Olaparib Plus Pembrolizumab Shows Efficacy in HRR Gene–Mutated Advanced Tumors With/Without HRD Positivity

Olaparib Plus Pembrolizumab in

HRR Gene–Mutated Tumors |

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Olaparib (Lynparza) in combination with pembrolizumab (Keytruda) showed promising activity in patients with homologous recombination repair (HRR) mutation– and/​or homologous recombination deficiency (HRD)–positive advanced cancer, especially in those with BRCA1/2-mutated disease, according to data from the tumor-agnostic phase 2 KEYLYNK-007 trial (NCT04123366) presented during the 2025 AACR Annual Meeting.

At a median follow-up of 13.4 months (range, 0.3-51.1), patients with BRCA1/2-mutated disease (subgroup 1; n = 132) experienced an objective response rate (ORR) of 27.3% (95% CI, 19.9%-35.7%), including a complete response (CR) rate of 8.3%. The disease control rate (DCR) was 64.4%. The median duration of response (DOR) was 19.1 months (95% CI, 10.7-not reached [NR]) and the 15-month DOR rate was 53.7%.

At a median follow-up of 10.4 months (range, 0.8-50.6), patients with non–BRCA-mutated disease with an HRR gene mutation (subgroup 2; n = 104) achieved an ORR of 11.5% (95% CI, 6.1%-19.3%), with a 1.9% CR rate; the DCR was 67.3%. Additionally, the median DOR was 8.3 months (95% CI, 4.2-NR) and the 15-month DOR rate was 47.6%.

At a median follow-up of 10.8 months (range, 1.0-50.3), the ORR among patients with HRR wild-type/HRD-positive disease (subgroup 3; n = 96) was 12.5% (95% CI, 6.6%-20.8%) and 5.2% of patients achieved a CR. The DCR was 62.5% and the median DOR was 11.5 months (95% CI, 6.2-26.7). The 15-month DOR rate was 41.7%.

“To the best of our knowledge, this is the largest dataset of molecularly-selected patients with HRR [gene]–mutated or HRD-positive, tumor-agnostic, advanced tumors treated with the combination of a PARP inhibitor and an anti–PD-1 or –PD-L1 [agent],” Timothy A. Yap, MBBS, PhD, FRCP, said during the presentation. “Early signals of durable antitumor efficacy were observed with this combination using molecularly-selected strategies in multiple indications where olaparib and/or pembrolizumab are not currently approved.”

Yap is the Ransom Horne, Jr. Endowed Professor for Cancer Research in the Division of Cancer Medicine, and vice president, head of clinical development in the Division of Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center (MD Anderson) in Houston. He is also a professor in the departments of Investigational cancer therapeutics (Phase I Program) and thoracic/head and neck medical oncology at MD Anderson.

Examining the Study Design and Baseline Characteristics

KEYLYNK-007 enrolled patients with HRR gene–mutated and/or HRD-positive advanced tumors who were ineligible for curative treatment and experienced disease progression following standard therapy. Eligible patients needed to be naive to PARP inhibitors and immunotherapy and have an ECOG performance status of 0 or 1. Patients in all 3 subgroups received olaparib at a dose of 300 mg twice daily in combination with 200 mg of intravenous pembrolizumab every 3 weeks for up to 35 cycles.

The primary end point was ORR per RECIST 1.1 criteria or Prostate Cancer Working Group–modified RECIST 1.1 criteria by blinded independent central review. Secondary end points included DOR, progression-free survival (PFS), overall survival (OS), and safety.

At baseline, the median age of the overall population (n = 332) was 58.5 years (range, 19-87). Most patients were females (55%) and had an ECOG performance status of 1 (57%). In terms of platinum status, patients had platinum-sensitive (41%), -resistant (23%), or -refractory (4%) disease and 33% did not receive platinum. Patients underwent 0 (6%), 1 (44%), 2 (29%), or 3 or more (20%) prior lines of systemic chemotherapy; these data were missing in 3 patients. Thirty-nine percent of patients had a PD-L1 combined positive score (CPS) of less than 1, 37% had a PD-L1 CPS of at least 1, and 23% were missing these data.

In subgroup 1, the most common tumor types were biliary (12%), pancreatic (11%), colorectal (9%), leiomyosarcoma (9%), and gastroesophageal (8%). The most common tumor types in subgroup 2 were prostate (15%), breast (15%), colorectal (14%), ovarian (10%), and pancreatic (8%). The most common mutation sites in subgroup 2 included ATM 27 (26%), CDK12 (17%), CHEK2 (14%), BRIP1 (10%), and PALB2 (10%). The most common tumor types in subgroup 3 were ovarian (24%), breast (17%), non–small cell lung cancer (10%), colorectal (8%), and sarcoma (7%).

Additional Data and Safety Findings

Additional findings demonstrated the median PFS in subgroups 1, 2, and 3 was 4.4 months (95% CI, 4.1-8.2), 3.7 months (95% CI, 2.3-4.1), and 4.1 months (95% CI, 2.2-5.7), respectively. The respective 12-month PFS rates were 31.6%, 9.3%, and 12.0%.

