As PARP inhibitors continue to emerge as a novel class of anticancer agents, BMN 673 has entered late-stage clinical development as a treatment for patients with locally advanced or metastatic breast cancer whose tumors test positive for germline BRCA1/2 mutations.
Joanne L. Blum, MD
Director, Hereditary Cancer Risk Program
Texas Oncology-Baylor Charles A. Sammons Cancer Center
As PARP inhibitors continue to emerge as a novel class of anticancer agents, BMN 673 has entered late-stage clinical development as a treatment for patients with locally advanced or metastatic breast cancer whose tumors test positive for germline BRCA1/2 mutations.1
The agent is being compared with treatment of physician’s choice in a phase III trial launched in October with a projected enrollment of 429 participants (Figure). Men and women are eligible. As a class, PARP inhibitors have received renewed attention recently, with several agents advancing in development in both breast and ovarian cancers. One of the first agents to “graduate” from the groundbreaking I-SPY 2 breast cancer clinical trial is veliparib (ABT-888), which also has entered a phase III study.
BMN 673 inhibits PARP 1/2, which are members of the nuclear enzyme poly(ADP-ribose) polymerase family that helps repair single-strand breaks in damaged DNA.2 The compound is an oral small molecule that selectively targets tumor cells with BRCA1, BRCA2, or PTEN gene mutations and is believed to be the most potent PARP inhibitor in development.2 Although the agent has been studied in ovarian cancer and other malignancies, the program is furthest along in breast cancer.
In updated phase I results presented at the 2013 San Antonio Breast Cancer Symposium in December, Mina LA et al3 reported that 13 of 18 patients (72%) with BRCA1/2-mutated breast cancer experienced a clinical benefit response from BMN 673 monotherapy, defined as complete response (CR), partial response (PR) or stable disease ≥24 weeks. The responders included 1 patient with a CR and 7 with a PR. The drug was generally well tolerated, with myelosuppression, fatigue, nausea, and alopecia among the most common adverse events, each occurring among less than onethird of patients.
Although it may be possible for a PARP inhibitor to be effective in tumors without BRCA defects, there is “a heightened sensitivity to tumors in BRCA mutation carriers that make them particularly susceptible to the impact of using a PARP inhibitor,” according to Joanne L. Blum, MD, principal investigator for the study and a medical oncologist who is director of the Hereditary Cancer Risk Program at Texas Oncology-Baylor Charles A. Sammons Cancer Center in Dallas, a practice in The US Oncology Network.
“PARP mediates single-strand break repair through the base excision repair pathway, and BRCA1 and BRCA2 proteins are crucial for homologous recombination for accurate DNA double-strand break repair,” said Blum. “In BRCA1 or BRCA2 mutation carriers, they have lost some of the ability to do this homologous recombination, and in their tumor, which we assume has lost a second copy, they really don’t have any functioning double-stranded, homologous recombination repair. If you knock out this single-strand base repair mechanism that PARP facilitates, by using the PARP inhibitor, then you are making it impossible for that cancer cell to repair DNA damage.”
In addition to BRCA status, a key criterion for the phase III trial now under way is whether a patient has received prior platinum-based treatment for metastatic disease. Blum said phase I findings indicate that patients who are resistant to prior platinum therapy would not benefit from a PARP inhibitor, therefore these patients are excluded from the trial.
Source: NIH Clinical Trials Registry, www.clinicaltrials.gov. NCT01945775
Enrollment in the BMN 673 trial will not be based on hormone status, which Blum said varies with BRCA mutations. “Most BRCA1 tumors, about 90%, are hormone receptor negative,” said Blum. “For BRCA2 mutation carriers, it’s just the reverse—90% are hormone receptor positive, and 10% are hormone receptor negative.”
Blum said patients with breast cancer whose tumors harbor BRCA1/2 mutations make up 5% to 7% of all breast cancers and that many of these patients will be cured before they develop metastatic disease, leaving an “exceedingly small” pool of patients eligible for the trial. She said it would take an international effort to recruit participants for the study.
In addition to US Oncology Research, patients are being recruited through the National Breast Cancer Coalition in the United States and through the international Translational Research in Oncology. BioMarin Pharmaceutical Inc, a California-based company specializing in rare genetic diseases, is sponsoring the clinical trial.
Leonard E. Post, PhD, chief scientific officer at Bio Marin, said the trial would give researchers an opportunity to study BMN 673 in a patient population whose BRCA mutation status provides “a good strong signal” for its potential efficacy.
“If this works well, this might delay when a patient would even need chemotherapy,” said Post. “[Patients] will take a less toxic agent for some period of time early in their disease, and I think that could make a difference. That’s more of a vision right now than anything we’ve proven.”
Post also anticipates that future studies might point to a role for the use of BMN 673 in combination regimens, although perhaps not for BRCA-mutated tumors because they are sensitive to single-agent PARP inhibition.