ORLANDO, May 31 — Patients with triple-negative breast cancer had significant improvement survival with a new class of therapy that targets an enzyme crucial to a cancer’s DNA repair mechanisms, a randomized trial showed.

• Explain to patients that a new type of drug demonstrated activity in advanced breast cancer when used alone or combined with conventional chemotherapy.
• The results came from studies involving relatively few patients.
• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

The breast cancer subtype, which accounts for about 15% of all breast cancer, derives its name from a lack of receptors for estrogen, progesterone, and HER2, which are targeted by many currently available drugs.

Progression-free survival doubled and overall survival increased from less than six months to more than nine in patients with triple-negative disease who were treated with BSI-201 plus chemotherapy, Joyce O’Shaughnessy, M.D., of Baylor Sammons Cancer Center in Dallas, reported at the American Society of Clinical Oncology meeting.

Patients treated with the targeted agent had a total clinical benefit of 62%, compared with 21% in patients who received only chemotherapy (P=0.0002).

The addition of BSI-201 also tripled the overall response rate, while adding no new toxicities, Dr. O’Shaughnessy said during a press briefing.

“The key findings are the event-free and overall survival,” said Dr. O’Shaughnessy. “There was a 50% reduction in the risk of death with BSI-201 in this small randomized phase 2 clinical trial, and that was statistically significant.”

Also at the briefing, a British investigator reported an overall response rate of 41% in a small clinical study of women with BRCA-deficient (mutated) breast cancer treated with another member of the new drug class, known as PARP inhibitors.

Cancer cells make extensive use of the enzyme poly (ADP-ribose) polymerase, or PARP, to repair DNA damage, including damage caused by chemotherapeutic agents.

PARP inhibitors evolved from the rationale that inhibition of the enzyme would disrupt cancer cells’ self-repair mechanisms, thereby potentiating chemotherapy’s ability to inflict DNA damage.

Triple-negative breast cancer is associated with BRCA mutations and defects in DNA repair, which contribute to an aggressive natural history.

Dr. O’Shaughnessy presented data from a clinical trial involving 116 women with metastatic triple-negative breast cancer. The patients received conventional chemotherapy with gemcitabine (Gemzar) and carboplatin and were randomized to BSI-201 or no additional therapy.

The addition of the PARP inhibitor to chemotherapy resulted in an overall response rate of 48% compared with 16% in the chemotherapy-only group (P=0.002).

The median progression-free survival was 6.9 months with BSI-201 versus 3.3 months without (P<0.0001).

Median overall survival was 9.2 months with the targeted agent and 5.7 months with chemotherapy alone (P=0.0005).

British investigators evaluated the oral PARP inhibitor olaparib in patients with BRCA-deficient (mutated) advanced breast cancer, another therapeutically challenging population. All of the patients had chemotherapy-refractory tumors, said Andrew Tutt, M.B. Ch.B., Ph.D., of Kings College in London.

The study involved 54 patients, who received either olaparib 400 mg BID or 100 mg BID. The higher dose led to one complete response and 10 partial responses for an overall response rate of 41% (11 of 27) compared with an overall response rate of 22% (six partial responses) with the lower dose.

Olaparib was well tolerated, with the most common adverse effects being low-grade nausea and fatigue, said Dr. Tutt.

Oncologists have anticipated the development of an effective targeted agent for use in advanced breast cancer, said Eric Winer, M.D., of Dana Farber Cancer Institute in Boston, who moderated the press briefing.

“We have been left largely with chemotherapy alone and there haven’t been any targeted agents,” said Dr. Winer, who was not involved in either study. “This, while still very preliminary, is one of the most exciting things we’ve seen in a long time.”

Investigators in the BSI-201 study included employees of BiPar Sciences. One or more investigators in the olaparib study disclosed relationships with AstraZeneca, Myriad Genetics, Kudos, and the Institute of Cancer Research. Dr. Winer disclosed that he has received research funding from Genentech.

Primary source: Journal of Clinical Oncology

Source reference:

O’Shaughnessy J et al. “Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: results of a randomized phase II trial” J Clin Oncol 2009; 27(15S): Abstract 3.

Additional source: Journal of Clinical Oncology

Source reference:

Tutt A et al. “Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer” J Clin Oncol 2009; 27(15S): Abstract CRA501.

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