In subgroups 1, 2, and 3, the median OS was 14.0 months (95% CI, 11.5-17.4), 10.4 months (95% CI, 7.9-14.6), and 10.8 months (95% CI, 8.3-15.5), respectively. The respective 12-month OS rates were 57.2%, 47.1%, and 47.9%.

In the overall safety population (n = 322), any-grade and grade 3 to 5 treatment-related adverse effects (TRAEs) were reported in 84% and 30% of patients, resepectively. One TRAE leading to death occurred and 5% of patients were forced to discontinue treatment due to a TRAE.

The most common any-grade TRAEs occurring in at least 10% of patients included anemia (40%), nausea (36%), and fatigue (15%). Grade 3 or higher TRAEs included anemia (17%), nausea (1.2%), fatigue (1.0%), hypothyroidism (1.0%), asthenia (1.0%), and decreased appetite (1.0%). Any-grade immune-mediated adverse effects included hypothyroidism (any grade, 16%; grade ≥3, 1.0%) and hyperthyroidism (any grade, 5%).

“The combination of olaparib and pembrolizumab demonstrated a manageable safety profile with no new safety signals. A biomarker analysis is currently ongoing for other predictive biomarkers of response,” Yap said in conclusion.

Disclosures: Yap reported being a consultant for AbbVie, Acrivon, Adagene, Aineid Therapeutics, Almac, Alterome Therapeutics, Aduro, Amgen, Amphista, Artios, Astex, AstraZeneca, Atavistik, Athena, Atrin, Avenzo, Avoro, Axiom, Baptist Health Systems, Bayer, Beigene, Bicycle, BioCity Pharma, Bloom Burton, Blueprint, Bluestar Bio, Boxer, BirdGene Biosciences, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research Horizons, Cancer Research UK, Carrick Therapeutics, Circle Pharma, Clasp, Clovis, Cybrexa, Daiichi Sankyo, DAiNA, Dark Blue Therapeutics, Dawn Manco, Debiopharm, Diffusion, Duke Street Bio, 858 Therapeutics, EcoR1 Capital, Eikon, Elipses Pharma, EMD Serono, Entos, Flagship Pioneering, Forbion, FoRx Therapeutics AG, F-Ster, Genesis Therapeutics, Genmab, Glenmark, GLG, Globe Life Sciences, Greu Wolf Therapeutics, GSK, Guardant, Guidepoint, Ideaya Biosciences, Idience, Ignyta, I-Mab, ImmuneSensor, Impact Therapeutics, Insitut Gustave Roussy, Intellisphere, Jansen, Jazz Pharma, Joint Scientific Committee for Phase I Trials in Hong Kong, Kyn, Kyowa Kirin, Lumanity, MEI Pharma, Mereo, Merck, Merit, Monte Rosa Therapeutics, Natera, Nested Therapeutics, Nexys, Nimbus, Novocure, Odyssey Therapeutics, OHSU, OncoSec, Ono Pharma, Onxeo, PanAngium Therapeutics, Pegascy, PER, Pfizer, Piper-Sandler, Pliant Therapeutics, Plexium, Prelude Therapeutics, Prolynx, Protai Bio, PSIM, Radiopharma Therapeutics, Repare, resTORbio, Roche, Ryvu Therapeutics, SAKK, Sanofi, Schrodinger, Servier, Stablix, Synnovation, Synthis Therapeutics, Tango TCG Crossover, TD2, Techspert.io, Terremoto Biosciences, Tessellate Bio, Theragnostics, Terns Pharmaceuticals, Thryz Therapeutics, Tolremo, Tome, Trevarx Biomedical, Varian, Veeva, Versant, Viblioma, Vivace, Voronoi, Xinthera, Zai Labs, and ZielBio. He also received grant/research support from 858 Therapeutics, Accent, Aprea Therapeutics, Artios, AstraZeneca, Bayer, Beigene, BioNTech, Blueprint, BMS, Boundless Bio, BirdGene BioScience, Circle Pharma, Clovis, Constellation, CPRIT, Cyteir, Department of Defense, Eisbach Bio, Eli Lilly, EMD Serono, Exelixis, Forbius, F-Start, GlaxoSmitheKline, Genentech, Gilead, Golfers Against Cancer, Haihe, Ideaya, ImmuneSensor, Insilico Medicine, Ionis, Ipsen, Jounce Karyopharm, KSQ, Kyowa, Loxo Oncology, Merck, Mirtai, Novartis, NIH/NCI, Pfizer, Piliant, Prelude, Ribon Therapeutics, Regeneron, Repare, Roche, Rubius, Sanofi, Scholar Rock, Seattle Genetics, SpingWorks, Synnovation, Tango, Tesaro, V Foundation, Vivace, Zenith, and Zentalis.

Reference

Yap TA, Shapira-Frommer R, Lugowska I, et al. KEYLYNK-007: tumor agnostic trial of olaparib plus pembrolizumab in homologous recombination repair mutation- and homologous recombination deficiency- positive advanced cancers. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT004.