治疗转移性三阴乳腺癌的药物进展

ASCO 2009: Investigational Agent for Metastatic Triple-Negative Breast Cancer Spotlighted, Hailed

Nick Mulcahy

June 1, 2009 (Orlando, Florida) — Clinicians might eventually have a new therapeutic option for patients with difficult-to-treat metastatic triple-negative breast cancer, according to a new study of an investigational agent.

Results with the agent, known as BSI-201, were presented at a plenary session here at the American Society of Clinical Oncology (ASCO) 45th Annual Meeting, even though they were only from a phase 2 clinical trial.

In combination with conventional chemotherapy, BSI-201 significantly improved overall and progression-free survival in women with metastatic triple-negative breast cancer, compared with chemotherapy alone, said Joyce O'Shaughnessy, MD, from Baylor-Charles A. Sammons Cancer Center in Dallas, Texas.

"It's one of the most exciting findings in breast cancer in a long time," said Eric Winer, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts. Dr. Winer was not involved with the study but moderated a press conference at which BSI-201 was highlighted. He pointed out that the new study results need to be confirmed.

Currently, there are limited treatment options for metastatic triple-negative breast cancer, Dr. O'Shaughnessy lamented. Triple-negative breast cancer is breast cancer that tests negative for estrogen and progesterone receptors and in which the protein HER2/neu is not overexpressed.

The new agent "potentiates" platinum-based chemotherapy and does not add toxicity, noted Dr. O'Shaughnessy. "It's very, very well tolerated," she said.

BSI-201 is an inhibitor of PARP-1, or poly (ADP-ribose) polymerase-1, which is an enzyme involved in DNA repair, especially in the repair of tumor cells. "The thought is that if you inhibit PARP, the chemotherapy might work a whole lot better," said Dr. O'Shaughnessy.

As more is learned about their efficacy, PARP inhibitors, such as BSI-201, might also allow less chemotherapy to be given to cancer patients, added Dr. Winer.

PARPs are currently being studied in a variety of tumor types, including ovarian, endometrial, and nonsmall-cell lung cancer, said Dr. O'Shaughnessy. They also have the potential to be used in melanoma, pancreatic cancer, head and neck cancers, and others, she noted.

A Second PARP Inhibitor at ASCO

Promising phase 2 findings on another PARP were also presented ASCO.

More than one third of women with BRCA1 or BRCA2 mutations and advanced breast cancer that persisted despite previous treatment had tumor shrinkage after receiving the investigational PARP inhibitor olaparib (AstraZeneca), said lead author Andrew Tutt, MB, ChB, PhD, director of the Breakthrough Breast Cancer Research Unit at Kings College in London, England. He spoke at the press conference along with Dr. O'Shaughnessy.

Olaparib is an oral agent and the current study will be followed up with a larger trial.

In the multicenter study, 116 patients with a median age of 52 years were randomized (1:1) to gemcitabine/carboplatin alone or gemcitabine/carboplatin plus BSI-201. Gemcitabine (1000 mg/m²) and carboplatin (AUC=2) were given on days 1 and 8, and intravenous BSI-201 (5.6 mg/kg) was administered biweekly, on days 1, 4, 8, and 11 every 21 days.

The end points were clinical benefit rate (defined by either complete/partial responses or stable disease of at least 6 months), progression-free survival, and overall survival.

Approximately 62% of the BSI-201 group showed clinical benefit, compared with 21% of the chemotherapy-alone group.

The BSI-201 group had a median overall survival of 9.2 months, compared with 5.7 months for the chemotherapy-alone group (P = .0005). Also, the BSI-201 group had a median progression-free survival of 6.9 months, compared with 3.3 months for the chemotherapy-alone group (P < .0001).

"You have to be careful about [putting] too much stock in the P value for overall survival because the study was not designed to assess overall survival," cautioned Dr. O'Shaughnessy.

She also explained that 40 patients from the chemotherapy-alone group crossed over to the BSI-201 group upon disease progression. The overall and progression-free survival data include those 40 patients. When asked if the result could have been even better without the crossover, Dr. O'Shaughnessy said "possibly."

The incidence of adverse effects was similar between the 2 treatment groups, said Dr. O'Shaughnessy. "BSI-201 does not add toxicity," she remarked.

A large phase 3 clinical trial of BSI-201 will start in June 2009, Dr. O'Shaughnessy added.

Dr. O'Shaughnessy disclosed no relevant financial relationships. Her coauthors are all staff members or executives at BiPar Sciences, the developers of BSI-201. Dr. Winer receives research support from Genentech. Dr. Tutt is in an employment or leadership position at the Institute of Cancer Research.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract 3 and CRA501. Presented May 31, 2009.