Olaparib, an investigational targeted therapy, resulted in a 61.5% response rate among women with platinum-sensitive, advanced ovarian cancer and a BRCA gene mutation. These results were recently published in the Journal of Clinical Oncology.
Although most ovarian cancer patients initially respond to platinum-based chemotherapy, most will eventually experience a return (relapse) of their cancer. Ovarian cancer patients who experience a relapse of their cancer after treatment with platinum-based chemotherapy are characterized as either platinum-sensitive (relapse/progression occurs more than six months after last treatment); platinum-resistant (relapse/progression occurs less than six months after last treatment); or platinum refractory (relapse/progression while undergoing treatment). 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.
In the current study, 50 patients with a BRCA mutation and advanced ovarian cancer were treated with daily olaparib. Olaparib was well tolerated, with the most common side effects being fatigue and mild gastrointestinal symptoms. Platinum-free interval (time-elapsed since completing platinum-based therapy) appears to be associated with the efficacy of olaparib. The response rates listed below are based on reduction in detectable cancer and/or a decline in CA-125 levels.
- 61.5% response rate in platinum-sensitive patients
- 41.7% response rate in platinum-resistant patients
- 15.4% response rate in platinum-refractory patients
The researchers concluded that olaparib showed promising safety and activity in advanced ovarian cancer with a BRCA mutation. They also concluded that resistance to platinum appears to decrease sensitivity to PARP inhibition. These results, however, will need to be confirmed in additional, larger studies.
 Fong PC, Yap TA, Boss DS, et al. Poly (ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer correlating With Platinum-Free Interval. Journal of Clinical Oncology [early online publication]. April 20, 2010.
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