Abstract P2-09-02: BMN 673 is a PARP inhibitor in clinical development for the treatment of breast cancer patients with deleterious germline BRCA 1 and 2 mutations

Abstract

Background: BMN 673 is the most potent and specific inhibitor of poly-ADP ribose polymerase (PARP) 1 and 2 in clinical development (IC50<1nM). In BRCA-related tumors, which are genetically dependent on PARP-mediated DNA repair by base excision repair, PARP inhibition induces synthetic lethality. Initial phase 1 results have been presented (de Bono et al JCO 31:5s, 2013 suppl; abstr 2580), showing good tolerability and anti-tumor activity with an MTD on a daily, oral dosing schedule of 1000 μ/day. Methods: In this 2-stage study, patients with solid tumors including BRCA-related cancers, were enrolled during dose-escalation followed by an expansion phase at the MTD in breast, ovarian, and pancreatic cancer patients with deleterious germline BRCA mutations and in small cell lung cancer and Ewing sarcoma patients to further characterize safety and efficacy. This abstract summarizes demographics and safety for all patients and efficacy for patients with BRCA-related cancers. Results: As of 17May2013, a total of 1 pancreatic, 18 breast (17F/1M), and 28 ovarian cancer pts with germline BRCA mutations were enrolled at doses from 100-1100 μg/day. All breast cancer patients were treated from 900-1100 μg/day. The median (range) age for all 70 patients is 51.5 (18-81), PS 0 (0-1) and # of prior therapies 4 (1-13), with 47 patients having deleterious BRCA mutations. An MTD of 1000 μg/day was established with thrombocytopenia being dose-limiting. Related adverse events occurring in > 10% of all 70 patients included fatigue, nausea, alopecia, anemia, thrombocytopenia and neutropenia. One patient has had related grade 4 thrombocytopenia. Grade 3 related AE's included fatigue in 1 patient (1%), anemia and thrombocytopenia in 9 each (13%) and neutropenia in 4 (6%). Dose reductions occurred in 11 pts due to myelosuppression. No patients discontinued for adverse events. Response in Germline BRCA PatientsBRCA Tumor TypeNDose Range (μ/day)ResponseBreast18900-11001CR/6PR/5SD≥12 weeksOvarian28100-11001CR/10PR/19GCIG/4SD≥24 weeksPancreas110001 SD ≥ 12weeksTwo of 2 BRCA breast responders had responded to prior platinum while 0 of 4 non-responders to prior platinum responded to BMN 673. Five of 12 breast cancer pts with no prior platinum have responded. Conclusions: BMN 673 is well tolerated with impressive anti-tumor activity in pts with deleterious germ line BRCA mutations. Myelosuppression and fatigue are the primary side effects associated with need for dose reduction. A phase 3 trial in metastatic breast cancer patients with deleterious germ line BRCA mutations is planned with single-agent, once-daily oral dosing of 1000 μg (1 mg) per day. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-02.

Surgical and Systemic Treatment of Hereditary Breast Cancer: A Mini-Review With a Focus on BRCA1 and BRCA2 Mutations

“…Talazoparib is a potent PARP inhibitor which has been studied for the treatment of BRCA1/2 mutation related breast cancer. In the early clinical trial, talazoparib showed promising activity in BRCA1/2 mutation related solid tumors including patients with breast cancer (55). EMBRACA was a phase III open label clinical trial, which randomised 431 metastatic breast cancer patients with germline BRCA1/2 mutations to talazoparib or physician's choice chemotherapy.…”

Systemic Treatment Strategies for Patients with Hereditary Breast Cancer Syndromes

“…Of these 18 patients, 1 had complete response, 6 had PR, and 5 had SD for at least 12 weeks. Notably, four of the BRCA‐associated breast cancer patients enrolled in the trial had not responded to prior platinum, none of which subsequently responded to talazoparib .…”

Standard of Care and Promising New Agents for Triple Negative Metastatic Breast Cancer

“…Promising results were also reported for BMN 673, which is a PARP inhibitor in clinical evaluation in BC patients with deleterious germline BRCA 1 and 2 mutations. Of the 18 patients treated with BMN 673, eight had partial responses [ 82 ].…”