This article from FORCE explains PARP (
Poly ADP-Ribose Polymerase) inhibitors and their mechanism...
Quote:
PARP Inhibitor research presented at ASCO 2009 Annual Conference
Three promising but early research studies on a class of drugs called PARP Inhibitors which may work preferentially for hereditary cancers were presented at the 2009 American Society of Clinical Oncology Annual Conference in Orlando.
One session presented results from a clinical trial for breast cancer patients with "triple-negative" cancers: cancers which do not express estrogen receptors, progesterone receptors, or the Her2neu protein. This study is particularly relevant to our community since "triple negative breast cancers" are the most common type of breast cancer in BRCA 1 mutation carriers. Approximate 85% of BRCA 1 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 triple-negative disease.
This randomized phase II study looked at the BiPar Sciences PARP Inhibitor BSI 201 in women with triple negative breast cancer which had metastasized (spread beyond the breast and lymph nodes). Women in the study with metastatic breast cancer were chosen randomized to be in one of two groups: one group that received the chemotherapy combination Gemcitabine and Carboplatin and the other group that received those two chemotherapies in combination with the PARP Inhibitor BSI 201 as an intravenous injection. Three times as many women in the PARP inhibitor arm of the study had improvement of their cancer compared to those who received chemotherapy alone. Women on the arm of the study that included PARP inhibitors went about 3 ½ months longer on average than those on chemotherapy alone without their disease progressing and lived about 3 ½ months longer on average than those on chemotherapy alone. Also the group that received the PARP Inhibitors along with the chemotherapy had no higher side-effects than the group on chemotherapy alone.
A second study investigated the AstraZeneca PARP Inhibitor drug formerly known as AZD2281 and now known by the name “olaparib." This phase II clinical trial studied women with known BRCA 1 or BRCA 2 mutations and metastatic breast cancer. In this study the PARP Inhibitor was given as a “single agent” (ie- with no other treatment) to women who had already received previous courses of chemotherapy and had progression of their cancer on prior treatments. Olaparib is an oral medication and women in the study were given one of two doses: a low dose (100 mg 2 times/day) or a high dose (400 mg 2 times/day). The higher dose led to one woman having a complete response (ie-there was no measurable cancer during treatment) and 10 partial responses (the cancer was measurably smaller or did not increase) for an overall response rate of 41%. The response rate with the lower dose was 22%. Most of the side effects were not severe and included primarily fatigue and nausea. Women who responded favorably to treatment included women with BRCA 1 and women with BRCA 2 mutations suggesting that the medication works for both mutation carrier populations. This particular study used the PARP Inhibitor alone. The presenters reported on one woman in the study who had lung metastasis and is still on the medication whose cancer has not progressed in the 18 months since she started the study.
A third study similar to the one presented above investigated olaparib for advanced ovarian cancer in BRCA mutation carriers. This phase II clinical trial studied women with known BRCA 1 or BRCA 2 mutations and recurrent ovarian cancer. In this study the PARP Inhibitor was given as a “single agent” (ie- with no other treatment) to women who had already received several previous courses of chemotherapy and had progression of their cancer on prior treatments. As in the breast cancer study, women in this trial were given one of two doses: a low dose (100 mg 2 times/day) or a high dose (400 mg 2 times/day). 33 were evaluable at 400 mg bd and 24 at 100 mg bd. The overall response rate was 33% at the higher dose(400 mg twice daily) and 12.5% at 100 mg twice daily dose. Of the women on the high dose, 58% experienced clinical benefit and 17% of the women on the lower dose experienced clinical benefit. Side effects were mild, and included nausea (44%); fatigue (35%); and anemia (14%). More serious side effects were rare and comprised primarily of nausea and low white blood cells. The researchers showed that olaparib is well tolerated and active in women with advanced ovarian cancer.
Although exciting, there is more research that is needed. Larger (phase III) studies will help show if PARP inhibitors can extend the life of women with advanced cancer. Future studies on 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.
Currently there are some open PARP inhibitor studies for women with BRCA mutations and cancer but not many.
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