Avelumab Plus Talazoparib in Patients With BRCA1/2- or ATM-Altered Advanced Solid Tumors: Results From JAVELIN BRCA/ATM, an Open-Label, Multicenter, Phase 2b, Tumor-Agnostic Trial.

Nonclinical studies suggest that the combination of poly(ADP-ribose) polymerase and programmed cell death 1/programmed cell death-ligand 1 inhibitors has enhanced antitumor activity; however, the patient populations that may benefit from this combination have not been identified.

To evaluate whether the combination of avelumab and talazoparib is effective in patients with pathogenic BRCA1/2 or ATM alterations, regardless of tumor type.

In this pan-cancer tumor-agnostic phase 2b nonrandomized controlled trial, patients with advanced BRCA1/2-altered or ATM-altered solid tumors were enrolled into 2 respective parallel cohorts. The study was conducted from July 2, 2018, to April 12, 2020, at 42 institutions in 9 countries.

Patients received 800 mg of avelumab every 2 weeks and 1 mg of talazoparib once daily.

The primary end point was confirmed objective response (OR) per RECIST 1.1 by blinded independent central review.

A total of 200 patients (median [range] age, 59.0 [26.0-89.0] years; 132 [66.0%] women; 15 [7.5%] Asian, 11 [5.5%] African American, and 154 [77.0%] White participants) were enrolled: 159 (79.5%) in the BRCA1/2 cohort and 41 (20.5%) in the ATM cohort. The confirmed OR rate was 26.4% (42 patients, including 9 complete responses [5.7%]) in the BRCA1/2 cohort and 4.9% (2 patients) in the ATM cohort. In the BRCA1/2 cohort, responses were more frequent (OR rate, 30.3%; 95% CI, 22.2%-39.3%, including 8 complete responses [6.7%]) and more durable (median duration of response: 10.9 months [95% CI, 6.2 months to not estimable]) in tumor types associated with increased heritable cancer risk (ie, BRCA1/2-associated cancer types, such as ovarian, breast, prostate, and pancreatic cancers) and in uterine leiomyosarcoma (objective response in 3 of 3 patients and with ongoing responses greater than 24 months) compared with non-BRCA-associated cancer types. Responses in the BRCA1/2 cohort were numerically higher for patients with tumor mutational burden of 10 or more mutations per megabase (mut/Mb) vs less than 10 mut/Mb. The combination was well tolerated, with no new safety signals identified.

In this phase 2b nonrandomized controlled trial, neither the BRCA1/2 nor ATM cohort met the prespecified OR rate of 40%. Antitumor activity for the combination of avelumab and talazoparib in patients with BRCA1/2 alterations was observed in some patients with BRCA1/2-associated tumor types and uterine leiomyosarcoma; benefit was minimal in non-BRCA-associated cancer types.

ClinicalTrials.gov Identifier: NCT03565991.

JAMA oncology. 2022 Nov 17 [Epub ahead of print]

Alison M Schram, Nicoletta Colombo, Edward Arrowsmith, Vivek Narayan, Kan Yonemori, Giovanni Scambia, Amelia Zelnak, Todd M Bauer, Ning Jin, Susanna V Ulahannan, Marco Colleoni, Philippe Aftimos, Mark T A Donoghue, Ezra Rosen, Vasilisa A Rudneva, Melinda L Telli, Susan M Domchek, Matthew D Galsky, Margaret Hoyle, Colombe Chappey, Ross Stewart, John A Blake-Haskins, Timothy A Yap

Memorial Sloan Kettering Cancer Center, New York, New York., University of Milan-Bicocca and Istituto Europeo di Oncologia, IRCCS, Milan, Italy., Tennessee Oncology/Sarah Cannon Research Institute, Chattanooga., Abramson Cancer Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia., National Cancer Center Hospital, Chuo-ku, Tokyo, Japan., Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy., Northside Hospital Inc, Atlanta, Georgia., Tennessee Oncology/Sarah Cannon Research Institute, Nashville., Division of Medical Oncology, Wexner Medical Center, The Ohio State University, Columbus., Stephenson Cancer Center, Oklahoma City, Oklahoma., Division of Medical Senology, European Institute of Oncology, IRCCS, Milan, Italy., Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium., Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Stanford University School of Medicine, Stanford, California., Basser Center for BRCA , Abramson Cancer Center, University of Pennsylvania, Philadelphia., Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Pfizer, Milan, Italy., Pfizer, San Francisco, California., now with Translational Medicine, Oncology at AstraZeneca, Cambridge, England, United Kingdom., Pfizer, La Jolla, California., The University of Texas MD Anderson Cancer Center, Houston.

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