The addition of the PD-1 inhibitor pembrolizumab to weekly paclitaxel, with or without the VEGFA-targeted bevacizumab, significantly improved progression-free survival and overall survival in patients with platinum-resistant recurrent ovarian cancer, in the randomized, double-blind, phase III ENGOT-ov65/KEYNOTE-B96 trial.¹ In patients expressing PD-L1 by combined positive score (CPS; ie, the PD-L1 CPS ≥ 1 population), the median progression-free survival was 8.3 months with pembrolizumab vs 7.2 months with placebo (hazard ratio [HR] = 0.72; P = .0014), crossing the primary endpoint’s prespecified nominal boundary for significance.

An October 2025 press release indicated that an overall survival benefit has now also been confirmed in the intention-to-treat population.² The regimen is now under Priority Review by the U.S. Food and Drug Administration for platinum-resistant recurrent ovarian cancer.

The findings of the first and second interim analyses were presented at a Presidential Symposium of the European Society for Medical Oncology (ESMO) Congress 2025 by Nicoletta Colombo, MD, PhD, of the University of Milan-Bicocca, and Director of the Gynecologic Oncology Program at the European Institute of Oncology.¹ “Pembrolizumab in combination with weekly paclitaxel with or without bevacizumab demonstrated statistically significant and clinically meaningful improvement in progression-free survival regardless of PD-L1 status and in overall survival in participants with PD-L1–expressing tumor (CPS ≥ 1) in ENGOT-ov65/KEYNOTE-B96,” said Dr. Colombo.

This is the first phase III study to report a statistically significant improvement in overall survival with an immune checkpoint inhibitor–based regimen in ovarian cancer.

— NICOLETTA COLOMBO, MD, PhD

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With the additional report of an overall survival benefit in all-comers, she added these comments: “This is the first phase III study to report a statistically significant improvement in overall survival with an immune checkpoint inhibitor–based regimen in ovarian cancer. The observed overall survival is among the longest reported in any clinical trial for platinum-resistant recurrent ovarian cancer, showing a clinically meaningful benefit of this regimen relative to the most active standard-of-care control, which is weekly paclitaxel with bevacizumab in bevacizumab-eligible patients.”

Study Rationale and Details

Platinum-resistant recurrent ovarian cancer remains a significant clinical challenge, with improvements in overall survival difficult to achieve with existing treatments. The phase III AURELIA study³ previously established weekly paclitaxel combined with bevacizumab as an effective chemotherapy regimen in this setting. The rationale for combining the anti–PD-1 drug pembrolizumab with chemotherapy stems from chemotherapy’s potential to enhance antitumor immunity.

The ENGOT-ov65/KEYNOTE-B96 trial evaluated the efficacy and safety of pembrolizumab in combination with weekly paclitaxel, with or without bevacizumab, in patients with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma who had received one to two prior systemic regimens (at least one platinum-based, with at least four cycles in the first line) and had developed platinum-resistant disease (progression within 6 months of platinum therapy). Patients with primary platinum-refractory disease were excluded.

Patients were randomly assigned to either pembrolizumab or placebo, each combined with weekly paclitaxel; bevacizumab was administered based on preplanned use, with treatment continued until disease progression. The primary endpoint was investigator-assessed progression-free survival, with overall survival as the key secondary endpoint.

A total of 643 patients represented 187 sites in 25 countries. Baseline characteristics were well balanced between the two treatment arms. Of note, 72% of patients had a PD-L1 CPS ≥ 1 tumor, and 73% received bevacizumab in the study, with 30% having received prior bevacizumab. A total of 46% had a platinum-free interval of up to 3 months, indicative of highly resistant disease.

Key Findings and Safety

At the first interim analysis, performed at a median follow-up of 15.6 months, the addition of pembrolizumab significantly improved progression-free survival in both prespecified populations:

• In the PD-L1 CPS ≥ 1 population, median progression-free survival was 8.3 months with pembrolizumab vs 7.2 months with placebo (HR = 0.72; P = .0014), crossing the prespecified nominal boundary for significance.
• In the overall (intention-to-treat) population, median progression-free survival was 8.3 months with pembrolizumab vs 6.4 months with placebo (HR = 0.70; P < .0001). This benefit was consistent across various prespecified subgroups and regardless of bevacizumab use.
• In the final analysis for progression-free survival, at a median follow-up of 26.6 months, the secondary endpoint of overall survival was significantly improved in the PD-L1 CPS ≥ 1 population, with a median of 18.2 months vs 14.0 months (HR = 0.76; P = .0053), respectively.

Dr. Colombo emphasized that this 4-month difference in median overall survival was observed despite a high-performing control arm and was consistent across various subgroups, including poor-prognostic subsets such as older patients, those with prior use of PARP inhibitors, and patients with a short platinum-free interval. The addition of pembrolizumab also led to higher objective response rates (53.0% vs 46.6% in the PD-L1 CPS ≥ 1 population) and longer duration of response.

The safety profile was reported to be manageable and consistent with the known profiles of the individual therapies, with no new safety signals. Grade ≥ 3 treatment-related adverse events occurred in 67.5% of participants in the pembrolizumab arm vs 55.3% in the placebo arm. Immune-mediated adverse events were more frequent in the pembrolizumab arm but were predominantly of low grade, though two deaths (one from colitis, one from pneumonitis) were reported. Common treatment-related adverse events included anemia, peripheral neuropathy, and alopecia, mainly attributed to chemotherapy.

