Highlights
– Two large randomized phase III trials tested whether adding atezolizumab to bevacizumab plus chemotherapy improves outcomes in recurrent ovarian cancer; neither trial met its primary endpoints.
– AGO-OVAR 2.29/ENGOT-ov34 (platinum‑ineligible/refractory population) showed no statistically significant OS or PFS benefit (OS HR 0.83, P = .06; PFS HR 0.87, P = .12).
– ATALANTE/ENGOT-ov29 (platinum‑sensitive population) failed its coprimary PFS objectives in both the ITT and PD‑L1–positive cohorts; OS data remain immature.
– Safety profiles were consistent with known toxicities of immune checkpoint inhibitors and anti‑VEGF therapy; grade ≥3 adverse events were frequent in both arms.
Background: clinical need and biological rationale
Recurrent epithelial ovarian cancer remains a leading cause of gynecologic cancer death. Treatment selection is driven by platinum sensitivity: platinum‑sensitive relapses (platinum‑free interval >6 months) are typically treated with platinum‑based doublets, often combined with bevacizumab for selected patients; platinum‑resistant disease (progression ≤6 months after platinum) has limited options and poor outcomes. The unmet need is greatest for platinum‑resistant patients, where median survival is measured in months and response rates to single agents are modest.
Biologic rationale for combining anti–PD‑L1 therapy with anti‑angiogenic agents and chemotherapy includes several putative mechanisms: chemotherapy can increase neoantigen exposure and immune infiltration, while VEGF blockade may normalize tumor vasculature, reduce immunosuppression, and enhance lymphocyte trafficking. Early-phase signals across tumor types and preclinical data supported testing an atezolizumab (anti–PD‑L1) plus bevacizumab backbone in ovarian cancer across different relapse settings.
Study designs and populations
Two randomized, double‑blind, placebo‑controlled phase III trials from the ENGOT/AGO consortium investigated atezolizumab added to bevacizumab and chemotherapy in recurrent ovarian cancer.
AGO‑OVAR 2.29 / ENGOT‑ov34 (NCT03353831)
Population: Patients with epithelial ovarian cancer at first or second relapse with platinum‑refractory/resistant disease (relapse ≤6 months after platinum) or third relapse regardless of platinum‑free interval. Key stratification factors included prior bevacizumab exposure, planned chemotherapy (weekly paclitaxel or pegylated liposomal doxorubicin [PLD]), number of prior lines, and PD‑L1 status (VENTANA SP142 assay on recent biopsy).
Intervention: All patients received bevacizumab plus investigator‑selected non‑platinum chemotherapy (weekly paclitaxel or PLD). Patients were randomized 1:1 to receive atezolizumab 840 mg q2w or placebo for up to 2 years. Coprimary endpoints were overall survival (OS) and investigator‑assessed progression‑free survival (PFS) in the intention‑to‑treat (ITT) population.
ATALANTE / ENGOT‑ov29 (NCT02891824)
Population: Patients with recurrent epithelial ovarian cancer who were platinum‑sensitive (PFI >6 months) after one to two prior lines. Stratification included PFI, PD‑L1 status, and chemotherapy regimen. The trial used a 2:1 randomization favoring atezolizumab.
Intervention: Patients received standard platinum‑based doublet chemotherapy plus concurrent and maintenance bevacizumab, with randomization to atezolizumab (1,200 mg q3w or equivalent) or placebo for up to 24 months. Coprimary endpoints were investigator‑assessed PFS in the ITT and PD‑L1–positive populations (each tested with α = 0.025).
Key findings
AGO‑OVAR 2.29 / ENGOT‑ov34 — platinum‑ineligible/refractory disease
Between September 2018 and July 2022, 574 patients were randomized (1:1). Baseline features: 72% had prior bevacizumab exposure, 36% had received three prior lines, 26% were PD‑L1 positive, and 54% received paclitaxel as the chemotherapy backbone.
Primary endpoints: After 418 deaths, OS showed a hazard ratio (HR) of 0.83 (95% CI, 0.68–1.01; P = .06); median OS was 14.2 months with atezolizumab versus 13.0 months with placebo. PFS HR was 0.87 (95% CI, 0.73–1.04; P = .12); median PFS was 6.4 months with atezolizumab versus 6.7 months with placebo.
Subgroups: OS hazard ratios did not differ substantially by PD‑L1 status. No prespecified subgroup demonstrated a convincing, statistically significant benefit. The point estimates favoring atezolizumab for OS did not meet conventional significance, and the PFS result trended toward but did not achieve improvement.
Safety: Grade ≥3 adverse events occurred in 72% of patients receiving atezolizumab and 69% receiving placebo. The safety profile was consistent with known toxicities of platinum‑sparing chemotherapy, bevacizumab, and immune checkpoint blockade.
ATALANTE / ENGOT‑ov29 — platinum‑sensitive disease
From September 2016 to October 2019, 614 patients were randomized 2:1 (410 atezolizumab, 204 placebo). PD‑L1 positivity was present in 38%.
