Olaparib Active Against Advanced Ovarian Cancer and Breast Cancer with BRCA Mutations

Previously treated advanced breast and ovarian cancer patients with BRCA1 or BRCA2 gene mutation may benefit from treatment with the oral investigational drug olaparib. These findings were recently published in the journal The Lancet.[1],[2]

Although most ovarian cancer patients initially respond to platinum-based chemotherapy, most will eventually experience a return (relapse) of their cancer. Treatment of metastatic breast cancer often includes chemotherapy, but options can become limited when the cancer stops responding to conventional chemotherapy regimens. Outcomes remain poor after treatment of relapsed disease, and researchers continue to explore new approaches to treatment.

Targeted therapies are anticancer drugs that interfere with specific pathways involved in cancer cell growth or survival. Some targeted therapies block growth signals from reaching cancer cells; others reduce the blood supply to cancer cells; and still others stimulate the immune system to recognize and attack the cancer cell. Depending on the specific “target,” targeted therapies may slow cancer cell growth or increase cancer cell death.

Olaparib is an oral investigational drug called a PARP inhibitor. The PARP enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. Drugs that inhibit this enzyme may contribute to cancer cell death and increased sensitivity to chemotherapy.

Cancers that result from BRCA1 or BRCA2 gene mutations may be particularly responsive to PARP inhibitors. The BRCA genes provide another source of DNA repair. BRCA gene mutations result in a loss of this DNA repair capability and may make cells particularly vulnerable to the loss of other DNA repair mechanisms such as those provided by PARP.

The current Phase II studies evaluated low and high doses of olaparib in previously treated breast cancer and ovarian cancer patients with BRCA1 or BRCA2 gene mutations. Patients in both studies were treated with either 100 mg or 400 mg of oral olaparib twice a day. The studies was designed to determine overall response rate in 57 ovarian cancer patients and 54 breast cancer patients in order to validate the concept of targeting treatment for the BRCA1 or BRCA2 gene mutation, regardless of disease.

Overall response rate in the ovarian cancer study was 33% in the high-dose group and 13% in the low-dose group. Patients in the low-dose group were reported to have prognostic factors somewhat worse than the patients in the high-dose group in this study.Overall response rate in the breast cancer study was 41% in the high-dose group and 22% in the low-dose group.Side effects were tolerable in both groups.

The researchers concluded that olaparib was active in previously treated ovarian and breast cancer patients and that BRCA1 or BRCA2 mutations may play a role as a predictor for responsiveness to olaparib. Further studies are warranted to confirm these data and determine the role of BRCA mutation as a predictive biomarker that may help individualize treatment strategies for optimal results.

References:

[1] Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. The Lancet [early online publication]. July 6, 2010.

[2] Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. The Lancet [early online publication]. July 6, 2010.

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Tykerb plus Taxol Is Active in Inflammatory Breast Cancer

TykerbR (lapatinib) plus TaxolR (paclitaxel) appears to provide benefit in the initial treatment of inflammatory breast cancer, according to results published in the Journal of Clinical Oncology.

Inflammatory breast cancer (IBC) is the most aggressive and lethal form of breast cancer. Many of these cancers express the tyrosine kinase receptors HER2 and/or EGFR. Tyrosine kinases are proteins involved in the proliferation and survival of cells. Because tyrosine kinases often function abnormally in cancer cells, drugs that interfere with these proteins play an important role in the treatment of several types of cancer. Tykerb is one such drug. It is an oral medication that targets both HER2 and EGFR.

To evaluate the efficacy, safety, and tolerability of first-line treatment of IBC with daily Tykerb followed by daily Tykerb plus weekly Taxol, researchers studied 49 women. Participants were divided into two groups: those with HER2-positive disease and those with HER2-negative, EGFR-positive disease. (However, due to low patient numbers and results from a parallel study indicating a lack of benefit of Tykerb in HER2-negative, EGFR-positive IBC, this group did not continue on the study.) Patients received 14 days of Tykerb followed by 12 weeks of daily Tykerb and weekly Taxol; they then underwent surgery or additional chemotherapy.

The overall response rate for the HER2-positive group was 78%. Common side effects, including diarrhea, rash, nausea, and alopecia, were consistent with expectations and observed in less than half of these patients.

The researchers concluded that daily Tykerb followed by daily Tykerb plus weekly Taxol is active in the treatment of patients with HER2-positive IBC. The combination was generally well tolerated and without unexpected side effects. There are ongoing randomized trials comparing this new approach versus Taxol and Herceptin in women with locally advanced HER2+ breast cancer.

Reference: Boussen H, Cristofanilli M, Zaks T, et al. Phase II study to evaluate the efficacy and safety of neoadjuvant lapatinib plus paclitaxel in patients with inflammatory breast cancer. Journal of Clinical Oncology [early online publication]. June 7, 2010.

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