Maintenance PARP Yields Impressive PFS Benefit in Recurrent, Platinum-Sensitive Ovarian Cancer

The addition of PARP inhibitors, such as olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca), to the maintenance treatment of patients with recurrent platinum-sensitive ovarian cancer has led to significant progression-free survival (PFS) benefit, regardless of mutational status, according to Amanda L. Jackson, MD, who added that now, the challenge will be to determine the optimal time to administer this treatment.

The PFS benefit with these agents were demonstrated in the phase 3 SOLO-2, NOVA, and ARIEL3 trials, respectively. In the SOLO-2 trial, results showed an investigator-assessed median PFS of 19.1 months (95% CI, 16.3-25.7) with olaparib versus 5.5 months with placebo (95% CI, 5.2-5.8; HR, 0.30; 95% CI, 0.22-0.41; P < .0001) in patients with platinum-sensitive relapsed ovarian cancer.¹ Results from the final analysis of the trial also showed an improvement in median overall survival with olaparib versus placebo at 51.7 months versus 38.8 months, respectively (HR, 0.74; 95% CI, 0.54-1.00; P =.0537).²

In the NOVA trial, niraparib also demonstrated an improvement in PFS compared with placebo in patients with (HR, 0.24; 95% CI, 0.13-0.44; P < .0001) and without a germline BRCA mutation (HR, 0.35; 95% CI, 0.23-0.53; P < .0001) who had a partial response to their last platinum-based treatment.³ Those who had a complete response to their last treatment and did not have a BRCA mutation experienced a significant PFS benefit with niraparib (HR, 0.58; 95% CI, 0.38-0.87; P =.0082).

In the ARIEL3 study, patients with ovarian cancer associated with a mutation in a non-BRCA homologous recombination repair gene were randomized to receive either rucaparib (n = 28) or placebo (n = 15). Results showed a median PFS was 11.1 months versus 5.5 months, respectively (HR, 0.21; 95% CI, 0.09-0.50).⁴

“The ARIEL3, NOVA, and SOLO-2 trials have definitely changed how we practice and treat patients with ovarian cancer. We know that there is a role for PARP maintenance [in these patients], because it seems to increase the time until they recur,” said Jackson. “In the frontline setting, hopefully, [PARP maintenance will] push even more patients into permanent remission. These studies help us see that all our patients benefit from a PARP inhibitor. It's just figuring out what's the best time to give it to them.”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Ovarian Cancer, Jackson, an associate professor of Obstetrics & Gynecology and division director of the University of Cincinnati Health, discussed the role of PARP inhibitors in the maintenance treatment of patients with recurrent platinum-sensitive ovarian cancer.

OncLive^®: What recent developments have been made in second-line maintenance therapies for patients with platinum-sensitive ovarian cancer?

Jackson: Currently, ovarian cancer has had so many advances and a lot of forward movement. [In terms of maintenance therapy] in this disease, [we have] 3 PARP inhibitors that are approved for use. Previously, bevacizumab (Avastin) was approved as a maintenance [therapy]. As such, we have 2 drug classes and 4 drugs total that have been approved in this setting for patients with recurrent, platinum-sensitive ovarian cancer.

When is it best to use a VEGF inhibitor versus a PARP inhibitor? What are the factors that you consider when making this decision?

A lot of this decision has to do with what a patient previously received for treatment and how they present with their cancer. With the new approval of PARP inhibitors for frontline maintenance, we are definitely going to see an increasing number of patients coming into their recurrence having [already been treated with] a PARP inhibitor.

If the patient hasn’t received a PARP inhibitor, then that’s definitely something that I [would] think of using, especially if they have homologous recombination deficiency or if they have a BRCA mutation, because we definitely know that they will experience significant benefit; however, we do see benefit [with these agents] across the board.

You also need to look at how [their disease] presented. Do they present with a lot of ascites or carcinomatosis? If they did, then we know that bevacizumab is useful. It’s all about looking at what they received in the frontline [setting] and then ensuring that we maximize [benefit] and expose patients to maintenance medications they haven't already received.

Could you highlight the key data from the NOVA, SOLO-2, and ARIEL3 trials?

The 3 key studies that looked at PARP inhibitors for the maintenance treatment of [patients with] platinum-sensitive ovarian cancer [were: NOVA, SOLO-2, and ARIEL3]. Participants all had received 2 or more previous platinum regimens and [achieved] a complete or a partial response to their platinum-containing regimen. The end points across the board were looking at PFS.

SOLO-2 varies a little bit from the other 2 trials because it looked at [patients with] BRCA1/2-mutated disease; this is the group that we know has a great response to PARP inhibitors. SOLO-2 was a double-blind, placebo-controlled phase 3 trial where [investigators] randomized patients in a 2:1 fashion [to olaparib or placebo]. With that study, we saw significant improvements in PFS in patients who were treated with the PARP inhibitor. The patients who received olaparib in that study experienced a PFS of 19.1 months versus approximately 5.5 months if they were on placebo. [These were] very impressive results.

