The outcomes from the phase III ENGOT-OV43/GOG-3036/KEYLYNK-001 trial in advanced BRCA-nonmutated ovarian cancer indicate a statistically significant and clinically meaningful benefit for the PD-1 inhibitor pembrolizumab and chemotherapy, followed by pembrolizumab plus maintenance with the PARP inhibitor olaparib, in newly diagnosed patients.¹ In addition, pembrolizumab plus chemotherapy, without olaparib, offered benefit in certain patient subsets not receiving the monoclonal antibody bevacizumab, which was a treatment option. Although hypothesis-generating alone, this observation was considered one of the more provocative findings. The results were reported at the 2025 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer by Matthew A. Powell, MD, the Ira C. and Judith Gall Professor in the Division of Gynecologic Oncology at Washington University School of Medicine in St. Louis.

“The study [KEYLYNK-001] met its primary outcome, with improvement in progression-free survival with pembrolizumab and olaparib, regardless of PD-L1 status.”

— MATTHEW A. POWELL, MD

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At a median follow-up of 30.1 months, median progression-free survival was 22.1 months in the pembrolizumab/olaparib arm, compared with 14.6 months in the chemotherapy-alone arm (hazard ratio [HR] = 0.68; P < .0001). At 3 years, 30.9% and 19.7% of the patients, respectively, were progression-free.

“The study met its primary outcome, with improvement in progression-free survival with pembrolizumab and olaparib, regardless of PD-L1 status. These clinically meaningful endpoints continued at our final analysis [at 49.6 months’ follow-up] and were generally consistent across prespecified subgroups,” Dr. Powell said.

The progression-free survival threshold of the other experimental arm—pembrolizumab alone vs chemotherapy in the Combined Positive Score (CPS) ≥ 10 population—was not met. Thus, formal testing of progression-free survival in the intention-to-treat population and overall survival was not performed.

“However, in a post hoc exploratory analysis—and we need to figure out more about this—it was exciting to see a 47% improvement in progression-free survival and a 39% improvement in the death rate,” noted Dr. Powell, “in patients receiving pembrolizumab alone who had low scores on a loss-of-heterozygosity assay, had a CPS ≥ 10, and did not receive bevacizumab. The potentially negative influence of bevacizumab was considered an intriguing finding worthy of more study,” he said.

About KEYLYNK-001

The KEYLYNK-001 trial included 1,367 patients with newly diagnosed stage III or IV epithelial ovarian, primary peritoneal, or fallopian tube cancer that was BRCA-nonmutated. Patients were randomly assigned to one of three arms:

• Pembrolizumab/olaparib: Chemotherapy (paclitaxel/carboplatin) plus pembrolizumab followed by pembrolizumab plus olaparib maintenance (n = 455)
• Pembrolizumab: Chemotherapy (paclitaxel/carboplatin) plus pembrolizumab followed by pembrolizumab maintenance (n = 458)
• Control: Chemotherapy alone (no maintenance; n = 454).

Pembrolizumab was given at 200 mg once every 3 weeks for 35 cycles, chemotherapy (carboplatin/paclitaxel) was given for 6 cycles, and maintenance olaparib at 300 mg twice daily was given for up to 2 years. Bevacizumab could be prescribed during chemotherapy and maintenance, an option chosen by about 45% of physicians/patients. The primary endpoint was progression-free survival, with overall survival being a secondary endpoint.

Under a somewhat complex statistical plan, the investigators evaluated outcomes in the intention-to-treat population and in patients with a CPS ≥ 10. The first interim analysis occurred in January 2023, at a median follow-up of 30.1 months; the final analysis was in August 2024, at a median follow-up of 49.6 months.

Survival Outcomes

In the 587 patients with a CPS ≥ 10, Dr. Powell reported a progression-free survival benefit with pembrolizumab/olaparib vs the control that was similar for the two analyses, a gain of about 8.6 months and hazard ratios of 0.63 and 0.66. Within the intent-to-treat population, the combination provided a significant benefit among patients with a CPS ≥ 10 (HR = 0.66) as well as < 10 (HR = 0.74). In the population with a CPS ≥ 10, there was a benefit whether patients received bevacizumab (HR = 0.75) or not (HR = 0.60).

In the final analysis, no differences were seen with pembrolizumab alone, either in the CPS ≥ 10 (HR = 0.95) or intention-to-treat (HR = 1.01) populations. On either experimental arm, at 48 months, 21% or fewer of both the CPS ≥ 10 and the intention-to-treat populations were progression-free.

