was observed with maintenance olaparib in HRD-negative patients, with 5-year OS rates of 32.3% and 25.7% (HR 1.19, 95% CI 0.88-1.63).

Updated PFS results showed that median PFS with olaparib plus bevacizumab was 46.8 months versus 17.6 months with bevacizumab plus placebo, with 5-year PFS rates of 46.1% and 19.2%, respectively.

No new safety signals were observed. AEs of special interest for olaparib in combination with bevacizumab versus bevacizumab alone included MDS/AML/aplastic anemia (1.7% vs 2.2%), new primary malignancies (4.1% vs 3.0%), and pneumonitis/interstitial lung disease/bronchiolitis (1.3% vs 0.7%).