PFS Benefit Sustained at 5-Year Follow-Up in SOLO-1 Trial of Maintenance Olaparib in Ovarian Cancer

William Bradley, MD

After long-term follow-up, olaparib (Lynparza) maintenance therapy demonstrated progression-free survival (PFS) benefit in almost half (48%) of the patients with ovarian cancer compared with 21% for those who received placebo, including consistent benefit in high- and low-risk patients.¹

These data from the phase 3 SOLO-1 trial (NCT01844986) have the longest duration of follow-up for any PARP inhibitor in the newly diagnosed advanced ovarian cancer setting, with 5 years of follow-up. Olaparib, the only PARP inhibitor that has shown efficacy after completion of therapy, demonstrated sustained PFS benefit after 2 years of treatment.

Patients on this double-blind, placebo-controlled, multicenter trial were randomized 2:1 to olaparib at 300 mg twice daily (n = 260) versus placebo (n = 131) for up to 2 years or until disease progression.2 The primary analysis cutoff date was May 2018 and the median PFS had not been reached at this time compared with 13.8 months with placebo (HR, 0.30; 95% CI, 0.23-0.41; P < .001). The data cutoff for long-term follow-up was March 2020.1

Patients on the SOLO-1 study had to be newly diagnosed, with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer.2 Those who were enrolled also had germline BRCA mutations, an ECOG performance status of 0 or 1, cytoreductive surgery, and complete response (CR) or partial response after platinum-based chemotherapy.

“Historically, advanced-stage ovarian cancer has a poor prognosis,” William Bradley, MD, said in his presentation at the Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer.1 “Less than half of the patients with newly diagnosed disease will survive for 5 years, and the risk of relapse for all patients is very high. Once relapse occurs, ovarian cancer is generally considered incurable. Treatment goals in this setting are therefore to delay recurrence and, for some patients, to increase the chance of cure.”

With olaparib, patients had a median treatment duration of 24.6 months versus 13.9 months with placebo. There were 74% and 35% of patients free from disease progression and death when receiving olaparib and placebo, respectively, at the end of treatment at 2 years. This benefit was sustained beyond the 2 years of treatment, with a median PFS of 56.0 months for those in the olaparib arm and 13.8 months for those on the placebo arm (HR, 0.33; 95% CI, 0.25-0.43).

Patients were also evaluated by clinical risk in a prespecified exploratory subgroup analysis. Those with high-risk disease were defined as being FIGO stage IV, FIGO stage III with residual risk of disease following primary debulking, or FIGO stage III and interval surgery. There were 146 patients who were high risk and received olaparib and 73 received placebo, but 5 patients recruited in China were excluded from the PFS analysis, which included 142 and 72 patients, respectively. The low-risk population was defined as those with FIGO stage III disease who did not have residual disease following primary debulking. In this subgroup, 114 patients received olaparib and 58 received placebo.

For both of these groups, PFS benefit remained consistent. The median PFS for high-risk patients given olaparib was 40.6 months versus 11.1 months for those given placebo, with a 65% reduction in the risk of progression or death (HR, 0.35; 95% CI, 0.25-0.49). The PFS rate at 5 years was 42% with olaparib and 17% with placebo. In patients with low-risk disease, the median PFS was not reached and with placebo it was 21.9 months (HR, 0.38; 95% CI, 0.25-0.59). There was a 56% and 25% PFS rate at 5 years with olaparib and placebo, respectively.

Beyond the primary end point of investigator-assessed PFS, secondary end points included time to second progression or death (PFS2), time to second subsequent therapy or death (TSST), and safety.

“Analyses of PFS2 or death and TSST support the PFS results. Data from these secondary end points demonstrate the impact of first-line maintenance olaparib on subsequent treatment,” said Bradley, an associate professor at the Medical College of Wisconsin. “In both the overall population and the subgroup of women in complete response at baseline, maintenance olaparib reduced the risk of PFS2 and TSST by half suggesting that the benefit of maintenance olaparib is maintained through subsequent lines of therapy.”

The median PFS2 in the overall cohort of patients was not reached with olaparib and was 42.1 months for patients who received placebo (HR, 0.46; 95% CI, 0.33-0.65). There were 64% of patients event free at 5 years in the olaparib arm and 41 % in the placebo arm. In patients with CR at baseline, those given olaparib (n = 189) also did not reach a median PFS2 and patients given placebo (n = 101) had a median of 52.9 months (HR, 0.48; 95% CI, 0.32-0.71). There were 68% who were event free at 5 years with olaparib compared with 44% given placebo.

In the overall group, median TSST was not reached in those who received olaparib and was 40.7 months in those who received placebo (HR, 0.46; 95% CI, 0.34-0.63). Sixty-two percent of patients were event free at 5 years with olaparib versus 36% with placebo. Patients with CR at baseline had not reached a median TSST in the olaparib group and the placebo group had a 47.7-months median (HR, 0.50; 95% CI, 0.35-0.72). There were 65% of patients who were event free at 5 years in this subgroup who were given olaparib and 39% of patients who received placebo.

This long-term follow-up showed that no new safety signals were observed, and the safety profile of olaparib remained consistent with what was reported at the primary data cutoff.^1,2 There were 98% and 92% of patients who experienced an adverse event (AE) of any grade. Grade 3 or higher AEs were observed in 40% of those who received olaparib and 19% of those who received placebo. There were 52% and 17% of patients who needed dose interruptions in each arm, respectively. Dose reductions were needed in 29% of patients on the olaparib arm and 3% of those on the placebo arm. Twelve percent of patients given olaparib discontinued treatment compared with 3% of patients given placebo.

There were no additional case of myelodysplastic syndrome and acute myeloid leukemia reported. The incidence remained at less than 1.5% in the olaparib arm, at 1% and no cases in the placebo arm. The follow-up for these cases continued until death by any cause. New primary malignancies were seen in 3% of patients who received olaparib and 4% who received placebo.

“These results further support the use of maintenance olaparib as a standard of care for women with newly diagnosed advanced ovarian cancer and a BRCA mutation and suggest the possibility of long-term remission or even cure for some patients,” Bradley concluded.

_References:

_{1. Bradley W, Moore K, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: 5-year follow-up from SOLO1. Slides presented at: Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-25, 2021; virtual.}

_{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}