Frontline Maintenance Efforts Evolve in Advanced Ovarian Cancer

Although there are several maintenance strategies to consider for patients with advanced ovarian cancer, the decision of which approach to pursue largely depends on the molecular makeup of an individual patient’s tumor.

Roisin E. O'Cearbhaill, MD

Although there are several maintenance strategies to consider for patients with advanced ovarian cancer, the decision of which approach to pursue largely depends on the molecular makeup of an individual patient’s tumor.

“It’s important to remember that while we’re focusing on genetic testing, this shouldn’t delay us from starting treatment. It’s important that you have access to timely genetic testing,” said Roisin E. O'Cearbhaill, MD, during a presentation at the 2019 OncLive® State of the Science Summit™ on Ovarian Cancer and Soft Tissue Sarcoma.

During the lecture, O'Cearbhaill, a medical oncologist at Memorial Sloan Kettering Cancer Center, shed light on the various maintenance therapeutic approaches for patients with advanced ovarian cancer.

Current Maintenance Strategies

For patients with advanced-stage disease who harbor BRCA1/2 mutations, the combination of carboplatin and paclitaxel followed by olaparib (Lynparza) maintenance is now a viable treatment path. However, in the absence of a BRCA1/2 mutation and presence of stage IV disease, suboptimal debulking, or ascites, carboplatin/paclitaxel and bevacizumab (Avastin) followed by bevacizumab maintenance may be an optimal approach. The combination of carboplatin and paclitaxel alone also serves as a potential option in this setting, said O’Cearbhaill.

Previously, paclitaxel and pazopanib (Votrient) had been listed as a maintenance strategy but given the lack of overall survival benefit with the combination and the added toxicity, the regimen is no longer recommended for use.

Continuous Maintenance

In June 2018, the FDA approved bevacizumab for use in combination with carboplatin and paclitaxel, followed by bevacizumab maintenance therapy, for the treatment of women with advanced ovarian cancer following initial surgical resection. The approval was based on data from the phase III GOG-0218 trial; both GOG-0218 and the phase III ICON-7 trial demonstrated the superiority of a carboplatin/paclitaxel doublet with bevacizumab versus the doublet alone.

Although data from both trials indicated a reduction in the risk of progression or death by nearly 40% in the bevacizumab-containing arms of the trials, the additive benefit of bevacizumab was restricted to patients with high-risk disease in ICON-7.

However, though the current approval indicates that bevacizumab should be administered at a dose of 15 mg/kg every 3 weeks, which was the dosage in GOG-0218, investigators administered the agent at 7.5 mg/kg in the ICON-7 trial.

Switch Maintenance

PARP inhibitors currently hold 6 FDA-approved indications, explained O'Cearbhaill. Olaparib and rucaparib (Rubraca) are approved in the treatment setting, whereas niraparib (Zejula), olaparib, and rucaparib are all approved for use as maintenance therapy for patients with recurrent disease following a complete or partial response (CR/PR) to platinum-based chemotherapy.

In addition, olaparib most recently received approval as frontline maintenance therapy in patients with stage II/IV disease and a deleterious or suspected deleterious germline or somatic BRCA1/2 mutation following a CR or PR to platinum-based chemotherapy in December 2018.

The approval came 2 months after the results of the phase III SOLO-1 trial were presented at the 2018 ESMO Congress. In the trial, patients with newly diagnosed stage III/IV high-grade serous or endometrioid cancer and a germline or somatic BRCA mutation were randomized 2:1 to receive either olaparib or placebo within 8 weeks of their last dose of chemotherapy. Outside the context of a clinical trial, O'Cearbhaill explained that olaparib is typically started 8 to 12 weeks after completing chemotherapy.

Upon finishing chemotherapy, patients randomized to olaparib received the PARP inhibitor in the form of 300-mg tablets twice daily. Patients had to have an ECOG performance status of 0 or 1 and must have achieved a CR or PR to platinum-based therapy at the time of enrollment.

Patients in the treatment arm were continued on olaparib for 2 years in the absence of disease progression. If patients had evidence of disease at 2 years but achieved a PR, they were allowed to continue treatment, said O'Cearbhaill. At 2 years, patients with no evidence of disease patients were advised to discontinue olaparib.

At 3 years, 60.4% of patients who received olaparib remained free of disease progression compared with 26.9% of the patients in the placebo arm.

“Although at this stage it’s too early to tell, we are really hopeful that this translates to an increased number of patients who are cured,” said O'Cearbhaill.

Common treatment-emergent adverse events (AEs) included nausea, fatigue, and vomiting. Overall, occurrences of anemia, diarrhea, constipation, dysgeusia, arthralgia, and neutropenia were more common in the olaparib arm compared with the placebo arm.

AEs of special interest, including myelodysplastic syndrome/acute myeloid leukemia (3 vs 0), new primary malignancies (5 vs 3), and pneumonitis/interstitial lung disease (5 vs 0) accounted for more cases in the olaparib arm (n = 260) versus the placebo arm (n = 130), respectively.

Anticipated Approaches

Although the choice of which frontline maintenance strategy to pursue is relatively straightforward, there are several outstanding trials that will add considerable complexity to these decisions, explained O'Cearbhaill.

In terms of continuous maintenance strategies, the 3-arm GOG-3005/VELIA/M13-694 trial (NCT02470585) is exploring the use concurrent therapy with carboplatin/paclitaxel and veliparib followed by veliparib maintenance. Although chemotherapy is typically not used in combination with PARP inhibitors due to high rates of myelosuppression, veliparib is one of the PARP inhibitors that has been shown to be successfully combined with chemotherapy, said O'Cearbhaill.

Additional trials of frontline maintenance therapy with immunotherapy are also ongoing, despite the recent discontinuation of the Javelin Ovarian PARP 100 trial, added O'Cearbhaill. Three notable phase III trials to anticipate include the IMaGYN50/GOG-3015/ENGOT-ov39 trial (NCT03038100), GOG 3025/DUO-O trial (NCT03737643), and FIRST Trial/ENGOT-OV44 trial (NCT03602859) which will investigate the use of maintenance atezolizumab (Tecentriq), durvalumab (Imfinzi), and the anti—PD-1 agent TSR042, respectively.

Moreover, the results of the PAOLA-1/ENGOT-ov25 trial are expected in 2019. The study, which has the potential to redefine the algorithm of maintenance therapy altogether, which is comparing the efficacy and safety of olaparib tablets in patients with advanced platinum-sensitive relapsed BRCA-mutated high grade serous ovarian cancer receiving bevacizumab maintenance therapy (NCT02477644).

Regarding switch maintenance strategies, physicians are anticipating the results of the GOG-3012/PRIMA trial (NCT02655016), which will replicate the design of SOLO-1, but with niraparib. Although the trial is open to all comers, all patients will undergo BRCA testing, said O'Cearbhaill.

Aside from immunotherapy, other switch maintenance trials are ongoing. In the ATHENA trial (NCT03522246), patients will be randomized to 1 of 4 arms: rucaparib and nivolumab (Opdivo; arm 1), rucaparib and placebo (arm 2), placebo and nivolumab (arm 3), and placebo (arm 4).

“It’s going to be quite tricky to determine what our maintenance strategy will look like when we get the results of these trials,” said O'Cearbhaill. “As we move forward with maintenance combinations, it will have significant financial implications,” she concluded.

Moore K, Colombo N, Scambia G, et al. Olaparib maintenance therapy following first-line platinum-based chemotherapy in patients with FIGO stage III—IV ovarian cancer (OC) with a BRCA1/2 mutation (BRCAm): phase III SOLO1 trial. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA7_PR.