Health
PARP Inhibitor Maintenance Therapy for Ovarian Cancer
Chirag A. Shah, MD: When we talk about the mechanism of action of PARP inhibitors, it is a molecule that’s primarily involved in DNA repair. In patients who have inherited a predisposition to inhibited DNA repair, our patients with BRCA mutations or other mutations in the Fanconi anemia pathway that are considered BRCA-like, we notice that those patients already have inhibited DNA repair. When they’re treated with platinum-based chemotherapy and there’s DNA damage, and when you come through afterward and inhibit the PARP molecule, which is one of the primary ways to repair DNA, you really get a dual benefit; this is called synthetic lethality. In the patients who don’t have a knockout that’s related to an inhibited mutation, you still can inhibit the repair of that DNA through the poly (ADP-ribose) polymerase pathway. As a result, if there are residual tumor cells still present, even though there’s radiographic and laboratory biomarker, CA-125 [cancer antigen 125]Undoubtedly on a molecular level, there are potentially clinically active cells that are still present. As those cells potentially try to multiply, you’re inhibiting their ability to multiply. by blocking that pathway and going down the much less efficient nonhomologous end junction repair pathway, which ultimately leads to cell death.
At this point, in the first line, we know that PARP inhibitors are efficacious in the treatment of women with ovarian cancers. The efficacy has been proven in 3 large-scale trials. We’ve mentioned 2 of them already, the PAOLA-1 trial, PRIMA, and SOLO-1. These trials all have some subtle differences. The niraparib trial included all comers, so it was any patient who had advanced ovarian cancer that had responded to platinum-based chemotherapy. The SOLO-1 trial was in BRCA-mutated ovarian cancers alone. The PAOLA-1 trial included patients who had BRCA mutations, but also had HRD [homologous recombination deficiency] testing that was evaluated, and the end points were slightly different based upon the inclusion criteria of the patient population. What we know is that all 3 trials met their end points in their respective patient populations, but there’s a fairly large difference between all 3 studies in terms of the patients who were included and in terms of the maintenance treatment options.
In the PRIMA trial, it was 2: 1 randomization of niraparib to placebo. There were similar randomizations, but SOLO-1 was olaparib alone; PAOLA-1 was olaparib plus bevacizumab. What we did find is in the PRIMA trial, niraparib was effective In the overall patient population, there was a greater than 5-month improvement in progression-free survival between patients who were given niraparib compared to the patients who weren ‘t. However, when the subgroup analysis was done, it was effective in HRD patients, like our patient discussed in this case, but also in HRP [homologous recombination proficient] patients and in the BRCA-mutated patients as well. There’s broad evidence of impact.
When the olaparib trial was published, it was similarly a landmark paper, although it preceded the PRIMA trial. We saw some of the biggest improvements in overall progression-free survival in BRCA-mutated patients. When you look at the significant impact across the trials, what we clearly see is based upon the mechanism of action, I feel that there should not be any question about the standard of care being PARP inhibitor maintenance therapy in women with BRCA-mutated ovarian cancer.
Transcript edited for clarity.
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