PARP inhibitors active in BRCA1/2, triple-negative breast cancers

2009 ASCO Annual Meeting

Two phase-2 studies presented at the 2009 ASCO Annual Meeting demonstrated that poly (ADP-ribose) polymerase inhibitors BSI-201 and olaparib increased survival and improved response rates in women with metastatic triple-negative and BRCA1/2-negative breast cancers.

“The clinical benefit rate, which is an objective response [defined as] a 30% reduction in tumor volume or stable disease for at least six months, just about tripled with the addition of BSI-201 to gemcitabine/carboplatin, as did the objective response rate,” Joyce O’Shaughnessy, MD, co-director of the Breast Cancer Research Program at Baylor-Charles A. Sammons Cancer Center, Dallas, said during her presentation.

BSI-201 is a small molecular PARP inhibitor that enhances the effects of chemotherapy-induced DNA damage. According to O’Shaughnessy, the drug demonstrated no dose-limiting toxicities in phase-1/2b studies either alone or in combination with chemotherapy.

O’Shaughnessy and colleagues conducted a randomized, phase-2 study in women with metastatic triple-negative breast cancer. Patients were randomly assigned to gemcitabine/carboplatin alone (n=44) or gemcitabine/carboplatin plus IV BSI-201 5.6 mg/kg every two weeks (n=42). The primary endpoints were clinical benefit rate, PFS and OS.

Compared with gemcitabine/carboplatin alone, BSI-201 plus chemotherapy improved clinical benefit rate (12% vs. 52%; P=.0012), median PFS (87 days vs. 211 days; P=.003) and median OS (169 days vs. >254 days; P=.0012). There was no difference in the frequency or nature of adverse events between the treatment arms. According to O’Shaughnessy, to date, about 40% of patients assigned chemotherapy alone crossed over to receive BSI-201.

Olaparib

Results from a second phase-2 study demonstrated a similar benefit from the PARP inhibitor olaparib in women with BRCA1 or BRCA2 mutations.

“This study shows clinical proof-of-concept for targeting abnormal BRCA1 and BRCA2 function in subtypes of breast cancer,” Andrew Tutt, MB ChB, PhD, director of the Breakthrough Breast Cancer Research Unit at Kings College in London, said during his presentation.

The study included 54 patients with BRCA1/BRCA2 mutations and recurrent, measurable chemotherapy-refractory breast cancer. Twenty-seven patients were assigned the maximum tolerated dose of continuous oral olaparib (400 mg twice daily) in 28-day cycles and 27 were assigned continuous oral olaparib 100 mg twice daily. The primary endpoint was best objective response rate; secondary endpoints included PFS and clinical benefit rate.

The objective response rate was 41% in the 400-mg group vs. 22% in the 100-mg group. Complete response occurred in 4% of the 400-mg group vs. zero in the 100-mg group. Thrity-seven percent of patients assigned 400 mg had a partial response vs. 22% of those assigned 100 mg. Median PFS was 5.7 months.

Fatigue, nausea, vomiting and anemia were the most common treatment-related grade-1/2 toxicities. Five patients experienced grade-3 or higher fatigue, nausea and anemia.

For more information:

O’Shaughnessy J. #P3.

Tutt A. #CRA501. Presented at: 2009 ASCO Annual Meeting; May 29-June 2, 2009; Orlando.