NOVA examined niraparib as a maintenance treatment. Again, these [received] 2 or more [prior] treatments and had to have responded to their last platinum agent. This study looked at all patients with recurrent platinum-sensitive ovarian cancer. Patients were stratified based on whether they had a germline BRCA mutation. Again, [investigators] looked at how patients responded, [as well as] PFS benefit.

Similarly, we saw that patients experienced an improvement in PFS when they were treated with niraparib versus placebo maintenance, with the most significant improvement being about 15 months in the BRCA carriers. However, even in the patients [whose tumors] did not harbor a BRCA mutation, we saw almost a 6-month improvement in PFS. The NOVA study had similar adverse effects (AEs) [to those seen with olaparib], but with niraparib we see a slightly higher rate of thrombocytopenia. This is before [we] started using [platelet counts] and [body] weight [to find the optimal dosage for niraparib], so maybe that [rate] will be lower in current practice.

Finally, ARIEL3 looked at rucaparib for platinum-sensitive maintenance. How this study varies from the others is that investigators allowed patients with some residual bulky disease to still enroll. In contrast, most of the other studies [didn’t allow patients to] have anything bigger than 2 centimeters. As such, this is potentially a more difficult group to treat. Investigators allowed all comers to enroll, as well.

Again, patients were stratified based on BRCA mutational status. They put BRCA carriers, germline and somatic, into 1 group, and then patients who did not have a mutation were put into the other group. Then, they further stratified those patients based off of their loss of heterozygosity into low-, high-, and intermediate groups. The BRCA carriers had about an 11-month improvement in PFS, noting again that this group probably had more disease going into the clinical trials. However, we did see an improvement across all the study arms.

What should be known about the differing toxicity profiles of the PARP inhibitors available in this setting?

Across the board for PARP inhibitors, we always think about thrombocytopenia, some anemia, fatigue, and gastrointestinal [AEs], such as nausea, vomiting, and diarrhea. We see those across the board in all of the different arms. For anemia, neutropenia, and the gastrointestinal symptoms, they seem to be pretty uniform in what was reported in the studies.

Olaparib in the SOLO-2 study reported a slightly lower rate of fatigue compared with the others, but it's hard to compare across studies. Maybe they were a different group of patients at baseline who were healthier or had a different amount of disease going into the study. It's kind of hard to know from that perspective, but olaparib possibly has less fatigue associated with it.

We do see a little bit of a difference in the thrombocytopenia rates across the PARP inhibitors, with niraparib having the highest reported rates of approximately 61% versus 8% with olaparib and 25% with rucaparib. However, as we continue to learn more about PARP inhibitors, we're noticing that a patient’s platelet [counts] and their weight when going into the study and starting treatment matters. As such, we’re identifying a group that probably should start [this drug] at a lower dose to decrease the thrombocytopenia [that we see].

Hypertension was reported with olaparib and niraparib, but not with rucaparib. Rucaparib did, however, have higher rates of elevated liver enzymes, [but that appeared to be manageable] by holding the drug. Some slight differences do exist, but they are very similar across the board.

Is there anything else that you would like to add?

There is definitely a role for using maintenance therapy in patients with platinum-resistant ovarian cancer, whether or not it is an angiogenesis inhibitor or a PARP inhibitor. They both appear to result in an improvement in PFS for patients, and overall, they are really well tolerated.

References

1. Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):P1274-1284. doi:10.1016/S1470-2045(17)30469-2
2. Poveda A, Floquet A, Ledermann JA, et al. Final overall survival (OS) results from SOLO2/ENGOT-ov21: a phase III trial assessing maintenance olaparib in patients (pts) with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation. J Clin Oncol.2020;38(suppl 15):6002. doi:10.1200/JCO.2020.38.15_suppl.6002
3. Del Campo JM, Matulonis UA, Malander S, et al. Niraparib maintenance therapy in patients with recurrent ovarian cancer after a partial response to the last platinum-based chemotherapy in the ENGOT-OV16/NOVA Trial. J Clin Oncol. 2019;37(32):2968-2973. doi:10.1200/JCO.18.02238
4. O’Malley DM, Oza AM, Lorusso D. Postprogression outcomes in patients with ovarian carcinoma associated with a mutation in a non-BRCA homologous recombination repair gene receiving rucaparib maintenance treatment: Results from the phase III study ARIEL3. Paper presented at: 2020 SGO Annual Meeting of Women’s Cancer; March 31, 2020; Toronto, Ontario. Accessed September 22, 2020. https://bit.ly/2RODj3a