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Avelumab Plus Talazoparib in Patients With BRCA1/2- or ATM-Altered Advanced Solid Tumors: Results From JAVELIN
Alison M Schram1, Nicoletta Colombo2, Edward Arrowsmith3
1Memorial Sloan Kettering Cancer Center, New York, New York.
Importance:
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.
Objective:
To 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 Participants:
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.
Interventions:
Patients received 800 mg of avelumab every 2 weeks and 1 mg of talazoparib once daily.
Main Outcomes And Measures:
The primary end point was confirmed objective response (OR) per RECIST 1.1 by blinded independent central review.
Results:
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.
Conclusions And Relevance:
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.
Trial Registration:
ClinicalTrials.gov Identifier: NCT03565991.
Insights
The combination of avelumab and talazoparib showed antitumor activity in patients with BRCA1/2 alterations, particularly in BRCA1/2-associated cancers and uterine leiomyosarcoma. Benefit was limited in non-BRCA-associated cancers, and neither cohort met the primary response rate goal.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Nonclinical studies indicate enhanced antitumor activity with combined poly(ADP-ribose) polymerase (PARP) and programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors.
- Identifying specific patient populations who benefit from this combination therapy is crucial.
Purpose of the Study:
- To assess the efficacy of combining avelumab (a PD-L1 inhibitor) with talazoparib (a PARP inhibitor) in patients harboring pathogenic BRCA1/2 or ATM alterations.
- This evaluation was conducted irrespective of the patients' tumor type.
Main Methods:
- A pan-cancer, tumor-agnostic, phase 2b nonrandomized controlled trial enrolled patients with advanced solid tumors featuring BRCA1/2 or ATM alterations.
- Patients received avelumab (800 mg IV every 2 weeks) and talazoparib (1 mg orally daily).
- The primary endpoint was confirmed objective response (OR) rate assessed by blinded independent central review.
Main Results:
- The study enrolled 200 patients (159 in the BRCA1/2 cohort, 41 in the ATM cohort).
- The confirmed OR rate was 26.4% in the BRCA1/2 cohort and 4.9% in the ATM cohort.
- In the BRCA1/2 cohort, responses were more frequent (30.3%) and durable (median 10.9 months) in BRCA1/2-associated cancers and uterine leiomyosarcoma compared to non-BRCA-associated cancers.
Conclusions:
- Neither the BRCA1/2 nor ATM cohort achieved the target objective response rate of 40%.
- The combination of avelumab and talazoparib demonstrated antitumor activity in specific patient subgroups, including those with BRCA1/2 alterations in associated tumor types and uterine leiomyosarcoma.
- Minimal benefit was observed in patients with non-BRCA-associated cancer types, suggesting a need for careful patient selection for this combination therapy.
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