Treatment With PARP Inhibitors for Patients With Ovarian Cancer
During a live virtual event, Matthew L. Anderson, MD, PhD, discussed the results of the PRIMA study of niraparib in patients with wild-type and BRCA-mutated ovarian cancer.
How does the PRIMA study (NCT02655016) affect your practice?
I think the importance of this study is it expanded SOLO-1 (NCT01844986) beyond germline mutations in BRCA1 or BRCA2 to include BRCA wild-type as well as other types of homologous repair deficient [HRD] cancer. [They enrolled patients who were] high risk for progressive disease by virtue of being stage III or IV, each individually. A requirement for enrollment was they had achieved either complete response or partial response with treatments of platinum‑based chemotherapy. [They were] randomized 2:1 to either niraparib [Zejula] 300 mg daily or placebo, and the end points that were assessed were progression-free survival by central review.1
What was the makeup of this study?
The characteristics of these patients [were] very well balanced between the arms. There was a little bit of difference in the proportion of patients who received the medication, slightly more patients with stage IV disease in the treatment arm compared with the control arm. A little bit higher proportion of patients who received neoadjuvant therapy compared with control, but in terms of number of previous cycles of chemotherapy, low-grade or high-grade tumor histology series vs endometroid, ECOG performance status, age, the 2 treatment groups were well balanced.
What were the results of this study?
PFS is the primary end point across the entire enrolled study population independent of BRCA mutation status or homologous recombination status and across all‑comers.1 Use of niraparib at starting dose of 300 mg improved PFS at 13.8 months in comparison with 8.2 [months] of PFS for those patients taking placebo. That translated to a hazard ratio of 0.62 that was statistically significant [95% CI, 0.50-0.76; P<.001]; again, you’re seeing a significant proportion of these patients who were kind of having this hysteresis, this kind of potential for increased long-term survival.
If you go back and focus only on outcomes for patients who are deficient in homologous recombination, this can be a couple of different ways.1 This could be BRCA mutated. The homologous recombination could be due to another type of mutation while BRCA1 and BRCA2 remain wild type. If you look across and compare the hazard ratios, again you’ll see an improvement in PFS for patients who are defined as HRD, BRCA1 or BRCA2 mutated or mutation of one of the other genes, PFS at 21.9 months compared with 10.4 months, again statistically significant results [HR, 0.43; 95% CI, 0.31-0.59; P<.001].
There’s a motion toward improved outcomes in patients who are BRCA mutated, kind of consistent with what we’ve seen in other studies that have looked at the use of niraparib in ovarian cancers.2 The responses seem to be most impressive when those patients have a tumor, either germline or somatic inherent to the tumor, that is either a mutation of BRCA1 or BRCA2. Median PFS for those patients in the study [who had a BRCA mutation] was 22.1 months compared with 10.09 months for patients who received placebo [HR, 0.40; 95% CI, 0.27-0.62; P<.001]. Then for the HRD tumors that have wild-type BRCA1 or BRCA2, for that subset of patients, you’ll see that again in this patient population, the patients who received niraparib had a significantly improved PFS, 19.6 months compared with 8.2 months for patients taking placebo [HR, 0.50; 95% CI, 0.31-0.83; P= .006].
Lastly, there were significant numbers of patients with homologous recombination–proficient tumors [and there was] still some benefit.1 Even though we can’t detect the mutation in BRCA1 and BRCA2, some other gene involved, homologous recombination, there’s still some patients mixed into this other subset of ovarian cancers, or some of these that we have not been able to define yet that obtain a benefit from the use of a PARP inhibitor. Median PFS is 8.1 months for patients who had a homologous recombination–proficient tumor yet remain platinum-sensitive compared with the 5.4 months as seen in the group receiving placebo [HR, 0.68; 95% CI, 0.49-0.94; P= .020].
Which other data from this trial are important for clinicians to understand?
When [individuals] went back and looked at the interim analysis of overall survival [OS], huge benefit in terms of favoring niraparib over placebo.2 There seems to be across the entire study, independent of homologous recombination or BRCA mutation status, improvement in OS to 84% among patients taking a PARP inhibitor compared with 77% of patients who received placebo at the 2-year interval time point for this analysis [HR, 0.70; 95% CI, 0.44-1.11]. The magnitude of that improvement appears to be most significant for patients who have homologous recombination–proficient tumors.
Do patients who have HRD tumors seem to do better? Yes. There’s this whole concept of tumor BRCA-ness that has been associated with other studies independent of these with survival in ovarian cancer and for whatever reason this patient seems to do better. Your BRCA patients are going to be the ones who have those long disease-free intervals, which raises the whole series of other interesting questions, and why it’s important to run prospective randomized trials with well-defined subgroups. But even in the homologous recombination–proficient population, PARP inhibitors are helping these patients to live longer. Now part of the problem with this is that the overall incidences of patients’ demise has been low. I would caution [individuals] against overinterpreting this data. But there’s going to be a lot more follow-up as the data continue to occur.
Looking at safety data, if you look at the frequency with which treatment-associated adverse events [AEs] were reported, roughly 70.5% of patients had grade 3 or greater treatment-associated AEs.1 Of those patients, the vast majority led to dose reduction or dose interruption. But again…if you manage the dose reductions or interruptions appropriately, it does not necessarily have to lead to discontinuation. These rates were also significantly higher than those patients receiving placebo.
1. González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019:381(25):2391-2402. doi:10.1056/NEJMoa1910962
2. Han SN, Monk BJ, González-Martín A. Time to first subsequent therapy (TFST) and progression-free survival 2 (PFS2) from the phase 3 randomized, double-blind PRIMA/ENGOT-OV26/GOG-3012 study in patients with newly diagnosed ovarian cancer. Abstract presented at: Society of Gynecologic Oncology 2020 Annual Meeting on Women’s Cancer. Accessed December 13, 2021. https://bit.ly/3rgvggX