Robust Activity Shown for Investigational PARP Inhibitor BMN673 in BRCA-Related Cancers
In patients with heavily pretreated advanced BRCA-related breast and ovarian cancers, the investigational poly (ADP-ribose) polymerase (PARP) inhibitor BMN673 produced an objective response rate of more than 40% and delayed disease progression by more than 6 months, according to a multicenter phase I first-in-human trial reported at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 19 to 23 in Boston (Abstract C295).
“BMN673 is the most potent PARP inhibitor in clinical development, and it has optimized pharmaceutical properties: It is well absorbed orally, has substantial single-agent antitumor activity, and has a long half-life allowing once-daily dosing,” said Zev A. Wainberg, MD, Assistant Professor of Medicine at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, School of Medicine.
“BMN673 has high single-agent antitumor activity in ovarian and breast cancer patients with deleterious germline mutations of BRCA1 and BRCA2,” he said at a press briefing. “The duration of response and progression-free survival appear to be promising in this early-phase trial.”
In tumors genetically dependent on DNA repair by homologous recombination, PARP inhibition induces synthetic lethality. Its role in BRCA-related breast and ovarian tumors has been known. PARP inhibition has also been shown to be effective in preclinical models of small cell lung cancer and Ewing sarcoma, possibly because these tumors also have high PARP expression.
Study of 87 Patients
The phase I dose-escalation and extension study of BMN673 enrolled a total of 87 patients, mostly with breast cancer, ovarian cancer, small cell lung cancer, and Ewing sarcoma, who had received a median of three prior treatment regimens (range, 1–13).
Phase I response data were reported for 18 patients with germline BRCA-mutated breast cancer, 28 patients with germline BRCA-mutant ovarian cancer, 24 patients with Ewing sarcoma, and 12 patients with small cell lung cancer.
Among 18 patients with germline BRCA-mutated breast cancer (7 with a BRCA1 mutation, 11 with a BRCA2 mutation), responses to single-agent BMN673 were observed in 44%, including one complete response; 72% of patients achieved clinical benefit, with disease stable for at least 24 weeks. At the recommended phase II dose of 1 mg/d, the response rate rose to 50%, and the clinical benefit rate was 86%, Dr. Wainberg reported.
“On the waterfall plot, you see that many patients had a durable response, with several ongoing,” he said.
For the patients with BRCA-related breast cancer, median duration of response to BMN673 was 27.9 weeks and median progression-free survival was 33.1 weeks.
In patients with BRCA-related ovarian cancer, the response rate was 46% and clinical benefit rate was 82% among 26 evaluable patients. Median duration of response was 26.9 weeks, and median progression-free survival was 33.4 weeks.
“The vast majority of patients [70%] also had reductions in CA-125 that were significant,” he noted. “Only one patient had an increase, and several had no change.”
The small cell lung cancer patient cohort—presumed to have non-BRCA disease—proved interesting, and this cohort is being expanded to 20 subjects, he said. Of seven evaluable patients, one had a confirmed partial response and 20% had minor responses.
The responding patient experienced a “dramatic reduction” in the size of a pericardial mass and a reduction in hepatic and pancreatic metastases. “Repeat imaging after 12 weeks of treatment showed complete response of pancreatic metastasis and overall a 55.7% decrease in tumor measurements,” he reported.
Ewing sarcoma patients, on the other hand, had no responses among nine evaluable patients, he reported.
Drug Well Tolerated
BMN673 was generally well tolerated, with the most common drug-related toxicities being myelosuppression, fatigue, nausea, and alopecia, each occurring in less than 30% of patients, Dr. Wainberg reported.
The response, reduction in neutrophils and platelets, and the need for blood transfusions and dose reductions appeared to correlate with BMN673 exposure.
A phase III trial in metastatic breast cancer patients comparing BMN673 at 1 mg/d to physician’s choice of capecitabine, eribulin (Halaven), gemcitabine, or vinorelbine is underway.
The study was sponsored by BioMarin Pharmaceutical.
Dr. Wainberg reported no potential conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
