Novel PARP Combinations Boost Responses in Ovarian Cancer

Floor J. Backes, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Floor J. Backes, MD

Combination regimens appear to result in improved responses in patients with ovarian cancer compared with single-agent therapies, according to Floor J. Backes, MD, and PARP inhibitors in particular are showing promising activity when combined with immunotherapies or antivascular agents.

In the phase I/II TOPACIO/KEYNOTE-162 trial, patients with recurrent platinum-resistant ovarian cancer received the combination of the PARP inhibitor niraparib (Zejula) and the PD-L1 inhibitor pembrolizumab (Keytruda). Results showed that the overall response rate (ORR) with the combination was 18% (90% CI, 11%-29%) with a disease control rate of 65% (90% CI, 54%-75%).¹

Notably, the combination showed promising antitumor activity regardless of a patient’s platinum status, biomarker status, or whether they received prior treatment with bevacizumab (Avastin). Additionally, the combination induced responses that were higher than expected with either agent when they are used as monotherapies in those without BRCA mutations or homologous recombination deficiency (HRD).

In March 2017, niraparib received approval from the FDA as a maintenance therapy for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In October 2019, the agent was also approved for use in those with advanced ovarian, fallopian tube, or primary peritoneal disease who have been treated with ≥3 prior chemotherapy regimens, and whose cancer is associated with HRD-positive status.

Two other PARP inhibitors have also received approved from the FDA for use as maintenance therapy in select patients with ovarian cancer: rucaparib (Rubraca) in April 2018, and olaparib (Lynparza) in December of the same year.

“Many of the ongoing studies are now combining the PARP inhibitors with antivascular therapy and/or immunotherapy to see whether we can continue identifying a larger group of patients who will be better candidates for this treatment and hopefully have better survival,” said Backes, an associate professor in the Division of Gynecologic Oncology at The Ohio State University Comprehensive Cancer Center—James.

One such study examining PARP inhibitors in combination with antivascular therapy is the phase III PAOLA-1 trial. Recent data showed that maintenance treatment with olaparib plus bevacizumab resulted in an improved median PFS by 5.5 months versus bevacizumab and placebo in patients with newly diagnosed, advanced disease following prior treatment with platinum-based chemotherapy plus bevacizumab.²

In an interview with OncLive, Backes discussed the latest advancements made in the treatment of patients with ovarian cancer and delved deeper into the ongoing research efforts that are being made with novel combinations.

OncLive: Could you discuss some of the combinations that are showing promising in ovarian cancer?

Backes: We have seen a couple of different combinations. For example, the TOPACIO study enrolled platinum-resistant patients with ovarian cancer. [Data from that trial] have been both presented and published. For that study, they used the PARP inhibitor niraparib combined with pembrolizumab. We have seen some encouraging improvements [in response with the combination] compared with the single-agent responses that we have seen; [these improvements have] really [been seen] across all biomarker types. Whether a patient had a BRCA1/2 mutation, HRD, PD-L1—positive or –negative disease, all saw responses across the board when the immunotherapy was combined with a PARP inhibitor.

We also discussed combinations with antivascular therapies, such as nivolumab (Opdivo) in combination with bevacizumab. We saw some improvements [with that regimen]. Additionally, we have seen nivolumab combined with the anti—CTLA-4 antibody ipilimumab (Yervoy). Compared with the single-agent treatments, we saw a doubling of the response rate as well as PFS [with this combination].

How has the role of PARP inhibitors evolved in ovarian cancer in recent years?

PARP inhibitors have now come to the front line as maintenance treatment in patients who harbor a BRCA mutation and have completed chemotherapy. We are awaiting another approval, and hopefully we will know more if [the use of these agents] will be expanded to all-comers or patients with HRD.

What has been your anecdotal experience with PARP inhibitors in this disease?

PARP inhibitors are a great class of drugs. We do see some adverse events with these agents. We need to prepare the patient; it is not a pill or multivitamin. We have learned how to manage the toxicity with the use of different medications or dose reductions. We have learned how to make these agents very tolerable as maintenance treatment for patients in the primary setting as well as the recurrent setting.

What has your experience been with rucaparib in practice?

We have a lot of experience with rucaparib. We have participated in clinical trials [examining this drug]. The agent has received FDA approval, so we use it, as well as the other PARP inhibitors, as maintenance and in the recurrent setting.

What are the immunotherapeutic options in ovarian cancer?

We have PD-1/PD-L1 antibodies and anti—CTLA-4 antibodies that are available for ovarian cancer. Many combinations with these [agents are] in development.

The checkpoint inhibitors we have currently in ovarian cancer haven’t [shown] very high responses. Responses [with these agents] have only [ranged] between 10% to 15%. As such, we started to look for more combinations [that might be more effective]. To do that, we [are combining] immunotherapy with antiangiogenic agents, anti—CTLA-4 antibodies, or PARP inhibitors. With all those [combinations], it always seems like we can achieve higher responses than [we can with] single agents.

What is your take-home message?

We need to further study these combinations and figure out which patients are most likely to benefit from them. We have to [determine effective] biomarkers so we can begin tailoring these treatments and make them more personalized to the tumors.

References

1. Kostantinopoulos PA, Waggoner S, Vidal GA. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma [published online June 13, 2019]. JAMA Oncol. doi: 10.1001/jamaoncol.2019.1048.
2. Ray-Coquard IL, Pautier P, Pignata S, et al. Phase III PAOLA-1/ENGOT-ov25 trial: olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OS) treated with platinum-based chemotherapy (PCh) plus bev. Ann Oncol. 2019;30(suppl 5; abstr LBA_PR. doi: 10.1093/annonc/mdz394.053.

<<< View more from the 2020 SGO Winter Meeting