The New England Journal of Medicine December 19, 2019

Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer

Isabelle Ray-Coquard, Patricia Pautier, Sandro Pignata, Philipp Harter et al.

Bottom Line

In women with newly diagnosed advanced ovarian cancer who had a response to first-line platinum-based chemotherapy plus bevacizumab, the addition of maintenance olaparib significantly prolonged progression-free survival, particularly in those with HRD-positive tumors.

Key Findings

1. In the overall intent-to-treat population, the median progression-free survival (PFS) was 22.1 months with olaparib plus bevacizumab compared to 16.6 months with placebo plus bevacizumab (hazard ratio [HR] for disease progression or death, 0.59; 95% CI, 0.49 to 0.72; P<0.001).

2. Patients with homologous-recombination deficiency (HRD)-positive tumors, including those with BRCA mutations, experienced a profound benefit with a median PFS of 37.2 months in the olaparib group versus 17.7 months in the placebo group (HR, 0.33; 95% CI, 0.25 to 0.45).

3. Patients with HRD-positive tumors that did not have BRCA mutations also derived substantial benefit, with a median PFS of 28.1 months versus 16.6 months (HR, 0.43; 95% CI, 0.28 to 0.66).

4. In patients with HRD-negative or unknown status tumors, the addition of olaparib did not provide a statistically significant PFS benefit (median PFS 16.9 vs. 16.0 months; HR, 0.92; 95% CI, 0.72 to 1.17).

Study Design

Design

Phase 3 RCT

Double-Blind

Sample

806

Patients

Duration

22.9 mo

Median

Setting

Multicenter, International

Population Women with newly diagnosed, advanced (FIGO stage III-IV), high-grade ovarian, primary peritoneal, or fallopian tube cancer who had a complete or partial response to first-line platinum-taxane chemotherapy plus bevacizumab.

Intervention Olaparib (300 mg twice daily for up to 24 months) plus Bevacizumab (15 mg/kg every 3 weeks for up to 15 months total)

Comparator Placebo (twice daily for up to 24 months) plus Bevacizumab (15 mg/kg every 3 weeks for up to 15 months total)

Outcome Investigator-assessed progression-free survival (PFS)

Study Limitations

• The trial design did not include an olaparib monotherapy arm, making it impossible to determine the independent contribution of bevacizumab to the efficacy of the combination regimen.

• Patients with HRD-negative tumors did not appear to derive a meaningful survival benefit, emphasizing the absolute necessity of accurate biomarker testing for patient selection.

• The exclusion of patients who experienced disease progression during initial chemotherapy limits the generalizability of these findings to primary refractory populations.

Clinical Significance

The PAOLA-1 trial established the combination of olaparib and bevacizumab as a standard-of-care first-line maintenance therapy for advanced ovarian cancer patients with HRD-positive tumors, successfully cementing HRD status as a critical predictive biomarker beyond standard BRCA testing.

Historical Context

Following the SOLO-1 trial, which established olaparib maintenance as a highly effective standard for BRCA-mutated advanced ovarian cancer, and earlier trials (GOG-0218, ICON7) that validated bevacizumab in the frontline setting, PAOLA-1 sought to determine if combining a PARP inhibitor with anti-angiogenic therapy could broaden clinical benefit. It ultimately proved that the combination is highly effective, though the benefit is primarily restricted to the HRD-positive subpopulation.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the concept of 'synthetic lethality' explain why olaparib is particularly effective in ovarian cancer patients with BRCA mutations or homologous recombination deficiency (HRD)?

Key Response

PARP inhibitors like olaparib block single-strand DNA break repair. In HRD-positive cells (such as those with BRCA mutations), double-strand repair is also defective. This simultaneous failure of two distinct repair pathways leads to a fatal accumulation of DNA damage, killing the cancer cells while sparing normal cells that have intact homologous recombination repair mechanisms.

Resident

Based on the PAOLA-1 results, which specific biomarker testing is mandatory for newly diagnosed advanced ovarian cancer patients, and how does it directly dictate your choice of maintenance therapy?

Key Response

HRD testing, which encompasses both BRCA mutations and genomic instability, is crucial. PAOLA-1 demonstrated a massive progression-free survival benefit when adding olaparib to bevacizumab in HRD-positive patients, but showed no significant benefit in HRD-negative (proficient) patients. Residents must use these biomarker results to justify the combination and avoid giving ineffective, toxic regimens to HRD-negative patients.

