Avelumab Plus Talazoparib in Patients With BRCA1/2- or ATM-Altered Advanced Solid Tumors

• DOI: 10.1001/jamaoncol.2022.5218
• Publication Date: 2022-11-17T16:01:25Z
• Authors: 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-Has...; Timothy A. Yap
• Keywords: Male; Leiomyosarcoma; 0301 basic medicine; Avelumab; BRCA1 Protein; Talazoparib; Généralités; Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Middle Aged; Poly(ADP-ribose) Polymerase Inhibitors; 3. Good health; 03 medical and health sciences; BRCA1/2; brca; Humans; Female; Immunotherapy; Original Investigation

ImportanceNonclinical 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.ObjectiveTo evaluate whether the combination of avelumab and talazoparib is effective in patients with pathogenic BRCA1/2 or ATM alterations, regardless of tumor type.Design, Setting, and ParticipantsIn 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.InterventionsPatients received 800 mg of avelumab every 2 weeks and 1 mg of talazoparib once daily.Main Outcomes and MeasuresThe primary end point was confirmed objective response (OR) per RECIST 1.1 by blinded independent central review.ResultsA 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.Conclusions and RelevanceIn 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.Trial RegistrationClinicalTrials.gov Identifier: NCT03565991