Dr. Rachel Grisham MSK ovarian cancer section head discussed clinical trials investigating PARP inhibitors for ovarian cancer patients. The event was a round table discussion and interview for Targeted Oncology.
The doctor first spoke of the factors taken into consideration when physicians choose an initial treatment for advanced-stage cancer patients. These factors include a BRCA mutation in the tumor and responses to chemotherapy.
Recent FDA approvals, studies, and NCCN guidelines have brought about substantial changes in the manner in which patients receive treatment. The guidelines call for molecular testing (looking for changes in genes) at the time of diagnosis.
What is HRD?
When DNA is damaged, which is often, it repairs itself. The process is called homologous recombination (HRD). When the body is deficient in HRD, it is unable to repair double-strand breaks in DNA (HRD deficiency).
Fifty percent of females with high-grade serous ovarian cancer, arising from the serous membrane, are HRD positive. The disease accounts for approximately seventy percent of ovarian cancers.
How Are BRCA1 and BRCA2 Involved?
BRCA1 and BRCA2 genes normally protect the body from cancer because they produce proteins that help to repair breaks in DNA. If, however, the breaks are not repaired and more breaks occur, this can lead to cancer. Mutations in BRCA1 and BRCA2 prevent the production of the repair protein.
Therefore, Dr. Grisham said it is generally recommended that both bevacizumab plus the PARP inhibitor olaparib (Lynparza) be given to people who are HRD positive.
In people who are HRD negative, the tumors have a more difficult time repairing themselves so that bevacizumab could be continued as a single agent.
About the Phase III SOLO-1 Trial
The findings in the Phase III study, SOLO-1, led to the FDA’s approval of olaparib (Lynparza). Olaparib is to be administered to patients with germline (inherited) or somatic (acquired) BRCA mutations as a single agent or combined with bevacizumab as maintenance after a patient’s initial surgery.
According to Dr. Grisham, the majority of patients who participated in the study had been newly diagnosed with germline mutations. All participants had been treated previously with platinum-based chemotherapy.
The results, which Dr. Grisham termed as being “fantastic,” were measured at the end of the study. After a five-year follow-up, the research team still noted a continuation of benefit. Half of the patients in the study experienced a relapse as opposed to almost eighty percent of the patients who received a placebo.
About PARP Inhibitors
Dr. Grisham strongly recommends that whether patients have somatic or germline mutations, they should receive maintenance with a PARP inhibitor. PARP is a protein (enzyme) in cells that helps to repair damaged cells.
In cancer, PARP inhibitors prevent PARP from helping cancer cells repair themselves and the cells die.
Adverse Events
The most common adverse events were headache, fatigue, nausea, and abdominal pain. Anti-nausea medication was used to mitigate nausea.
Information on the PRIMA trial investigating the PARP inhibitor niraparib (Zejula) to treat patients with advanced ovarian cancer, is available here.
About the Phase 3 PAOLA-1 Study
The PAOLA-1 Study examined maintenance therapies using bevacizumab and placebo vs. bevacizumab plus olaparib.
Patients in the PAOLA trial had been diagnosed with advanced ovarian cancer. Treatment consisted of surgery, platinum-based chemotherapy, and bevacizumab (Avastin). The participants were ineligible if they had been treated previously with PARP inhibitor therapy.
As in the SOLO-1 trial, patients in the PAOLA trial experienced either partial or complete responses. The endpoint of progression-free survival was greater in the combined bevacizumab and olaparib group than in the bevacizumab and placebo cohort. The AEs were similar to the SOLO-1 group.
Dr. Grisham’s recommendation is that all patients with either somatic or germline BRCA mutations be given PARP inhibitor maintenance.
