Ovarian Cancer : Episode 14

Case 3: Benefit of PARP Inhibitor Maintenance in Ovarian Cancer


Chad Hamilton, MD: Data supporting a second maintenance platform emerged with the use of PARP inhibitors in these 4 clinical trials that led to 3 FDA approvals in this space. We’ve seen how PARPs have moved from advanced recurrent ovarian cancer to second-line maintenance to first-line maintenance, with the impact of this class of drugs seeming to increase the further we move them up into a patient’s treatment regimen.

These studies demonstrated the benefit of the PARP inhibitors, but as we’ve highlighted, there was differential benefit among biomarker-defined groups. The progression-free survival [PFS] in the germline BRCA [gBRCA] groups ranged, as you can see on the slide, from 11.2 to 15.5 months, and this translated into a 70% to 77% reduction in risk of progression. The progression-free survival, even in the non-gBRCA groups, were also significantly improved, but as we mentioned, not to the extent of the germline or the HRD [homologous recombination deficient]-defined treatment groups.

The randomized phase 3 NOVA trial assessed niraparib as maintenance therapy for patients with platinum-sensitive ovarian cancer in response to their recurrence platinum therapy. The trial consisted of 2 independent cohorts based on germline BRCA status. There was a gBRCA cohort and there was a non-gBRCA. Within each of those, there were randomized 2:1 to niraparib versus placebo. This figure shows the Kaplan-Meier plots of the progression-free survival in the germline BRCA cohort. These curves showed an early and sustained divergence with a median progression-free survival of 21 months in the niraparib group versus 5.5 months in the placebo group, with 62% of women progression free at a year versus 16% in the placebo group, and at 18 months, 50% versus 16%.

The data also demonstrated that niraparib increased PFS regardless of whether the patients had a BRCA mutation when compared to placebo. To highlight your attention, this bottom curve highlights the non-gBRCA cohort with a PFS of 9.3 versus 3.9 months, and then within that group, for those who were HRD-positive, a biomarker demonstrating probably more efficacy in that group, 12.9 versus 3.8 months survival.

I won’t go into all the details of this slide, but for those taking niraparib, grade 3 or 4 adverse events that were commonly reported, as most of us have gotten pretty comfortable with now, are the thrombocytopenia at 34%, anemia at 25%, and neutropenia at 19%. Highlighted here, 66% of the patients had treatment-emergent adverse events that led to dose reduction, with a resulting almost 15% discontinuing treatment because of those adverse events.

The phase 3 ARIEL trial affirmed the results of the NOVA trial as well as SOLO2, which we haven’t had time to highlight, which also has some fairly exciting survival results coming out. As far as ARIEL3, the eligibility criteria were similar to those described in NOVA, but specifically in this trial, women were allowed to enroll if they had bulky residual disease. In contrast to the NOVA trial, the responders in this trial were about two-thirds partial responders versus one-third complete responders, whereas it was about 50/50 in the NOVA trial: a bit poorer prognosis group in the ARIEL3 study.

The primary end point of this was an investigator-assessed PFS in 3 analyzed groups in which they used an ordered step-down, multiple conversions, multiple comparisons procedure, where statistical significance was required in 1 group before moving on to the next nested group. They looked at BRCA mutated as you can see here, HRD, and then in all-comers, intent-to-treat population.

The primary outcome of PFS was significantly longer with rucaparib in each of the 3 analyzed groups. In the BRCA-mutated, HRD, and intent-to-treat population—16.6 versus 5.4 months in BRCA-mutated, 13.6 versus 5.4 months in the HRD group, and even 10.8 versus 5.4 months in the intent-to-treat group. What differentiated ARIEL3 from the other PARP trials is the verification that rucaparib itself was an active agent. Not only was a response to platinum maintained in some patients, but some of the patients with measurable disease also had a continued response on treatment, and 20% achieved an overall response to the rucaparib treatment.

The trials are very similar, but there are subtle differences that it’s important to take note of when comparing these 3/4 trials. Adverse event rates were similar to the other PARP trials: 54% of patients requiring a dose reduction and 13.4% of patients discontinuing treatment.

Transcript edited for clarity.

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