More than three-quarters of all patients received chemotherapy after disease progression; many patients received bevacizumab and PARP inhibitors. At the final analysis, neither pembrolizumab alone nor pembrolizumab plus olaparib had a beneficial effect on overall survival. In the CPS ≥ 10 population, the median overall survival was 56.4 months with pembrolizumab (HR = 0.94) and 50.2 months with pembrolizumab/olaparib (HR = 0.98) vs 51.6 months with chemotherapy. In the intention-to-treat population, median overall survival was less than 48 months in all arms.

And What About Bevacizumab?

The investigators looked at outcomes according to loss of heterozygosity [Foundation Medicine assay] and homologous repair deficiency (HRD) [Myriad myChoice CDx assay] as biomarkers that are known predictors of outcomes in ovarian cancer. With a focus on outcomes for patients testing with low loss of heterozygosity, differences were observed in progression-free survival favoring both the pembrolizumab and pembrolizumab/olaparib arms—interestingly, in patients who did not receive bevacizumab. Some, noted Dr. Powell, were “quite striking.”

For example, hazard ratios for pembrolizumab alone for patients with low loss of heterozygosity who were not receiving bevacizumab were 0.56 in the CPS ≥ 10 analysis and 0.66 in the intention-to-treat analysis. For pembrolizumab/olaparib, these hazard ratios were 0.53 and 0.69, respectively.

“We start to see a long tail in the CPS ≥ 10 group, where progressions are slowing down, which is intriguing,” Dr. Powell commented. He reported a median progression-free survival of almost 16 months in the patients with low loss of heterozygosity and a CPS ≥ 10 who were receiving pembrolizumab/olaparib without bevacizumab.

This benefit extended to overall survival, which the investigators found particularly noteworthy among patients randomly assigned to the pembrolizumab-alone arm. Again, in those patients who did not receive bevacizumab, median overall survival was not reached (HR = 0.61 vs controls) in the CPS ≥ 10 group; it was 44.5 months in the intention-to-treat group (HR = 0.80). This means patients with a CPS ≥ 10 treated with pembrolizumab alone and not receiving bevacizumab lived 26 months longer than their peers in the control arm, the investigators calculated.

“For some reason, these patients are living significantly longer [without bevacizumab],” noted Dr. Powell. “We are scratching our heads trying to figure out what is going on here…. Most of the trend seems to be driven by the CPS ≥ 10 patients,” he explained. “Obviously, this is exploratory, but it does come from 141 randomly assigned patients.” 

DISCLOSURE: Dr. Powell reported personal financial relationships with GlaxoSmithKline, Merck, Eisai, Seagen, AstraZeneca, and Aadi Bioscience.

REFERENCE

1. Powell M, Cibula D, Van Nieuwenhuysen E, et al: Chemotherapy with or without pembrolizumab followed by maintenance with olaparib or placebo for first-line treatment of advanced BRCA nonmutated epithelial ovarian cancer: Results from the randomized phase III ENGOT-OV43/GOG-3036/KEYLYNK-001 study. 2025 SGO Annual Meeting on Women’s Cancer. Abstract LBA7. Presented March 15, 2025.

EXPERT POINT OF VIEW

Invited discussant Charles N. Landen, Jr, MD, MS, of the University of Virginia School of Medicine, Charlottesville, noted that KEYLYNK-001 demonstrated a strong benefit for pembrolizumab plus olaparib. “The key findings of the study in BRCA–wild-type patients were that upfront chemotherapy (carboplatin/paclitaxel) with pembrolizumab, and pembrolizumab and olaparib in maintenance, improved progression-free survival overall (hazard ratio = 0.63) and in most subsets, providing an 8.5-month advantage. Surprisingly, there was a benefit in both the CPS [Combined Positive Score] ≥ 10 and < 10 groups, which is a little different from what we’ve seen before with pembrolizumab,” he noted.

Dr. Landen found the nuances in outcomes related to the receipt of bevacizumab in KEYLYNK-001 particularly provocative. “As Dr. Powell mentioned, it was really interesting that in some subsets, bevacizumab seemed to reduce the efficacy of pembrolizumab alone.”

Remaining Questions

According to Dr. Landen, these study findings raise the following questions:

• To what extent is most of the benefit driven by olaparib?
• Should KEYLYNK-001 reanalyze its data with a focus on the use of bevacizumab?
• Going forward, should trials containing pembrolizumab-alone arms exclude the option to use bevacizumab?
• Should clinical trials allow bevacizumab to be given by physicians’ choice (for nonbiologic reasons), or should it be protocol-assigned?

Preclinical research may shed light on the bevacizumab effect, stated Dr. Landen. For example, bevacizumab might be reducing the efficacy of pembrolizumab by suppressing tumor-infiltrating lymphocytes. “We need to see preclinically what’s going on from an inflammatory standpoint in the tumor…,” he continued. “We need a better understanding of how these biologics may be combined.” 

DISCLOSURE: Dr. Landen reported no conflicts of interest.