乌鸦传媒

AMSTERDAM -- Patients with BRCA-mutant breast or ovarian cancer had high response and clinical benefit rates when treated with an investigational PARP inhibitor, results of a preliminary clinical trial showed.

The response rate with BMN 673 exceeded 40% by RECIST criteria for both tumor types, and 70% of the patients with ovarian cancer had responses by tumor marker criteria.

More than 70% of the breast cancer patients had either objective responses or prolonged stable disease (used as a determinant of clinical benefit). Response and benefit rates were even higher in patients treated with the dose chosen for phase III clinical evaluation, , of Scottsdale Healthcare in Arizona, reported here at the European Cancer Congress.

Platinum sensitivity appeared to predict response to BMN 673 in patients with ovarian cancer.

"Duration of response and progression-free survival appear to be promising in this early-phase trial. BMN 673 is generally well tolerated with the most common drug-related toxicities being myelosuppression, fatigue, nausea, and alopecia, occurring in less than 30% of patients," said Ramanathan.

Invited discussant Peter Dubsky, MD, of the Medical University of Vienna in Austria, cut to the chase in his assessment of the results.

"There is very little to discuss here," said Dubsky. "This is a flat-out, very successful phase I trial."

PARP inhibitors have a checkered history in oncology clinical investigation. Iniparib (BMS-201), the first agent in the class, demonstrated promising activity in early trials involving patients with metastatic triple-negative breast cancer. However, the agent failed to meet the primary endpoint in a phase III clinical trial, leading to discontinuation of clinical development.

Olaparib achieved a favorable clinical record in recurrent ovarian cancer, including significant improvement in progression-free survival (PFS) in a randomized trial. Even so, the manufacturer put clinical development on hold while reviewing data to determine whether the body of clinical results warranted continued development (which recently resumed).

BMN 673 shares attributes common to other PARP inhibitors, such as tumor selectivity, but has demonstrated and more favorable pharmacokinetics.

Ramanathan reported findings from a phase I trial of BMN 673 involving patients with breast, ovarian, and small-cell lung cancer, as well as tumors from the Ewing sarcoma family. The presentation was limited to 28 patients with ovarian cancer and 18 with breast cancer, all with germline BRCA1/2 mutations. Ramanathan said BMN 673 has demonstrated synthetic lethality in tumors with loss of BRCA protein function.

The study population consisted of 45 women and one man with breast cancer. The ovarian cancer group comprised 22 women with platinum-sensitive disease, four with platinum resistance, and two with platinum-refractory tumors. All but 3 of the ovarian cancer patients had platinum-free intervals of at least 6 months.

In the ovarian group, 20 patients had BRCA1 mutations and eight had BRCA2 mutations. Mutation types in the breast cancer group were BRCA1 in seven cases and BRCA2 in 11.

Ramanathan reported that 11 of 28 patients in the ovarian cancer group had partial responses to BMN 673 (seven with BRCA1 mutations and four with BRCA2 mutations). By CA-125 criteria, 13 of 20 patients with BRCA1 mutations and six of eight with BRCA2 mutations responded, resulting in an overall response rate of 70%. Additionally, four patients had stable disease for 24 weeks or longer. Nine patients had normalization of CA-125 levels.

The ovarian cancer group had a median duration of response of 26.9 weeks and median progression-free survival of 32.3 weeks.

Of the 18 patients in the breast cancer group, seven had partial responses, two of them had BRCA1 mutations and five with BRCA2 mutations. Another 5 patients had stable disease for at least 24 weeks. The median duration of response was 27.9 weeks and median PFS was 33.1 weeks.

Adverse events among 80 patients in the overall expansion cohort included fatigue in 28.8%, anemia in 27.5%, alopecia in 26.3%, nausea in 26.3%, thrombocytopenia in 25%, and neutropenia in 15%.

Grade 4 adverse events were limited to a single case of thrombocytopenia. The most common grade 3 events were thrombocytopenia (17.5%) and anemia (15%).

The phase I results will likely make the outcome of a recently launched phase III trial much anticipated, he added. The 429-patient study will consist entirely of women with BRCA-deficient tumors.

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