First-line maintenance therapy with olaparib extended survival beyond historical expectations in some women with newly diagnosed advanced ovarian cancer, according to two phase III studies presented at the European Society for Medical Oncology (ESMO) 2022 Congress.^1,2 

In the SOLO1 trial,¹ more than two-thirds of patients with advanced BRCA-mutated ovarian cancer treated with olaparib maintenance therapy were alive at 7 years compared with 46% of those randomly assigned to placebo, translating to a 45% reduction in death. The study set the statistical significance bar at a P value < .0001, and survival results achieved a P value of .0004. 

These 7-year results provide further confirmation that the benefit of maintenance olaparib extends well beyond its 2-year treatment cap.

— Paul DiSilvestro, MD

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“These 7-year results provide further confirmation that the benefit of maintenance olaparib extends well beyond its 2-year treatment cap,” said Paul DiSilvestro, MD, of Women and Infants Hospital, Providence, Rhode Island. According to Dr. DiSilvestro, these results “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 SOLO1 were published in the Journal of Clinical Oncology³ to coincide with Dr. DiSilvestro’s presentation, which was greeted with an enthusiastic ovation at the meeting.

In the PAOLA-1 trial,² no significant benefit in overall survival was observed in women with newly diagnosed advanced ovarian cancer with the addition of olaparib to bevacizumab maintenance therapy in the overall population. However, a meaningful improvement in overall survival was observed in the homologous recombination deficiency (HRD)-positive subgroup. In this subgroup, the 5-year overall survival rates were 65.5% with the addition of olaparib vs 48.4% with bevacizumab maintenance alone, representing a 38% improvement.

“These data confirm the addition of olaparib to bevacizumab as a standard of care for HRD-positive patients in this setting, as well as the importance of precision medicine and biomarker testing to guide treatment decisions,” said lead author of PAOLA-1, Isabelle Ray-Coquard, MD, PhD, of Centre Léon Bérard, Lyon, France, and President of the GINECO group.

Isabelle Ray-Coquard, MD, PhD

SOLO1: Key Results

SOLO1 was a double-blind phase III trial that included 391 women with newly diagnosed advanced BRCA-mutant ovarian cancer. Participants were randomly assigned 2:1 to maintenance therapy with olaparib or placebo for up to 2 years. Only platinum-responsive patients were enrolled. The median duration of treatment was 24.6 months with olaparib and 13.9 months with placebo. Median follow-up exceeded 87 months in both study arms.

The median time from randomization to first subsequent therapy or death served as a surrogate for progression-free survival. Median progression-free survival was 64 months with olaparib vs 15.1 months with placebo, representing a 63% improvement with olaparib. At data cutoff, 45.3% of women in the olaparib arm had not been treated with 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,” Dr. DiSilvestro commented.

The time to the second subsequent therapy also favored maintenance therapy with olaparib: median 93.2 months for olaparib vs 40.7 months with placebo. “This indicates a continued benefit [for olaparib] after the first subsequent therapy,” Dr. DiSilvestro observed.

No new safety signals for olaparib emerged during the study. Nausea and vomiting, fatigue, and anemia were the most common adverse events. The most common grade 3 and higher adverse events were anemia and neutropenia.

One new case of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) was reported in each arm of the trial since the primary data cutoff 4 years ago, for a total of four cases at 7 years with olaparib vs one case with placebo. New primary malignancies were well balanced between the two arms. Breast cancer was the most common type.

A total of 38.1% of events have occurred thus far, and the final survival analysis will be conducted when 60% of events have occurred. “It may be many years before we reach that final analysis,” Dr. DiSilvestro predicted.

PAOLA-1: Overall Outcomes and Exploratory Analysis

The phase III PAOLA-1 study assigned 537 patients with newly diagnosed ovarian cancer to receive olaparib plus bevacizumab, and 269 were assigned to receive placebo plus bevacizumab.Median follow-up was 62 months. Median overall survival in the intent-to-treat population did not significantly differ between the two study arms: 56.8 months with olaparib plus bevacizumab vs 51.6 months with placebo. The 5-year overall survival rates were 47.3% and 41.5%, respectively.

The 5-year overall survival rates were significantly better with olaparib plus bevacizumab in the subset of patients with a BRCA mutation: 73.2% with olaparib plus bevacizumab and 53.8% with placebo, a 19.8% absolute improvement associated with the addition of olaparib to bevacizumab maintenance therapy.

In an exploratory analysis of HRD-positive patients that excluded BRCA-positive patients, the 5-year overall survival rates were 54.7% with olaparib plus bevacizumab vs 44.2% with placebo, an improvement of 29%; also 55% of patients in the control arm received a PARP inhibitor in the subsequent lines of treatments after relapse. However, no benefit of maintenance olaparib plus bevacizumab was observed in the HRD-negative subgroup.

In the HRD-positive population, median progression-free survival rates were 46.8 months with olaparib plus bevacizumab vs 17.6 months with bevacizumab plus placebo. The 5-year progression-free survival rates were 46.1% and 19.2%, respectively. In the olaparib plus bevacizumab arm, the percentage of patients who had not relapsed after 5 years (46%) was more than double the percentage in the placebo arm (19%), suggesting that the addition of olaparib to bevacizumab may have the potential to cure more than double the number of newly diagnosed HRD-positive patients, said Dr. Ray-Coquard.

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

DISCLOSURE: Dr. DiSilvestro reported no conflicts of interest. Dr. Ray-­Coquard reported financial relationships with AbbVie, Agenus, Advaxis, Bristol Myers Squibb, PharmaMax, GenMab, AstraZeneca, Pfizer, Roche, GlaxoSmithKline, MSD, Deciphera, Mersena, Merck Serono, Novartis, Amgen, Tesaro, and Clovis.

REFERENCES

1. DiSilvestro P, et al: Overall survival at 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation who received maintenance olaparib in the SOLO1/GOG-3004 trial. ESMO Congress 2022. Abstract 517O. Presented September 9, 2022.

2. Ray-Coquard I, et al: Final overall survival results from the phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib plus bevacizumab in patientswith newly diagnosed advanced ovarian cancer. ESMO Congress 2022. Abstract LBA29. Presented September 9, 2022.

3. DiSilvestro P, et al: Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation. J Clin Oncol. September 9, 2022 (early release online).