NCCN Ovarian Cancer Guidelines Add Options for PARP Inhibitors, Bevacizumab

David O’Malley, MD, of the James Cancer Hospital and Solove Research Institute at The Ohio State University Comprehensive Cancer Center, reminded those at the 2019 annual conference of the National Comprehensive Cancer Network (NCCN) just how far things have come in ovarian cancer:

He opened his talk Saturday with a slide of the first ovarian cancer guideline, issued in 2007. “It was all on 1 page,” he said. “There wasn’t much for us to do.”

By contrast, the new guidelines updated earlier this month cover 126 pages. “In the last 10 years we’ve seen an unprecedented time of drug development. We’ve had more agents and more indications in 5 years than in the previous 50 years,” O’Malley said.

The big news has come in 2 areas: new uses for the antivascular therapy bevacizumab (Avastin), and in approvals in ovarian cancer for poly (ADP-ribose) polymerase (PARP) inhibitors, targeted therapies that kill cancer cells by blocking enzymes that let the cells repair DNA. There therapies are effective in patients who have certain genetic mutations, including BRCA1/2. There are now 3 FDA-approved PARP inhibitors in ovarian cancer: olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca).

Findings that include GOG-218,¹ SOLO-1,² and ARIEL-3,³ and subsequent FDA approvals, have caused O’Malley to question assumptions about the treatment of ovarian cancer, which CDC still ranks as the fifth leading cause of cancer death for women.^. However, median survival has increased from less than 3 years to 5 years, he said.

“Is maintenance treatment curing people? I used to say no, but we may have to look at that,” O’Malley said. “Can we cure people after recurrence? I used to tell people, ‘no,’ but I need to question my counseling.”

Major updates in maintenance therapy

The guidelines make several updates in maintenance therapy in stage 2, 3, and 4 disease:

Olaparib is recommended as first-line maintenance therapy for patients with BRCA1/2 mutations in complete clinical remission or partial remission. The recommendation is Category 1 for germline mutations and Category 2B for somatic mutations; O’Malley said this occurred because there were so few patients with somatic mutations studied. The recommendation applies whether or not the patient was previously treated with bevacizumab.

The recommendation for olaparib is based on results from the SOLO-1 trial, which evaluated progession-free survival (PFS) based on RECIST criteria and found that compared to placebo, median PFS was not reached in the olaparib arm and was 13.8 months in the placebo arm (hazard ratio [HR] 0.30; 95% CI: 0.23-0.41; P <0.0001).² Bevacizumab is also recommended for maintenance therapy post-remission for patients with partial or complete responses who received it in primary treatment, or for patients with stable disease.

Updates for bevacizumab were based on the GOG-218¹ and the ICON7⁴ trials, which O’Malley reviewed. GOG-218 was cited in the June 13, 2018, FDA approval for bevacizumab in combination with paclitaxel or carboplatin, followed by bevacizumab as a single agent, for stage 3 or 4 epithelial ovarian, fallopian tube, or primary peritoneal cancer after initial resection.⁵

The GOG-218 trial randomized 1873 women into 3 groups: the control group took chemotherapy and had a median PFS of 10.3 months; a second started bevacizumab with chemotherapy but stopped, and PFS was 11.2 months; the final group continued with bevacizumab throughout treatment. The HR for progression to death relative to the control group was 0.717 for those treated with bevacizumab throughout (95% CI, 0.625 to 0.824; P <0.001).¹

In reviewing the ICON7 results, O’Malley noted that although the overall results for did not reach statistical significance, bevacizumab was very effective for the highest-risk patients; published results show that the estimated median PFS was 10.5 months with standard therapy, vs. 15.9 months with bevacizumab (HR, 0.68; 95% CI, 0.55 to 0.85; P <0.001).⁴

Persistent and resistant disease and recurrence

If patients have platinum-sensitive disease and relapse more than 6 months after completing chemotherapy, a new algorithm in the guidelines calls for 2 platinum therapies (a platinum doublet), possibly alongside bevacizumab or a PARP inhibitor. The algorithm allows these options if patients with advanced cancer are in complete or partial response to platinum-based chemotherapy. All 3 PARP inhibitors—olaparib, rucaparib, and niraparib&mdash;are listed. In support of these updates, O’Malley presented findings from the OCEANS trial⁶ involving bevacizumab with carboplatin and gemcitabine, the GOG-213 trial,⁷ and separate trials involving each PARP inhibitor.

Rucaparib received FDA approval for this indication in April 2018 based results of the ARIEL-3 trial, which found that median PFS for the overall study population was 10.8 months vs. 5.4 months for placebo.⁸ For patients in BRCA-mutated subgroups, the risk of progression to death fell 77%; median PFS was 16.6 vs 5.4 months (HR 0.23; 95% CI: 0.16, 0.34; P <0.0001). Niraparib received approval in this setting in 2017 based on the NOVA trial.⁹

Bevacizumab is also the centerpiece of regimens with non-platinum combinations, O’Malley said, based on results from the 2014 AURELIA trial.¹⁰

Testing recommendations upgraded

As was seen across the updated NCCN guidelines during the conference, the updated recommendations in ovarian cancer call for tumor molecular testing if not previously done. Validated molecular testing should include BRCA1/2 and microsatellite instability or DNA mismatch repair, if not previously done. Homologous recombination deficiency testing can be considered.

Because a PARP inhibitor may be used, “All patients should have germline testing,” O’Malley said. “But we should not delay therapy for testing.”

References

1. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-2483. doi: 10.1056/NEJMoa1104390.
2. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505. doi: 10.1056/NEJMoa1810858.
3. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):1949-1961. doi: 10.1016/S0140-6736(17)32440-6.
4. Perren TJ, Swart AM, Pfisterer J., et al, for the ICON7 investigators. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484-2496. DOI: 10.1056/NEJMoa1103799.
5. Drugs. FDA approves bevacizumab in combination with chemotherapy for ovarian cancer. FDA website. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm610664.htm. Updated June 13, 2018. Accessed March 24, 2019.
6. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrentn epithelial ovarian primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039-2045. doi: 10.1200/JCO.2012.42.0505.
7. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(6):779-791. doi: 10.1016/S1470-2045(17)30279-6.
8. Drugs. FDA approves rucaparib for maintenance treatment of recurrent ovarian, fallopian tube, or primary peritoneal cancer. FDA website. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm603997.htm. Published April 6, 201 Accessed March 24, 2019.
9. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.
10. Poveda AM, Selle F, Hilpert F, Bevacizumab combined with weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan in platinum-resistant recurrent ovarian cancer: analysis by chemotherapy cohort of the randomized phase III AURELIA Trial. et al. J Clin Oncol. 2015;33(32):3836-3838. doi: 1200/JCO.2015.63.1408.