Avelumab Plus Talazoparib in Patients With Advanced Solid Tumors: The JAVELIN PARP Medley Nonrandomized Controlled Trial

Abstract

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.

Figure 1.. Trial Profile

In total, 3 patients in the phase 1b portion experienced dose-limiting toxic effects leading to dose interruption. Of them, 2 patients (with thrombocytopenia) continued therapy following talazoparib dose reductions and recovery of platelet counts. Both patients subsequently discontinued from study treatment because of progressive disease; 1 patient discontinued 2 months after the start of treatment, and 1 withdrew from the study after 10 months of treatment. Only 1 patient permanently discontinued talazoparib because of neutropenia (after approximately 3 months); however, this patient continued to receive avelumab for a total of 5 months before discontinuing because of progressive disease. DDR indicates DNA damage repair; ERBB2, human epidermal growth factor receptor 2; HR, hormone receptor; mCRPC, metastatic castration-resistant prostate cancer; NSCLC, non–small-cell lung cancer; and TNBC, triple-negative breast cancer.

Figure 2.. Best Percentage Change in Size of Target Lesions Assessed by Investigators per RECIST v1.1 While Receiving Treatment in the Dose-Expansion Phase

The blue dashed lines represent the threshold for progressive disease (PD), defined as an increase of at least 20% in target lesion diameter from baseline. The lower dashed lines represent the threshold for a partial response, defined as a decrease of at least 30% in target lesion diameter from baseline. In patients with DNA damage repair–positive (DDR+) status but for whom a DDR alteration is not specified, DDR status was confirmed by germline loss of heterozygosity (gLOH) score. Presence of a germline DDR+ alteration (gDDR) alone did not confirm DDR+ status. In the absence of positive solid tumor or circulating tumor DNA alteration results, detection of a known or likely deleterious germline variant suggested that a patient had a DDR+ tumor, provided that solid tumor and circulating tumor DNA results did not both suggest DDR-negative (DDR−). (Three patients were considered to have DDR+ tumors at enrollment, determined by a gLOH score above the predefined cutoff; however, their tumors were subsequently considered DDR− because of a change in gLOH assay specifications. Two patients were enrolled based on a local test result but received negative results centrally.) Arrows indicate ongoing treatment; bDDR, blood DDR; bTMB, blood tumor mutational burden; ERBB2, human epidermal growth factor receptor 2; HR, hormone receptor; PD-L1, programmed cell death 1 ligand 1; SD, stable disease; tDDR, tumor DDR. For some items, the genetic variation is written in vertical text above the bar, with black font indicating tDDR alteration and teal font, bDDR alteration.