DISCLOSURE: Dr. Colombo reported financial relationships with Roche, AstraZeneca, MSD/Merck, GSK, ImmunoGen, Eisai, OncXerna Therapeutics, Nuvation Bio, Gilead Sciences, Regeneron, Novocure, Seagen, AbbVie, Lilly, BeOne Medicines, Corcept Therapeutics, and BioNTech.

REFERENCES

1. Colombo N, Zsiros E, Sebastianelli A, et al: Pembrolizumab vs placebo plus weekly paclitaxel ± bevacizumab in platinum-resistant recurrent ovarian cancer: Results from the randomized double-blind phase III ENGOT-ov65/KEYNOTE-B96 study. ESMO Congress 2025. Abstract LBA3. Presented October 18, 2025.
2. Merck announces phase 3 KEYNOTE-B96 trial met secondary endpoint of overall survival in all comers population of patients with platinum-resistant recurrent ovarian cancer. October 16, 2025. Available at https://www.merck.com/news/merck-announces-phase-3-keynote-b96-trial-met-secondary-endpoint-of-overall-survival-os-in-all-comers-population-of-patients-with-platinum-resistant-recurrent-ovarian-cancer/. Accessed October 27, 2025.
3. Pujade-Lauraine E, Hilpert F, Weber B, et al: Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 32:1302-1308, 2014.

Expert Point of View

Invited discussant Isabelle Ray-Coquard, MD, PhD, an oncologist at the Centre Leon Berard and Professor of Medicine at Université Claude Bernard Lyon I, France, praised the results of the ENGOT-ov65/KEYNOTE-B96 study as “an important step forward after so many years with negative clinical trials exploring immunotherapy in ovarian cancer.”

Isabelle Ray-Coquard, MD, PhD

Dr. Ray-Coquard underscored the significant unmet need in platinum-resistant recurrent ovarian cancer, where disease progression after first-line treatment is common, and effective options have been scarce for more than a decade. She noted the historical challenges for checkpoint inhibitors in ovarian cancer, often deemed an immunosuppressive “cold tumor,” where PD-L1 expression alone has been an unreliable predictor of response.

A Turning Point?

The KEYNOTE-B96 trial represents a turning point, Dr. Ray-Coquard said, as she highlighted a clinically meaningful 4-month overall survival benefit in the CPS (combined positive score) ≥ 1 population (and in the overall population, per an October 2025 press release).¹ She also praised the manageable safety profile of the triplet regimen. Although PD-L1 CPS positivity is a validated biomarker, she added, “before saying this regimen is indicated for all comers/patients, I would like to see the data for the exploratory CPS-negative population, with or without bevacizumab, and the impact of post progression therapies.”

According to Dr. Ray-Coquard, several key elements contribute to this success, foremost being the choice of weekly paclitaxel as the chemotherapy backbone. Paclitaxel does not merely act as an antitumor agent but critically modulates the immune response, making it a “perfect partner for PD-1 inhibition,” she pointed out. The inclusion of bevacizumab, by normalizing the tumor vasculature and reducing immunosuppression, also likely contributed, with the combination of three drugs mechanistically addressing multiple barriers to immune activation. She noted a consistency with exploratory post hoc analyses from the AGO-OVAR 2.29 trial, where weekly paclitaxel enhanced atezolizumab activity.²

Dr. Ray-Coquard further lauded the rigorous methodology of this international study’s phase III design. It had a hierarchical analysis and adequate power, used validated endpoints, and enrolled a well-selected patient population (two prior lines, many with prior bevacizumab, and a substantial biomarker-positive group).

Next Steps

Looking ahead, Dr. Ray-Coquard discussed the complexities of integrating this new strategy into the treatment algorithm, particularly alongside other emerging options such as the antibody-drug conjugate mirvetuximab soravtansine-gynx and the gluococorticoid receptor antagonist relacorilant. She also stressed that defining therapeutic strategies will require considering not just efficacy and safety, but also feasibility, access to bevacizumab, and biomarker selection. She called for an integrated biomarker profiling approach, addressing overlaps with other markers like folate receptor alpha, and collaborative prospective studies to optimize sequencing of active drugs.

“Altogether, these studies are reshaping the post-platinum landscape, and having several options is always important, particularly in this population,” Dr. Ray-Coquard commented. Meanwhile, weekly paclitaxel remains an optimal chemotherapy partner for both bevacizumab and now immunotherapy in platinum-resistant ovarian cancer, she concluded.

DISCLOSURE: Dr. Ray-Coquard reported financial interests with Agenus, AbbVie, Blueprint Medicines, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GSK, MSD, Deciphera, DSI, Immunocore, Lilly, Incite, Scorpion, Antares Pharma, Tubulis, Merck Serono, Novartis, Amgen, MacroGenics, Tesaro, Clovis Oncology, Eisai, Genmab, Gilead Sciences, Regeneron, and Roche/Genentech.

REFERENCES

1. Merck announces phase 3 KEYNOTE-B96 trial met secondary endpoint of overall survival in all comers population of patients with platinum-resistant recurrent ovarian cancer. October 16, 2025. Available at https://www.merck.com/news/merck-announces-phase-3-keynote-b96-trial-met-secondary-endpoint-of-overall-survival-os-in-all-comers-population-of-patients-with-platinum-resistant-recurrent-ovarian-cancer/. Accessed October 27, 2025.
2. Marmé F, Harter P, Redondo A, et al: Atezolizumab versus placebo in combination with bevacizumab and non-platinum-based chemotherapy in recurrent ovarian cancer: Final overall and progression-free survival results from the AGO-OVAR 2.29/ENGOT-ov34 study. 2024 ASCO Annual Meeting. Abstract LBA5501. Presented June 2, 2024.