September 8, 2020
PARP inhibitors significantly improve outcomes
- PARP inhibitors are available to almost all women, though they may be more effective in those with BRCA gene mutations
- New ASCO guidelines recommend niraparib as maintenance therapy for women with newly diagnosed stage III or IV epithelial ovarian cancer that is in complete or partial response to first-line platinum-based chemotherapy
- Patients treated with a PARP inhibitor had a similar quality of life as those receiving placebo
PARP inhibitors are a class of drugs that inhibit one of the backup systems of DNA damage repair. Ovarian cancers with BRCA1, BRCA2, or certain other mutations have a defect in a major DNA damage repair pathway and are highly dependent on secondary pathways for their survival. Tumors with these types of mutations are the most sensitive to the effect of PARP inhibitors. When exposed to PARP inhibitors, the cancer cells will not be able to effectively repair DNA damage, which will build up and cause the death of the cancer cell — a process called synthetic lethality.
There are other mechanisms by which cells may have lost the primary pathway for DNA repair. There are commercially available tests that can assess if an individual’s cancer has a deficit in the primary mechanism of DNA damage repair, which is called homologous recombination repair deficiency. Carboplatin and other drugs in that class work by causing DNA damage. Sensitivity to these drugs is a rough marker for cancer cells that may have defects in DNA damage repair.
On August 13, 2020, the American Society of Clinical Oncology published guidelines for the use of PARP inhibitors for the management of ovarian cancer. Among these was the recommendation that the PARP inhibitor, niraparib, should be offered as maintenance therapy for all women with newly diagnosed stage III or IV epithelial ovarian cancer that is in complete or partial response to first-line platinum-based chemotherapy.
The Evidence on PARP Inhibitors
The safety and effectiveness of PARP inhibitors among women with advanced stage ovarian cancer following primary therapy has been evaluated in two randomized trials. In SOLO1, patients whose tumors had a somatic or germline BRCA1 or BRCA2 mutation and who experienced a partial or complete response to primary, platinum-based therapy were treated with either the PARP inhibitor, olaparib, or placebo for two years if there was no evidence of disease at the end of therapy or to progression if there was persistent disease.
Patients treated with olaparib had a 70% lower risk of disease recurrence than those treated with placebo. Preliminary data suggest that the time to next treatment or death was significantly improved from 15.1 months in patients receiving placebo to 51.8 months in those receiving olaparib. This degree of improvement in patient outcomes is highly unusual for any anticancer therapy.
In the PRIMA trial, niraparib maintenance for 3 years or until progression of disease in patients with persistent disease was compared to placebo in patients whose cancers had demonstrated some response to platinum-based therapy. This trial included all patients, not just those who had a BRCA1 or BRCA2 mutation. Taking the results for all patients, the time to progression of disease was significantly longer in those receiving niraparib at 13.8 months versus 10.4 months for those receiving placebo.
Patients whose tumors had underlying deficiency in DNA damage repair (homologous recombination repair deficiency) had the best outcomes, with a progression-free survival of 21.9 months as compared to 10.4 months in patients receiving placebo. Patients who did not have an underlying DNA damage repair deficiency (homologous recombination repair proficiency) who received niraparib had a progression-free survival of 8.1 months as compared to 5.4 months in those receiving placebo. This was similar to the roughly three month improvement in progression-free survival seen with the use of bevacizumab during, and as maintenance after primary therapy for advanced ovarian cancer that had led to its approval by the FDA for this indication.
Side Effects and Costs
In both the SOLO1 and PRIMA trials, patients treated with a PARP inhibitor had a similar quality of life as compared to those receiving placebo. Common side effects of PARP inhibitor therapy include fatigue, nausea, vomiting, anemia, decreased white blood cell counts, and decreased platelets. Each PARP inhibitor has its own unique side effects, as well. There appears to be an increased risk of pre-leukemia or leukemia in patients who take PARP inhibitor therapy. Although most patients tolerate PARP inhibitor therapy well, some may require dose adjustments or even discontinuation of therapy.
Finally, there is significant financial toxicity associated with PARP inhibitor therapy, with a third-party payer cost estimated at $14,700 per month in one study. Even for patients with prescription drug coverage, co-pays may be large. There are patient assistance programs available from the manufacturers of both olaparib and niraparib.
PARP inhibitor maintenance has shown clear benefit for patients after the completion of primary therapy for ovarian cancer. The SOLO1 and PRIMA studies demonstrate that there is a gradient in the benefit seen with PARP inhibitor maintenance, with the benefit being greatest among women whose tumors have BRCA1 or BRCA2 mutations, intermediate among women whose tumors have other DNA damage repair deficits (homologous recombination repair deficiency), and least among women whose tumors have intact DNA damage repair mechanisms (homologous recombination repair proficiency).
Given the variable benefit as well as the potential physical and financial toxicity of these agents, the choice for maintenance therapy should be individualized. Knowing the patient’s BRCA1 and BRCA2 mutation status as well as the homologous recombination repair status of the patient’s tumor are important to helping a patient, in collaboration with her oncologist, make an informed decision regarding whether PARP inhibitor therapy is right for her.