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PARP Inhibitor Research

Presented at 2009 ASCO Conference

by Sue Friedman

Early and promising research on a class of drugs called PARP inhibitors that may work preferentially for hereditary cancers was presented at the 2009 American Society of Clinical Oncology (ASCO) annual conference in Orlando.

One ASCO session presented results from a clinical trial for breast cancer patients with triple-negative cancers—cancers that do not express estrogen receptors, progesterone receptors, or the Her2neu protein. This study is particularly relevant to our community since almost 85% of BRCA1 mutation carriers who have breast cancer have triple-negative disease. Some BRCA2 carriers and women with non-hereditary breast cancer, especially African-American women, also develop triplenegative disease.

This phase II study involved BiPar Sciences’ PARP inhibitor BSI-201. Participants with triple-negative breast cancer that had metastasized beyond the breast and lymph nodes were divided into two groups: one group received a chemotherapy combination of gemcitabine and carboplatin. The other group received both these medications in combination with the PARP inhibitor BSI- 201. Three times as many women who took the PARP inhibitor had improvement of their cancer compared to those who received chemotherapy alone. On average, the PARP inhibitor participants had no disease progression for about 3.5 months longer and lived about 3.5 months longer than those on chemotherapy alone. Side effects were similar in both groups.

A second study investigatedadifferentdrug manufacturer’s PARP inhibitor product, AstraZeneca ’ solaparib, formerly known as AZD2281. Fifty-four women with known BRCA1/ BRCA2 mutations and metastatic breast cancer received the PARP inhibitor as a “single agent,” with no other treatment. The study was open to women whose cancer had progressed after previous courses of chemotherapy. Women in the study took either a low dose (100 mg twice daily) or a high dose (400 mg twice daily) of olaparib orally.

One woman who took the higher dose had a complete response: she was found to have no measurable cancer during the trial. Ten other participants had a partial response—their cancers were measurably smaller or did not increase. The overall positive response rate was 41 percent in the high-dose group and 22 percent in the group who took the lower dose. Side effects were primarily fatigue and nausea, but were not severe. Both BRCA1 and BRCA2 carriers responded favorably, suggesting that the medication is effective for both mutation populations. The presenters also noted that one participant’s lung metastasis has not progressed in the 18 months since she started the study, and she remains on the medication.

A separate phase II clinical trial studied the use of olaparib for advanced ovarian cancer in BRCA mutation carriers. In this research, the olaparib was also given as a single agent to women whose cancers had progressed following several previous courses of chemotherapy. The dose of olaparib studied mirrored the AstraZeneca breast cancer trial: 24 women took a low dose (100 mg twice daily) while 33 women took high dose (400 mg twice daily). The overall response rate was 33% at the higher dose and 12.5% at the lower dose. Among the trial participants, 58% of those in the high-dose group experienced clinical benefit from the olaparib, while 17% of the women on the lower dose experienced clinical benefit. Side effects were mild, including nausea, fatigue and anemia. More serious nausea and low white blood count occurred rarely.

This research shows that olaparib is well-tolerated and active in women with advanced BRCA-associated breast or ovarian cancer. Although exciting, larger studies are needed to show if PARP inhibitors can extend the life of women with advanced cancer. Future studies of women with early-stage disease will be needed to determine if these medications might be used to prevent recurrence in women with early-stage cancer.

PARP Inhibitor Studies

The following studies were enrolling participants in Fall 2009. For a list of all open studies, visit the our “Clinical Trials and Research” area or clinicaltrials.gov.

Study title: Phase II Study of Standard Chemotherapy Plus BSI-201 (a PARP Inhibitor) in the Neoadjuvant Treatment of Triple-Negative Breast Cancer

Cancer type: Breast

Study type: Phase II neoadjuvant study

Details of diagnosis: Stages I–III, triplenegative breast cancer. Open to newlydiagnosed women who have not yet had surgical removal of cancer

Medication/s: PARP Inhibitor BSI-201 and chemotherapy agents gemcitabine and carboplatin.

Location/Contact: Stanford Cancer Center. Contact Meredith Mills (650-724-5223 or bluett@stanford.edu)

 

Study title: Study of Gemcitabine/ Carboplatin, with or without BSI-201, in Patients with ER-, PR-, and Her2-negative Metastatic Breast Cancer

Cancer type: Breast Study type: Phase III randomized trial

Details of diagnosis: Women with triplenegative, metastatic (stage IV) breast cancer

Medication/s: Women will be randomized to receive gemcitabine and carboplatin chemotherapy with or without the PARP inhibitor BSI-201

Location/Contact: 80 U.S. locations. Contact BiPar Sciences (866-668-2232 or clinicaltrials@BiParSciences.com)

 

Study title: Phase I Study of PARP Inhibi tor AZD2281(KU-0059436) Combined with Carboplatin in Breast and Ovarian Cancer in BRCA1/2 Mutation Carriers and Familial Breast and Ovarian Cancer

Cancer type: Breast or ovarian

Study type: Phase I study

Details of diagnosis: Metastatic or unsectable breast or ovarian cancer in women with BRCA mutation or high likelihood of carrying a mutation

Medication/s: Women will receive the PARP inhibitor olaparib and carboplatin chemotherapy

Location/Contact: NIH Bethesda, MD Contact Clinical Trials Referral Office (888-624-1937) or Jennifer Squires, Research Coordinator (301-443-643)

 

Study title: Assessment of Efficacy of AZD2281 in Platinum-Sensitive Serous Ovarian Cancer

Cancer type: Ovarian

Study type: Phase II randomized study

Details of diagnosis: Women with serous ovarian cancer must have completed at least 2 previous courses of platinumcontaining therapy; cancer must be platinum sensitive to the previous 2 chemotherapy regimens. Patients must be enrolled in the study within 8 wks of completion of their final dose of the platinum-containing regimen

Medication/s: Women will receive the PARP inhibitor olaparib or placebo

Location/Contact: AstraZeneca Cancer Study Locator Services (877-400-4656 or astrazeneca@emergingmed.com) or visit www.emergingmed.com/networks/AstraZeneca and refer to ClinicalTrials.gov identifier: NCT00753545

 

Study title: MK4827 in Patients with Advanced Solid Tumors and BRCA Mutant Ovarian Cancer

Cancer type: Ovarian or solid tumors

Study type: Phase I study

Details of diagnosis: Open to people with locally-advanced solid tumors or BRCA mutation and ovarian cancer Medication/s: The PARP inhibitor MK4287 will be administered orally once daily in capsule form in 21-day cycles

Location/Contact: Tampa, FL and Madison, WI. Contact Merck’s clinical trials information center (888-577-8839) and refer to clinicaltrials.gov study identifier: NCT00749502

 

Study title: Study to Assess the Safety and Tolerability of a PARP Inhibi tor in Combination with Gemcitabine in Pancreatic Cancer

Cancer type: Pancreatic

Study type: Phase I study

Details of diagnosis: Open to people with cytologically confirmed adenocarcinoma of pancreas

Medication/s: Patients will receive the PARP inhibitor olaparib and gemcitabine chemotherapy

Location/Contact: AstraZeneca Cancer Study Locator Services (877-400-4656 or astrazeneca@emergingmed.com) or visit www.emergingmed.com/networks/AstraZeneca and refer to ClinicalTrials.gov identifier: NCT00515866

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