Fellow

The PAOLA-1 trial required all patients to have received upfront bevacizumab, whereas the PRIMA and SOLO-1 trials did not. How do you decide clinically whether to use the PAOLA-1 regimen versus a PARP inhibitor alone in a newly diagnosed HRD-positive patient?

Key Response

Decision-making relies on baseline clinical risk factors. Upfront bevacizumab is typically chosen for high-risk features like stage IV disease, large volume ascites, or suboptimal surgical debulking. If the patient was started on upfront bevacizumab for these reasons, PAOLA-1 justifies adding olaparib. If the patient has lower-risk features and achieved complete resection without upfront bevacizumab, monotherapy per SOLO-1 or PRIMA is appropriate.

Attending

The trial showed no significant PFS benefit for the olaparib-bevacizumab combination in the HR-proficient subgroup. How do you navigate shared decision-making with a patient requesting aggressive combination therapy, balancing hope with the realities of compounded toxicity?

Key Response

Attendings must lead shared decision-making by explaining that in HR-proficient disease, adding olaparib provides no oncologic benefit but adds fatigue, anemia, immense financial toxicity, and a rare but serious risk of MDS/AML. This highlights the vital role of the attending in practicing evidence-based stewardship and protecting patients from harm without benefit.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

PAOLA-1 utilized the Myriad myChoice assay to define HRD status based on a genomic scar. What are the methodological limitations of using a static DNA scar assay to predict response to PARP inhibition, and how could future trial designs improve upon this biomarker?

Key Response

Genomic scars indicate historical HRD but cannot detect functional restoration of homologous recombination, such as secondary reversion mutations in BRCA. Future trial designs should incorporate dynamic, functional assays (e.g., RAD51 foci formation) to more accurately measure real-time HR proficiency and better predict actual PARP inhibitor efficacy.

Journal Editor

A notable structural limitation of the PAOLA-1 trial design is the absence of an olaparib monotherapy arm. As a peer reviewer, how does this omission impact the internal validity and interpretation of the combination's true synergistic efficacy?

Key Response

Without an olaparib-alone control arm, it is impossible to definitively determine if the impressive PFS in the HRD-positive subgroup requires the addition of bevacizumab, or if the benefit is driven entirely by olaparib. This limits the ability of the study to isolate and attribute the exact synergistic versus additive effects of the intervention.

Guideline Committee

Given the divergent outcomes in PAOLA-1 based on HRD status, how should current NCCN and ASCO guidelines stratify recommendations for olaparib plus bevacizumab, and what level of evidence supports withholding this combination in HR-proficient patients?

Key Response

Guidelines must provide a strong Category 1 recommendation for the combination specifically in HRD-positive patients who received upfront bevacizumab. Conversely, guidelines must explicitly recommend against this combination for HRD-proficient patients, as the lack of PFS benefit does not justify the added toxicity, fundamentally shifting frontline ovarian cancer maintenance to a strict biomarker-driven paradigm.

Clinical Landscape

Noteworthy Related Trials

2011

GOG-0218 Trial

n = 1873 · NEJM

Tested

Bevacizumab concurrent with chemotherapy followed by maintenance

Population

Newly diagnosed stage III or IV epithelial ovarian cancer

Comparator

Chemotherapy plus placebo

Endpoint

Progression-free survival (PFS)

Key result: The addition of bevacizumab to standard chemotherapy followed by maintenance bevacizumab significantly extended progression-free survival.

2018

SOLO-1 Trial

n = 391 · NEJM

Tested

Olaparib 300 mg twice daily

Population

Newly diagnosed advanced ovarian cancer with BRCA1/2 mutation

Comparator

Placebo

Endpoint

Progression-free survival (PFS)

Key result: Olaparib significantly improved progression-free survival compared to placebo in BRCA-mutated patients.

2019

PRIMA Trial

n = 733 · NEJM

Tested

Niraparib once daily

Population

Newly diagnosed advanced ovarian cancer at high risk for relapse

Comparator

Placebo

Endpoint

Progression-free survival (PFS)

Key result: Niraparib significantly prolonged progression-free survival in the overall population, regardless of homologous recombination deficiency (HRD) status.

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