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PARP inhibitor shows promise in treatment of breast, ovarian cancers
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The novel PARP inhibitor BMN 673 improved response in patients with BRCA-related breast and ovarian cancers, according to study results presented at the International Conference on Molecular Targets and Cancer Therapeutics.
Zev Wainberg, MD, assistant professor of medicine at the UCLA Jonsson Comprehensive Cancer Center, and colleagues evaluated the highly potent (IC50 <5 nm) BMN 673 (BioMarin) in 87 patients with germline BRCA-mutant breast cancer (n=18), germline BRCA-mutant ovarian cancer (n=28), Ewing’s sarcoma family of tumors (n=14) or small cell lung cancer (n=12).
“The rationale for tumor selection in the case of BRCA tumors is based on the premise that the inhibition of PARP results in synthetic lethality in tumors and loss of BRCA protein function,” Wainberg said during a press conference. “In SCLC, it’s based on preclinical data that demonstrated high expression of PARP in SCLC models, and cell lines in in vivo models of SCLC are very sensitive to PARP inhibition. In the Ewing’s sarcoma family of tumors, the common translocations are associated with increased PARP expression, and human models have also been shown sensitive to PARP inhibition.”
The median age of the patients was 53 years. The population had been treated with a mean of three previous chemotherapy regimens.
Each patient received a maximum 1 mg daily of BMN 673.
Twelve of 26 RECIST-evaluable patients with germline BRCA-mutant ovarian cancer demonstrated complete or partial response. The clinical benefit response rate — which included those who demonstrated complete response, partial response or stable disease lasting 24 weeks — was 82%.
The median duration of response in this cohort was 26.9 weeks (95% CI, 15.9-27.4) and median PFS was 33.4 weeks (95% CI, 28.1-40.4).
RECIST criteria for partial or complete response were achieved in 44% of patients with germline BRCA-mutant breast cancer. The clinical benefit response rate was 72%.
Median duration of response for patients with breast cancer was 27.9 weeks (95% CI, 19.9-40.3). Median PFS was 33.1 weeks (95% CI, 13.1-40.4).
Patients with SCLC demonstrated a 55.7% decrease in tumor size after 12 weeks of treatment. Twenty percent of patients achieved minor response. Researchers have initiated an evaluation of BMN 673 in a larger cohort of 20 patients with SCLC, Wainberg said.
No patients with Ewing’s sarcoma demonstrated response.
The treatment was generally well tolerated, Wainberg said. The most common adverse events, observed in 25% to 30% of patients, were mild to moderate myelosuppression with fatigue, nausea and alopecia. Grade 3 adverse events included thrombocytopenia (17.5%), anemia (15%) and neutropenia (6.3%).
Based on these data, researchers have initiated a phase 3 trial designed to evaluate BMN 673 combined with chemotherapy in patients with metastatic breast cancer.
For more information:
Wainberg Z. Abstract #C295. Presented at: International Conference on Molecular Targets and Cancer Therapeutics; Oct. 19-23, 2013; Boston.
Disclosure: The study was funded by BioMarin Pharmaceutical.