Abstract OT2-18-01: Harnessing olaparib, palbociclib, and endocrine therapy (HOPE): Phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic breast cancer
Authors: Torres Alexandra , Kokkonen Carey , Oladeji Mary , D'Andrea Kurt , Mick Rosemarie , Narayan Vivek , Mallamaci Michael , Ewing Gayle , Knollman Hayley , Tung Nadine M. , Robson Mark , Nathanson Katherine L. , Domchek Susan , Shah Payal D. 
Published: March 2022

Abstract
Background: Hormone receptor-positive (HR+) metastatic breast cancer (MBC) that occurs in the context of a germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation has dual drivers: hormone receptor signaling and homologous recombination deficiency. The PALOMA-3 trial studied the selective estrogen receptor downregulator fulvestrant and the CDK4 and CDK6 inhibitor (CDK4/6i) palbociclib in patients with HR+ MBC. Compared with fulvestrant and placebo, combination fulvestrant and palbociclib demonstrated significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival. The OlympiAD trial examined patients with HER2-negative MBC and a germline BRCA1/2 mutation who were treated with the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib or non-platinum chemotherapy. Olaparib resulted in improved PFS, double the response rate, and a lower risk of disease progression or death compared to chemotherapy. Despite these remarkable therapeutic advances, resistance to treatment inevitably develops and contributes to mortality in patients with MBC. Targeting dual therapeutic drivers concurrently may delay or circumvent resistance; however, olaparib and palbociclib have overlapping hematologic toxicity and the safety of combined olaparib, palbociclib and fulvestrant has not been determined. Methods: HOPE (NCT03685331) is a phase I/II clinical trial to evaluate the safety and efficacy of olaparib, palbociclib and fulvestrant in patients with HR+ MBC and a pathogenic or likely pathogenic germline or somatic variant in BRCA1/2. Eligible patients are biological males, postmenopausal females, or premenopausal females on ovarian suppression who have an ECOG performance status 0-1, measureable/evaluable breast cancer, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior platinum chemotherapy is allowed for curative intent treatment if completed at least 12 months prior to diagnosis of metastatic disease, or for MBC if there was no progression during therapy. Prior PARPi and prior CDK4/6i are permitted without restriction during phase I, and are permitted during phase II provided there was no progression on these therapies. Treatment (28-day cycles) consists of: olaparib 300mg by mouth twice daily continuously; fulvestrant 500mg intramuscularly on day 1 of each cycle and day 15 of the first cycle; and oral palbociclib once daily on days 1-21. For phase I, palbociclib dose is based on dosing cohort. Dose Levels (DL) are: DL 0 (starting level), 75mg; DL 1, 100mg; DL 2, 125mg. Phase I treatment begins with a 28-day safety run-in of fulvestrant and olaparib alone. For phase II, palbociclib will be dosed at MTD. Subjects will have archival tissue collection or fresh biopsy at baseline as well as research blood samples for cfDNA analysis at baseline, at progression, and at all scan timepoints (every 3 cycles). The phase I primary endpoint is determination of MTD. A 3+3 dose escalation design will be utilized with a 30% rate of dose limiting toxicity (DLT) deemed acceptable, and 6 patients treated at a dose for it to be declared MTD. This schema yields a minimum of 2 and a maximum of 18 patients on the phase I. For the phase II trial, the primary endpoint is PFS estimated using Kaplan-Meier methods and secondary efficacy endpoints are objective response rate and 24-week clinical benefit rate. The phase II trial will evaluate 54 subjects to provide 80% power to detect an increase in PFS from 7 months with olaparib monotherapy to 10 months. Exploratory objectives include examination of baseline tissue for PARPi predictive biomarkers and measures of tumor immunogenicity as well as serial serum evaluation for reversion mutations. Enrollment has begun.
Citation Format: Alexandra Torres, Carey Kokkonen, Mary Oladeji, Kurt D'Andrea, Rosemarie Mick, Vivek Narayan, Michael Mallamaci, Gayle Ewing, Hayley Knollman, Nadine M. Tung, Mark Robson, Katherine L. Nathanson, Susan Domchek, Payal D. Shah. Harnessing olaparib, palbociclib, and endocrine therapy (HOPE): Phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-18-01.