LBA35 - Phase II study of PARP inhibitor talazoparib and PD-L1 inhibitor avelumab in patients (pts) with microsatellite stable (MSS) recurrent/persistent endometrial cancer

Background

Preclinical studies have demonstrated synergistic antitumor activity for combinations of PARP inhibitors (PARPi) with PD-1/PD-L1 inhibitors (PD-1/PD-L1i) which is at least partly mediated by activation of the Stimulator of Interferon Genes (STING) pathway. Given that PD-1/PD-L1i exhibit only modest activity as monotherapy against MSS endometrial cancer (EC), we evaluated whether the combination of the PARPi talazoparib and the PD-L1i avelumab would demonstrate promising activity and acceptable toxicity in that setting.

Methods

We conducted a single-arm phase 2 study to evaluate avelumab and talazoparib in recurrent MSS EC (MSS determined by IHC). Eligibility criteria included measurable disease, no limit on prior therapies, and all EC histologies including carcinosarcomas. Co-primary endpoints were objective response rate (ORR) by RECIST 1.1 and progression-free survival rate at 6 months (PFS6). Talazoparib 1mg PO daily and avelumab 10 mg/kg IV every 2 weeks were administered until progression or unacceptable toxicity. A two-stage design was employed to allow for early stopping for futility. In the 1st stage, 16 pts were enrolled; if there were ≥2 ORs or ≥2 PFS6 responses, accrual would continue to the 2nd stage with enrollment of 19 additional pts. Overall, if there were ≥4 ORs or ≥8 PFS6 responses, avelumab+talazoparib would be considered worthy of further study.

Results

As of June, 5th 2020, 35 pts initiated therapy. Three pts exhibited OR [3PRs, ORR 8.6% (95% CI 1.8%-23.1%)] and 8 exhibited PFS6 responses (PFS6 responses by histology: 3 endometrioid, 3 serous, 1 clear cell and 1 carcinosarcoma), 5 ongoing. PFS at 6 months was 25.8% (95% CI 12.4%-41.4%) and median PFS was 3.65 months (95% CI: 2.4-5.4 months). Most common G3+ treatment-related toxicities were anemia (n=16, 45.7%), thrombocytopenia (n=10, 28.6%) and neutropenia (n=4, 11.4%). Seven (20%) pts had dose reductions; no pt discontinued therapy because of toxicity.

Conclusions

Avelumab and talazoparib met the predetermined PFS6 response criterion to be considered worthy of further evaluation in this pt population of recurrent MSS EC. Correlation with biomarkers of response to PARPi and PD-1/PD-L1i is ongoing.

Clinical trial identification

NCT02912572.

Editorial acknowledgement

Legal entity responsible for the study

Panagiotis Konstantinopoulos.

Funding

Pfizer.

Disclosure

P.A. Konstantinopoulos: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Tesaro/GSK; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Alkermes; Research grant/Funding (institution): Merck KGaA; Research grant/Funding (institution): Eli Lilly. J.F. Liu: Advisory/Consultancy, Research grant/Funding (institution): Tesaro/GSK; Advisory/Consultancy, Research grant/Funding (institution): Clovis; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Merck; Advisory/Consultancy: Genentech; Research grant/Funding (institution): 2X Oncology; Research grant/Funding (institution): Aravive; Research grant/Funding (institution): Arch Oncology; Research grant/Funding (institution): Bristol Myers Squibb; Research grant/Funding (institution): CytoMX Therapeutics; Research grant/Funding (institution): Regeneron; Research grant/Funding (institution): Surface Oncology; Research grant/Funding (institution): Vigeo Therapeutics. R.T. Penson: Advisory/Consultancy, Also participation in DSMB: AbbVie; Advisory/Consultancy, Research grant/Funding (institution), Also participation in DSMB: AstraZeneca; Advisory/Consultancy: Clovis; Advisory/Consultancy, Research grant/Funding (institution): Eisai; Advisory/Consultancy, Research grant/Funding (institution): Genentech; Advisory/Consultancy: Janssen Oncology (J&J); Advisory/Consultancy: Merck & Co; Advisory/Consultancy: NewLink Genetics; Advisory/Consultancy: Pieris Pharma Inc; Advisory/Consultancy: Roche; Advisory/Consultancy: Sutro Biopharma; Advisory/Consultancy: Syndax Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (institution): Tesaro; Advisory/Consultancy, Research grant/Funding (institution): Vascular Biogenics Ltd.; Research grant/Funding (institution): Array BioPharma Inc.; Research grant/Funding (institution): Regeneron; Research grant/Funding (institution): Sanofi-Aventis US Llc. G. Fleming: Honoraria (self): Curio Science; Advisory/Consultancy: GSK; Research grant/Funding (institution), Research IP Supply: Corcept; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Tesaro/GSK; Research grant/Funding (institution): Syndax; Research grant/Funding (institution): 47inc; Research grant/Funding (institution): Iovance; Research grant/Funding (institution): Syros; Research grant/Funding (institution): Astex; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Sermonix; Research grant/Funding (institution): Compugen; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Eisai. U.A. Matulonis: Advisory/Consultancy: Novartis; Travel/Accommodation/Expenses: AstraZeneca. All other authors have declared no conflicts of interest.