Several Ongoing Trials Exploring PARP Combinations in Ovarian Cancer

Camille Gunderson, MD

Camille Gunderson, MD

Combination regimens with PARP inhibitors have the potential to enhance the relatively modest benefit seen with monotherapy approaches in patients with ovarian cancer, according to Camille Gunderson, MD.

At the 2018 Society of Gynecologic Oncology Annual Winter Meeting, Gunderson, assistant professor, University of Oklahoma Health Sciences Center, detailed ongoing research exploring combination regimens with PARP inhibitors and other treatment modalities.

“Targeted agents have modest activity so far, but combining them is likely to make them more active,” she said. “There are a number of agents which enhance antigen presentation and T-cell activation, including conventional chemotherapy agents, radiation treatment, and also newer targeted agents, such as PARP inhibitors.”

Gunderson detailed some of the active trials currently exploring PARP inhibitors in combination with either anti-VEGF therapy or immunotherapy, to show what the future may hold for these regimens.

PARP Plus Angiogenesis Inhibitors

Gunderson said Study 19 generated a lot of excitement for olaparib as maintenance therapy in patients with ovarian cancer.¹In the trial, patients with platinum-sensitive, recurrent high-grade serous ovarian cancer (n = 265) were randomized to olaparib capsules at 400 mg twice daily (n = 136) or placebo (n = 129). Patients had received 2 or more prior regimens of platinum-based chemotherapy and experienced complete response or partial response to their most recent regimen.

The median progression-free survival (PFS) for patients receiving maintenance olaparib was 8.4 months, compared to 4.8 months for the control group (hazard ratio [HR], 0.35;P<.0001). For those with&nbsp;BRCAmutations, the median PFS was 11.2 versus 4.3 months for placebo, representing an 82% reduction in the risk of progression or death (HR, 0.18;&nbsp;P<.0001).

Findings from Study 19, along with the phase III SOLO2 trial, led to the August 2017 approval of olaparib tablets as a maintenance therapy for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy, regardless ofBRCAstatus.

The positive initial data with olaparib inspired a phase II trial by Joyce F. Liu, MD, and colleagues comparing cediranib, an oral antiangiogenic inhibitor of VEGFR 1-3, and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer.²Median PFS favored the combination, at 17.7 months versus 9.0 months (HR, 0.42; 95% CI, 95% CI 0.23-0.76;P= .005).

Those results led to the initiation of NRG-GY004 (NCT02446600), a randomized, phase III trial comparing olaparib monotherapy versus the combination of cediranib maleate and olaparib versus standard platinum-based chemotherapy for patients with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer. That study has finished accrual and is scheduled for completion in 2019.

A separate randomized phase II/III trial, NRG-GY005 (NCT02502266), is evaluating cediranib and olaparib alone and in combination compared with standard chemotherapy in women with recurrent platinum-resistant or platinum-refractory ovarian, fallopian tube, or primary peritoneal cancer. Phase II results are pending, and will determine whether the study advances to phase III.

Researchers are also examining whether the addition of a PARP inhibitor can enhance the impact of the angiogenesis inhibitor bevacizumab (Avastin). The randomized, double-blind, phase III trial PAOLA-1 (NCT02477644) trial is assessing olaparib versus placebo in patients with advanced FIGO stage IIIb/IV high grade serous or endometrioid ovarian, fallopian tube, or peritoneal cancer treated with standard first-line treatment, combining platinum-taxane chemotherapy and the VEGF inhibitor bevacizumab concurrent with chemotherapy and in maintenance.

&ldquo;Both arms have bevacizumab, one arm has olaparib,&rdquo; Gunderson said. &ldquo;It has not completed enrollment but it will very soon, and we will be excited to hear the results.&rdquo;

PARP Plus Immunotherapy

Gunderson said preclinical evidence for PARP inhibitors in combination with immune checkpoint inhibitors suggests that the 2 are synergistic, and together deliver a much stronger therapeutic benefit for women with ovarian cancer. The TOPACIO/Keynote-162 trial (NCT02657889) will explore that potential in greater depth. The phase I/II trial will evaluate the safety and efficacy of combination treatment with niraparib (Zejula) and pembrolizumab (Keytruda) in patients with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian cancer.

In results from a dose-finding study published last year inAnnals of Oncology, the niraparib/pembrolizumab combination showed early signs of efficacy. Out of 8 evaluable patients with ovarian cancer, 4 responded and the remainder had stable disease.³Gunderson said the response was impressive, especially for patients who wereBRCAwild-type and PD-L1 negative.

Investigators are also currently recruiting patients for a phase I/II study evaluating the combination of olaparib and the CTLA-4 inhibitor tremelimumab in women with recurrent ovarian cancer harboring a BRCA1 or BRCA2 mutation (NCT02571725).

&ldquo;The phase I data was recently presented at the NRG [meeting] but is not yet in the public domain,&rdquo; Gunderson said. &ldquo;We will continue to see what happens with this combination.&rdquo;

References:

1. Gourley C, Friedlander M, Matalonis U, et al. Clinically significant long-term maintenance treatment with olaparib in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (PSR SOC).J Clin Oncol.2017;35 (suppl; abstr 5533).
2. Liu JF, Barry WT, Birrer M, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.Lancet Oncol.2014;15(11):1207-1214. doi: 10.1016/S1470-2045(14)70391-2.
3. Konstantinopoulos PA, Sachdev JC, Schwartzberg L, et al. Dose-finding combination study of niraparib and pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC) or recurrent platinum-resistant epithelial ovarian cancer (OC) (TOPACIO/KEYNOTE-162).Ann Oncol.2017;28(suppl 5). doi: 10.1093/annonc/mdx376.009.