As reported in JAMA Oncology by Schram et al, the phase IIb tumor-agnostic JAVELIN BRCA/ATM trial has shown that the combination of avelumab and talazoparib did not meet the prespecified objective response rate goal among patients with advanced BRCA1/2-altered or ATM-altered solid tumors. The combination appeared to be more active in a subgroup of patients in the BRCA1/2-altered cohort.

Study Details

The study enrolled 159 patients into the BRCA1/2 cohort and 41 patients into the ATM cohort from sites in nine countries between July 2018 and April 2020. Patients received avelumab at 800 mg every 2 weeks and talazoparib at 1 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was confirmed objective response on blinded independent central review, with the objective of achieving a response rate of 40% in each cohort.

Responses

Among the 159 patients in the BRCA1/2 cohort, objective response was observed in 42 (26.4%, 95% confidence interval [CI] = 19.7%–34.0%), including complete response in 9 (5.7%). Median duration of response was 10.9 months (95% CI = 6.2 months to not estimable); responses were ongoing in 17 responders at data cutoff.  Among the 41 patients in the ATM cohort, objective response was observed in 2 (4.9%, 95% CI = 0.6%–16.5%).

In the BRCA1/2 cohort, among 119 patients with BRCA1/2-associated tumor types (defined as breast, ovarian, prostate, and pancreatic cancers) vs 40 with non–BRCA1/2-associated cancer types, objective response rates were 30.3% (95% CI = 22.2%–39.3%), including 8 complete responses, vs 15.0% (95% CI = 5.7%–29.8%). The group with non–BRCA1/2-associated tumor types included three patients with uterine leiomyosarcoma; response was observed in all three, with responses ongoing for longer than 24 months. In an exploratory analysis combining the patients with uterine leiomyosarcoma and those with BRCA1/2-associated tumor types into a group defined as BRCA1/2-dependent cancer types, response rates were 32.0% (95% CI = 23.8%–41.0%) in the BRCA1/2-dependent cancer types group vs 8.1% (95% CI = 1.7%–21.9%) in the non–BRCA1/2-dependent cancer types group, with median response durations of 12.5 months (95% CI = 7.4 months to not estimable) vs 5.8 months (95% CI = 5.7 months to not estimable).

Among patients in the BRCA1/2 cohort with available data, objective response was observed in 5 (62.5%) of 8 patients with tumor mutational burden (TMB) ≥ 10 mut/Mb vs 22 (23.9%) of 92 with TMB < 10 mut/Mb.

Adverse Events

Grade ≥ 3 treatment-related adverse events occurred in 49.0% of all patients, most commonly anemia (34.0%), thrombocytopenia (15.0%), and neutropenia (11.0%). Treatment-related adverse events led to the discontinuation of any study drug in 11 patients (5.5%). Immune-related adverse events occurred in 25 patients (12.5%) and were grade ≥ 3 in 5 (2.5%). No treatment-related deaths occurred.

The investigators concluded, “In this phase IIb nonrandomized controlled trial, neither the BRCA1/2 nor ATM cohort met the prespecified objective response 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.”

Timothy A. Yap, MBBS, PhD, of The University of Texas MD Anderson Cancer Center, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by Pfizer, Merck, and others. For full disclosures of the study authors, visit jamanetwork.com.