Insights From: Michael Birrer, MD, ONeal Comprehensive Cancer Center; Ursula A. Matulonis, MD, Dana-Farber Cancer Institute; Kathleen Moore, MD, Stephenson Cancer Center
Ursula A. Matulonis, MD: PARP [poly (ADP-ribose) polymerase] inhibitor development was a little slow to start but eventually picked up. There were a number of different strategies around PARP inhibitor development. There was use as a single agent, so that was 1 trial called Study 12 in which the drug olaparib was being compared with a drug called pegylated liposomal doxorubicin in women with BRCA-mutated recurrent ovarian cancer.
Second was adding olaparib to carboplatin and paclitaxel chemotherapy, compared with carboplatin-paclitaxel chemotherapy alone. And though there was a progression-free survival [PFS] benefit of around 4 months, that trial required the dose reduction of the chemotherapy in addition to the olaparib when the 2 are combined because of the overlapping bone marrow suppression.
And then a third strategy, which is the one that really took hold and progressed further, was to use PARP inhibitors as maintenance therapies. So patients with platinum-sensitive, recurrent, mostly high-grade serous cancers—sometimes high-grade endometrioid cancers—were allowed in as well. And for patients who had penultimate platinum sensitivity and the most recent platinum also showing response, at the completion of the chemotherapy for these patients with recurrent disease, there was a trial called Study 19 that was published in the New England Journal of Medicine a number of years ago. And for those patients, it was a 1:1 randomization between olaparib versus placebo in this very highly distilled patient population of high-grade serous cancer, platinum sensitive to the most recent platinum, and penultimate platinum sensitivity as well. So you’re really distilling out a patient population who has a high degree of platinum sensitivity and thus underlying homologous recombination deficiency.
We saw a benefit of the oral PARP inhibitor versus placebo in terms of delaying progression and improving progression-free survival. And in a retrospective analysis for Study 19, that increase in improvement in progression-free survival was really seen in patients who had underlying BRCA mutations, either somatic or germline. And that improvement in progression-free survival was about 7 months. And that led to SOLO-2, which was mandated by the FDA for approval of PARP inhibitors and focused on this patient population of platinum-sensitive recurrent cancer, mostly high-grade serous, penultimate platinum sensitivity, and most recently sensitive to platinum. They are using a 2:1 randomization of olaparib tablets for SOLO1 versus placebo.
And then there are 2 other trials using niraparib as the PARP inhibitor, which is Tesaro’s PARP inhibitor. A trial called NOVA was an international phase III study of patients who were not just BRCA mutated as in SOLO-2, but now divided women into either germline BRCA-mutated or non-germline BRCA-mutated. And those patients were, before they started on the trial, split into 1 of those 2 groups based upon their germline testing.
In the NOVA trial, patients were grouped into 1 of 2 groups, either germline BRCA positivity or non-germline BRCA positivity. And patients were randomized 2:1 to either niraparib versus placebo and placed into 1 of those 2 groups. And the results of those 2 groups were analyzed simultaneously. And then the third trial was using the PARP inhibitor rucaparib in patients not just with germline BRCA positivity but also either HRD [homologous recombination deficiency]-positive or non–HRD-positive groups: those patients who either did not have a germline or somatic BRCA mutation and were not homologous recombination deficient given what you can pick up on a test.
And in all 3 of those trials, there was a benefit to receiving the PARP inhibitor compared with not receiving the PARP inhibitor in terms of delaying progression or improvement in progression-free survival. And those results were most striking in women who have an underlying BRCA mutation, either germline or somatic. And what’s also really striking is in all 3 of those trials, for the patients who did not receive the PARP inhibitor, their progression-free survivals are quite similar. It’s around 5.5 months.
So it really tells you that in terms of efficacy of these PARP inhibitors, they’re quite similar in how well they work and in how well they delay progression, really showing the greatest benefits in women who have an underlying BRCA mutation and the least benefits in those patients who are not BRCA-mutated, so BRCA wild type, and who have no evidence of homologous recombination deficiency. Even in those patients, there was about a 3-month improvement in PFS. Whereas in patients who have a BRCA mutation, it’s closer to a little under 2 years. So yes, I think the PARP inhibitors are very good PARP inhibitors. Olaparib, niraparib, and rucaparib work in 2 ways: to trap PARP on damaged DNA, now allowing the PARP enzyme to work; and also just inhibiting the PARP enzyme.