PARP Inhibition Strategies Refined in Ovarian Cancer Guidelines

David O'Malley, MD

An updated guideline (version 1.2019) from the National Comprehensive Cancer Network (NCCN) for the management of ovarian cancer recommends specific PARP inhibitors for the treatment of recurrent disease, describes patient selection criteria for each agent, and establishes criteria for PARP inhibitor maintenance therapy.

With several new agents approved by the FDA for the treatment of patients with ovarian cancer over the past few years, median overall survival has gone from <3 years to 5 years, said David O’Malley, MD, professor and director, Gynecologic Cancer Clinical Research, The Ohio State University, Columbus, in reviewing the guideline at the 2019 NCCN Annual Conference.¹

“It’s not uncommon in some subpopulations that 50% of patients will live 10 years,” he said. “Those are the patients in whom we can reduce all of the disease at the time of primary surgery, and then give them the best therapies upfront.”

Upfront therapy with a bevacizumab (Avastin)-containing regimen for patients with stage II-IV ovarian cancer is one of the principles of systemic therapy in the guideline, based on data from the randomized phase III GOG-218² and ICON-7³ clinical trials. In both trials, investigators assessed a carboplatin/paclitaxel doublet with or without bevacizumab (15 mg/kg in GOG-218; 7.5 mg/kg in ICON-7).

GOG-218 was a 3-arm trial in which 1 arm also received bevacizumab maintenance for 1 year after upfront therapy. ICON-7 was a 2-arm trial in which total treatment, including maintenance, was 12 months.

A modest improvement in median progression-free survival (PFS) was observed in the bevacizumab arm with bevacizumab maintenance versus the chemotherapy-only arm in GOG-218 (14.1 vs. 10.3 months, HR 0.7, P <.001). ICON-7 did not meet the primary endpoint for an improvement in median PFS with the addition of bevacizumab to the platinum doublet (19.9 vs. 17.5 months; HR 0.93, P =.25).

Platinum-sensitive disease

Platinum-resistant disease

No increase in overall survival (OS) was observed in the bevacizumab-containing arms in the overall study populations in either trial. However, patients with high-risk disease in ICON-7 did experience a significant improvement in OS of about 8 months in the bevacizumab-containing arms, as did those in the bevacizumab maintenance arm in GOG-218.In patients with platinum-sensitive disease who achieve complete remission and experience relapse ≥6 months after completing chemotherapy, the guideline recommends a platinum doublet and consideration of maintenance therapy with a PARP inhibitor or bevacizumab. This recommendation is based on data from the phase III OCEANS trial,⁴ in which median PFS was found to be significantly greater with the addition of bevacizumab to carboplatin and gemcitabine, as well as the phase III GOG-213 trial,⁵ which showed a significant improvement in OS with the addition of bevacizumab to carboplatin and paclitaxel.Patients with recurrence within 6 months of their most recent platinum-based treatment qualify as being platinum-resistant, according to the guideline. The NCCN lists 5 bevacizumab-containing regimens as potential options for patients with platinum resistance: cyclophosphamide (oral)/bevacizumab, liposomal doxorubicin/bevacizumab, paclitaxel (weekly)/bevacizumab, topotecan/bevacizumab, and bevacizumab.

First-line PARP inhibitor maintenance

The AURELIA study⁶ assessed 3 of these regimens and showed clear differences in outcomes in favor of bevacizumab compared with standard chemotherapy. Bevacizumab plus paclitaxel was associated with a median PFS of 9.6 months, compared with 6.2 months for bevacizumab plus topotecan and 5.1 months with bevacizumab plus paclitaxel and pegylated liposomal doxorubicin.In patients with stage II-IV ovarian cancer, the guideline recommends consideration of olaparib (Lynparza) as maintenance therapy in patients with germline or somatic BRCA1/2 mutations. In the SOLO-1 trial,7 patients with stage III-IV ovarian cancer with a germline or somatic BRCA mutation who achieved partial or complete response to a platinum doublet were randomized to receive either olaparib, 300 mg twice daily, or placebo, for 2 years if no evidence of disease was observed or the option to continue beyond 2 years if they achieved a partial response.

PARP inhibitor maintenance for platinum-sensitive disease

Median PFS was not reached in the olaparib arm compared with 13.8 months in the placebo arm, translating to a 70% improvement in PFS with olaparib (HR 0.30, P <.0001). Patients on standard chemotherapy had a 26.9% chance of being progression-free at 3 years, compared with a 60.4% chance when treated with olaparib. With the benefit of olaparib persisting beyond the 2-year maintenance treatment period, the possibility of a 50% curative rate was raised by O’Malley. “Time will tell,” he said.Maintenance therapy options for patients with platinum-sensitive disease include bevacizumab or a PARP inhibitor, according to the guideline.

Treatment with PARP inhibitors

The results from 3 randomized phase III trials—ARIEL-3 (rucaparib; Rubraca),⁸ NOVA (niraparib; Zejula),⁹ and SOLO-2 (olaparib)¹⁰—served as the basis for inclusion of a PARP inhibitor for this recommendation. In patients with germline and nongermline BRCA mutations, PFS was observed to be significantly superior with PARP inhibitor maintenance compared with placebo in all 3 trials.Of the PARP inhibitors, olaparib is approved by the FDA for patients with recurrent germline BRCA-mutated ovarian cancer following ≥3 lines of chemotherapy, and rucaparib is approved for the treatment of recurrent somatic or germline BRCA-mutated ovarian cancer after ≥2 lines of chemotherapy.

“For years, the NCCN guidelines said that for all patients who are diagnosed with ovarian cancer, strong consideration should be given to genetic counseling and discussion,” said O’Malley. “This year, we went one step further. We said that all patients should have germline testing; however, we should not delay therapy for testing.”

At recurrence, the newest guideline states that validated molecular testing should be performed and, at the least, should include BRCA, microsatellite instability, DNA mismatch repair proteins, and consideration of evaluation of homologous recombination deficiency.

References

1. O’Malley DM. New therapies for ovarian cancer. Presented at 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.
2. 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.
3. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484-2496. doi: 10.1056/NEJMoa1103799.
4. 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 recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039-2045. doi: 10.1200/JCO.2012.42.0505.
5. 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.
6. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302-1308. doi: 10.1200/JCO.2013.51.4489.
7. 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.
8. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL 3): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet. 2017;390(10106):1949-1961. doi: 10.1016/S0140-6736(17)32440-6.
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. doi: 10.1056/NEJMoa1611310.
10. 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, randomized, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274-1284. doi: 10.1016/S1470-2045(17)30469-2.

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