PARP Inhibition Strategies Refined in Ovarian Cancer Guidelines

Wayne Kuznar
Published: Sunday, Mar 24, 2019

David O' Malley, MD
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).

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.

Platinum-sensitive disease

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.

Platinum-resistant disease

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.

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.

First-line PARP inhibitor maintenance

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.

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