Primary endpoints: With median follow‑up of ~3 years, the trial did not meet its coprimary PFS objectives. In the ITT population, PFS HR was 0.83 (95% CI, 0.69–0.99; P = .041) with median PFS 13.5 versus 11.3 months (atezolizumab v placebo). The PD‑L1–positive population had HR 0.86 (95% CI, 0.63–1.16; P = .30) with median PFS 15.2 versus 13.1 months. Because the coprimary endpoints were tested with prespecified alpha allocation (.025 for each), the observed P value in the ITT population did not meet the stricter threshold for statistical significance. Overall survival follow‑up remains immature; the interim OS HR was 0.81 (95% CI, 0.65–1.01) with medians of 35.5 versus 30.6 months.
Safety and quality of life: Grade ≥3 adverse events were common in both arms (88% with atezolizumab vs 87% with placebo). Immune‑related grade ≥3 events were more frequent with atezolizumab (13% v 8%). Global health‑related quality of life did not differ meaningfully between arms.
Interpretation and clinical implications
Collectively, these large, well‑conducted phase III trials do not support routine addition of atezolizumab to bevacizumab plus chemotherapy for recurrent ovarian cancer in either platinum‑sensitive or platinum‑resistant settings. While both studies produced point estimates suggesting modest improvement in some endpoints, neither met prespecified thresholds for statistical significance. The AGO‑OVAR 2.29 OS P value of .06 is provocative but remains below the usual cutoff for definitive benefit, and PFS did not improve.
These negative results mirror several prior negative or modest findings of PD‑1/PD‑L1 monotherapy and combination immunotherapy trials in ovarian cancer, suggesting intrinsic tumor and microenvironment features (low mutational burden, immunosuppressive stroma, heterogeneous PD‑L1 expression) limit responsiveness for many patients.
Expert commentary: strengths, limitations, and next steps
Strengths of these programs include large sample sizes, double‑blind placebo control, contemporary PD‑L1 testing on recent biopsies, and clinically relevant stratification. The trials reflect real‑world heterogeneity in prior therapies (including prior bevacizumab exposure) and used commonly applied chemotherapy backbones.
Key limitations and considerations:
- Biomarker selection remains imperfect. PD‑L1 assessed by SP142 did not identify a clearly benefitting subgroup. Additional immune biomarkers (tumor‑infiltrating lymphocytes, gene expression signatures, tumor mutational burden, spatial immune profiling) may better discriminate responders.
- Timing and sequencing matters. Concurrent bevacizumab and chemotherapy may interact with immunotherapy differently than other sequences. Immune priming strategies or different anti‑angiogenic agents could yield different results.
- Heterogeneity of prior treatments, including prior bevacizumab exposure and number of prior lines, may dilute signal; subset hypotheses deserve careful, preplanned exploration but risk multiplicity.
- High rates of grade ≥3 adverse events underscore the need to weigh incremental efficacy against toxicity and quality of life, particularly in the platinum‑resistant population with limited life expectancy.
Research priorities include deep immune profiling of trial biospecimens to define predictive biomarkers, exploration of alternative immunomodulatory combinations (e.g., CTLA‑4 blockade, adoptive cell therapies), and trials testing sequencing strategies that might maximize synergy while minimizing added toxicity.
Conclusion
Adding atezolizumab to bevacizumab and chemotherapy did not produce a clinically or statistically significant improvement in PFS or OS in recurrent ovarian cancer across both platinum‑sensitive and platinum‑resistant settings in two large randomized trials. These results highlight the persistent challenge of achieving meaningful benefit with PD‑L1 blockade in ovarian cancer and emphasize the urgent need for robust predictive biomarkers and novel immunomodulatory strategies.
Funding and clinicaltrials.gov identifiers
ClinicalTrials.gov identifiers: AGO‑OVAR 2.29 / ENGOT‑ov34 — NCT03353831; ATALANTE / ENGOT‑ov29 — NCT02891824. Funding sources are reported in the original trial publications.
References
1. Harter P, Marmé F, Redondo A, et al. Atezolizumab With Bevacizumab and Nonplatinum Chemotherapy for Recurrent Ovarian Cancer: Final Results From the Placebo‑Controlled AGO‑OVAR 2.29/ENGOT‑ov34 Phase III Trial. J Clin Oncol. 2025 Dec 3: JCO2501210. doi:10.1200/JCO-25-01210 . Epub ahead of print. PMID: 41337696 .
2. Kurtz JE, Pujade‑Lauraine E, Oaknin A, et al; ATALANTE/ENGOT‑ov29 Investigators. Atezolizumab Combined With Bevacizumab and Platinum‑Based Therapy for Platinum‑Sensitive Ovarian Cancer: Placebo‑Controlled Randomized Phase III ATALANTE/ENGOT‑ov29 Trial. J Clin Oncol. 2023;41(30):4768–4778. doi:10.1200/JCO.23.00529 . PMID: 37643382 ; PMCID: PMC10602539 .