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Avelumab Plus Talazoparib in Patients With Advanced Solid Tumors: The JAVELIN PARP Medley Nonrandomized Controlled
Timothy A Yap1, Aditya Bardia2, Michael Dvorkin3
1The University of Texas MD Anderson Cancer Center, Houston.
Importance:
Preclinical data suggest that poly(ADP-ribose) polymerase (PARP) inhibitors have synergistic activity when combined with immune checkpoint inhibitors (ICIs); however, it is unknown which tumor types or molecular subtypes may benefit from this combination.
Objective:
To investigate responses associated with the combination of avelumab and talazoparib in different tumor types and/or molecular subtypes.
Design, Setting, And Participants:
In this phase 1b and 2 basket nonrandomized controlled trial, patients with advanced solid tumors were enrolled in the following cohorts: non-small cell lung cancer (NSCLC); DNA damage response (DDR)-positive NSCLC; triple-negative breast cancer (TNBC); hormone receptor-positive, human epidermal growth factor receptor 2 (ERBB2)-negative, DDR-positive breast cancer; recurrent, platinum-sensitive ovarian cancer (OC); recurrent, platinum-sensitive, BRCA1/2-altered OC; urothelial cancer; metastatic castration-resistant prostate cancer (mCRPC); DDR-positive mCRPC; and BRCA1/2- or ATM-altered solid tumors. Data were analyzed between June 17, 2021, and August 6, 2021.
Interventions:
All patients in phases 1b and 2 received avelumab plus talazoparib.
Main Outcomes And Measures:
The phase 1b primary end point was dose-limiting toxic effects. The phase 2 primary end point was objective response, measured as objective response rate (ORR). Secondary end points included safety, time to response, duration of response (DOR), progression-free survival, time to prostate-specific antigen progression and PSA response of 50% or greater (for mCRPC), cancer antigen 125 response (for OC), pharmacokinetics, immunogenicity, and biomarkers.
Results:
A total of 223 patients (mean [SD] age, 63.2 [11.0] years; 117 [52.5%] men) were treated, including 12 patients in phase 1b and 211 patients in phase 2. The recommended phase 2 dose was avelumab 800 mg every 2 weeks plus talazoparib 1 mg once daily. In phase 2, the ORR was 18.2% (95% CI, 5.2%-40.3%) in patients with TNBC; 34.8% (95% CI, 16.4%-57.3%) in patients with HR-positive, ERBB2-negative, and DDR-positive BC; and 63.6% (95% CI, 30.8%-89.1%) in patients with platinum-sensitive, BRCA1/2-altered OC. Responses occurred more frequently in patients with BRCA1/2-altered tumors. Durable responses were observed in patients with TNBC (median [range] DOR, 11.1 [3.4-20.4] months); HR-positive, ERBB2-negative, and DDR-positive BC (median [range] DOR, 15.7 [3.9 to ≥20.6] months); and BRCA1/2-altered OC (median DOR not reached; range, 5.6 to ≥18.4 months). The most common grade 3 or greater treatment-related adverse events were anemia (75 patients [33.6%]), thrombocytopenia (48 patients [21.5%]), and neutropenia (31 patients [13.9%]).
Conclusions And Relevance:
This nonrandomized controlled trial found that ORRs for avelumab plus talazoparib were comparable with those with PARP inhibitor or ICI monotherapy. Prolonged DOR in patients with TNBC; HR-positive, ERBB2-negative, and DDR-positive BC; and BRCA1/2-altered OC warrant further investigation in randomized clinical trials. These data highlight the importance of prospective patient selection in future studies of ICI and PARP-inhibitor combinations.
Trial Registration:
ClinicalTrials.gov Identifier: NCT03330405.
Insights
The combination of avelumab and talazoparib showed promising objective response rates (ORRs) in specific advanced solid tumors, particularly BRCA1/2-altered ovarian cancer and triple-negative breast cancer. Further research is warranted to confirm these findings in randomized trials.
Area of Science:
- Oncology
- Immunotherapy
- Genomic Medicine
Background:
- Preclinical studies suggest synergistic activity between poly(ADP-ribose) polymerase (PARP) inhibitors and immune checkpoint inhibitors (ICIs).
- Optimal patient selection for this combination therapy remains unclear across different tumor types and molecular subtypes.
Purpose of the Study:
- To evaluate the efficacy and safety of combining avelumab (an ICI) with talazoparib (a PARP inhibitor) in patients with various advanced solid tumors.
- To identify specific tumor types and molecular alterations that may benefit from this combination therapy.
Main Methods:
- A phase 1b/2 basket nonrandomized controlled trial enrolled patients with advanced solid tumors, including non-small cell lung cancer, triple-negative breast cancer, ovarian cancer, urothelial cancer, and prostate cancer.
- Patients received avelumab plus talazoparib, with objective response rate (ORR) as the primary endpoint in phase 2.
- Specific cohorts included DDR-positive and BRCA1/2-altered tumors.
Main Results:
- The objective response rate (ORR) was 18.2% for triple-negative breast cancer (TNBC), 34.8% for HR-positive, ERBB2-negative, DDR-positive breast cancer, and 63.6% for platinum-sensitive, BRCA1/2-altered ovarian cancer.
- Durable responses were observed in TNBC, HR-positive/ERBB2-negative/DDR-positive breast cancer, and BRCA1/2-altered ovarian cancer.
- Common grade 3 or greater adverse events included anemia (33.6%), thrombocytopenia (21.5%), and neutropenia (13.9%).
Conclusions:
- The combination of avelumab and talazoparib demonstrated notable objective response rates in select patient populations, including those with BRCA1/2-altered ovarian cancer and triple-negative breast cancer.
- Prolonged duration of response in these subgroups suggests potential clinical benefit, warranting further investigation in randomized trials.
- Prospective patient selection based on molecular characteristics is crucial for future studies evaluating PARP inhibitor and ICI combinations.
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