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Update: PARP Inhibitor Research

by Sue Friedman

PARP inhibitors (PARPis) are experimental medications that were found in early studies to be specifically effective against BRCA-related cancers. These drugs block an enzyme used by cells to mend breaks in DNA. Cancer cells in people with BRCA mutations have problems repairing DNA already, and the PARPis make that worse. Theoretically, these drugs should spare healthy cells that have at least one working copy of the BRCA gene, with limited side effects or toxicity. Because they are not yet FDA-approved, PARPis are not available outside clinical trials, but several such trials are currently recruiting participants.

Early PARPi research generated a lot of excitement. In the first trials, the drugs effectively treated some people with BRCA mutations and advanced cancers, including those who have already undergone multiple prior treatments with standard chemotherapy drugs. Not all patients benefitted, but enough did to warrant larger trials. Overall, PARPis were well tolerated, although some patients developed fatigue, nausea, anemia, and low platelet counts. After early successes, trials that expanded to include more people without BRCA mutations were less successful and received quite a bit of negative attention. But closer inspection revealed several reasons why these later studies may have been less successful. These insights (shown below) provide hope that researching these agents remains worthwhile.

  • A study using the PARPi Olaparib was opened to all women with advanced ovarian cancer, rather than just women with BRCA mutations. The study showed some benefit, but not enough to receive FDA approval.
  • Another Olaparib ovarian study did not show a survival benefit compared to chemotherapy. However, the group that received PARPis appeared to have more women with platinum resistance compared to the non-PARPi group, which may have affected results. Based on this study, researchers believe there is a correlation between platinum sensitivity and PARPi response in ovarian cancer.
  • The drug Iniparib was studied in women with advanced triple-negative breast cancer. The drug worked for some study participants; however, Iniparib did not sufficiently improve overall survival for enough women to be granted FDA approval. Experts believe Iniparib failed in part because the study was open to all women with triple-negative breast cancer— triple-negative breast cancer may behave differently in women with BRCA mutations compared to women without mutations. More importantly, Iniparib is not considered a true PARP inhibitor, and in fact works through a different pathway.

Despite these setbacks, PARPi research continues and is now focused on the population for which these drugs were initially developed: people with BRCA mutations. If these studies are successful, PARPi research could expand to earlier-stage cancers or prevention. Ongoing investigations of PARPis include:

  • A phase II study for women with BRCA mutations diagnosed with ovarian, fallopian tube, or primary peritoneal cancer was conducted through the Gynecologic Oncology Group (GOG) examining the PARPi Veliparib. Results will be reported at the American Society of Clinical Oncology (ASCO) conference in June. If positive, this may pave the way for a larger study that would be open to hundreds of ovarian, fallopian tube, and primary peritoneal cancer patients with BRCA mutations.
  • A phase II study used the PARPi Olaparib to treat almost 300 patients with BRCA mutations and different types of advanced cancers, including pancreatic prostate, breast, and ovarian cancers. The results of this study will be presented at the ASCO meeting in June, and if positive, could lead to expanded studies of PARPis in BRCAmutated cancers.
  • The large BROCADE study is looking at Veliparib in combination with chemotherapy for advanced hereditary breast cancer. This effort includes many study sites across the U.S. and in other countries.
  • Other smaller PARP inhibitor studies are open or will be opening soon, including projects for women with ovarian cancer, and research for early-stage breast cancer patients who have residual cancer after neoadjuvant chemotherapy. Phase III trials in metastatic breast and ovarian cancer are likely to open soon and could provide the data required for FDA approval.

The participation of the HBOC community in PARPi research is critical. If enrollment falls short, scientists and pharmaceutical companies may decide that the HBOC community is too difficult to research, and fewer studies will be designed. If you are interested in participating, ask your oncologist about studies in your area. Prior treatment sometimes affects participation eligibility; if you are newly diagnosed with a primary or recurring cancer, consider enrolling in a PARP inhibitor trial as early after diagnosis as possible. Share this information with friends and relatives. Review the FORCE and clinicaltrials.gov websites for finding PARP inhibitor studies.

PARPi References

Ledermann J, et. al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. Volume 366:15 (2012): 1382-1392.

Kaye SB, et. al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J. Clin. Oncol. Volume 30:4 (2012): 372-379.

Gelmon KA, et. al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncology. Volume 12:9 (2011): 852-861.

Patel AG, et. al. Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro. Clin. Cancer Res. Volume 18:6 (2012): 1655-1662.

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