Patients with recurrent, platinum-sensitive ovarian cancer and germline <em>BRCA</em> mutations had significant improvement in progression-free survival (PFS) with no decrement in health-related quality of life (hr-QoL) during maintenance therapy with olaparib (Lynparza), according to a review of patient-reported outcomes in a randomized trial.
Michael Friedlander, PhD
Patients with recurrent, platinum-sensitive ovarian cancer and germlineBRCAmutations had significant improvement in progression-free survival (PFS) with no decrement in health-related quality of life (hr-QoL) during maintenance therapy with olaparib (Lynparza), according to a review of patient-reported outcomes in a randomized trial.
During a mean follow-up of 12 months, the average score on the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) Trial Outcome Index (TOI) did not change significantly from baseline among patients treated with olaparib and did not differ from the control group. However, the duration of time with disease-related symptoms or toxicity (TWiST) was significantly longer in olaparib-treated patients, Michael Friedlander, PhD, reported at the 2017 ASCO Annual Meeting in Chicago.1
“Treatment with olaparib led to a significant improvement in the primary endpoint of investigator-assessed progression-free survival versus placebo and in the secondary time-dependent efficacy endpoints of time to first subsequent therapy (TFST), second progression-free survival (PFS2), and time to second subsequent therapy (TSST),” said Friedlander, professor of medicine at the University of New South Wales in Sydney, Australia.
“There was no significant detrimental effect of olaparib versus placebo on health-related quality of life. Despite the toxicity associated with olaparib versus placebo, significant patient-centered benefits of olaparib versus placebo were observed, including significantly longer quality-adjusted progression-free survival and significantly longer time without symptoms of disease or treatment toxicity.”
The findings came from a secondary analysis of the SOLO-2 trial, reported earlier this year at the Society of Gynecologic Oncology meeting. The trial was designed in accordance with commendations of the 5th Ovarian Cancer Consensus Conference, which included recommendations for endpoint selection in clinical trials of recurrent ovarian cancer.2
Authors of the consensus statement concluded that PFS is an acceptable primary endpoint only if supported by additional endpoints, said Friedlander. Among patients with an expected median overall survival exceeding 12 months, survival depends largely on subsequent therapy. In such patient cohorts, PFS supported by TSST and patient-reported outcomes are preferred endpoints. The consensus authors further recommended that context-specific patient-reported outcomes (PROs) should be selected to support the study objectives.
“Progression-free survival does not take into account health-related quality of life of patients on treatment,” Friedlander noted. “Patients are relatively well and do not have cancer-related symptoms at randomization. Toxicity of treatment should be acceptable, with limited impact on health-related quality of life. Delay in disease progression should also be associated with a longer duration of ‘good quality of life’ for patients.”
As previously described, the phase III SOLO-2 trial involved patients who had recurrent ovarian cancer associated with germlineBRCAmutations, who had received 2 or more prior lines of platinum-based therapy, and who had attained complete or partial remission during treatment with the most recent line of therapy. They were randomized 2:1 to olaparib or placebo, and the trial had a primary endpoint of investigator assessed PFS.
The results showed a significant improvement in median PFS with olaparib (19.1 vs 5.5 months,P< .0001). Treatment with olaparib also led to significant prolongation of TFST (27.9 vs 7.1 months,P< .0001) and TSST (not reached vs 18.2 months,P< .0001).
Friedlander reported findings from the primary hr-QoL endpoint: change from baseline in the TOI, an established, single-targeted index derived from the FACT-O. The TOI takes into account the most relevant ovarian cancer symptoms, as well as functional and physical well-being. The FACT-O and other hr-QoL instruments were administered at baseline, day 29, at every response assessment, at discontinuation of study treatment, 30 days after the last dose of randomized therapy, and then every 12 weeks until the primary data analysis.
The study population had a mean baseline TOI score of 75, reflecting relatively good hr-QoL. During follow-up to 12 months, the TOI scores of the olaparib and placebo groups tracked along graph lines that were almost superimposable. The adjusted mean change from baseline was -2.90 in the olaparib group and -2.87 in the placebo group (P= .98).
Investigators also assessed quality-adjusted PFS, derived from the combination of area-under-the-curve calculation of PFS and average utility of the EQ-5D-5L QoL assessment tool. The analysis showed that quality-adjusted PFS was significantly increased with olaparib (13.95 vs 7.28 months,P< .0001).
As a secondary analysis of patient-centered benefits, investigators evaluated TWiST, which captures the duration of good quality of life, taking into account adverse effects, as well as toxicity (defined as the period with significant symptoms from post-randomization to protocol-defined disease progression. More simply defined, TWiST represents the mean PFS minus mean toxicity.
The analysis yielded a mean TWiST of 13.5 months for the olaparib group and 7.21 months for the placebo group (P< .0001). The toxicity durations were 3.69 and 0.71 months for olaparib and placebo, respectively (P= .0002).
A second study at ASCO represented an expanded analysis of adverse events in the SOLO-2 trial, which was the first clinical evaluation of a tablet formulation of the PARP inhibitor.3Previous trials had used a capsule formulation, and the tablet was developed to improve convention (pill burden) and tolerability.
The initial report of the SOLO-2 results showed that the most common adverse events (occurring in >35% of patients) associated with olaparib were nausea, vomiting, fatigue/asthenia, and anemia. The ASCO presentation examined those adverse events in greater detail, and included details about less common adverse events.
“Nausea , vomiting, fatigue/asthenia, and anemia were generally reported early with most events of grade ≥2 first occurring during the first month of treatment,” Jonathan Ledermann, MD, professor of Medical Oncology at University College London, and colleagues stated in a poster presentation.
Overall, 76% of patients in the olaparib arm had nausea at some point, as compared with 33% of the placebo group. Additionally, vomiting occurred in 37% of the olaparib group and 19% of the placebo group. Grade 3/4 nausea and vomiting occurred in 3% of olaparib-treated patients only. Nausea resolved in 63% of affected patients and vomiting in 36%. The investigators reported that 41% of olaparib-treated patients received supportive treatment for nausea, and 9% received supportive treatment for vomiting.
Persistence of grade ≥2 was about 10% at any given time, and persistence of grade ≥2 vomiting was <5%. The prevalence of grade ≥2 fatigue/asthenia increased during the first 3 months, reaching approximately 20% in the olaparib treatment arm. After the first month of treatment, the prevalence of grade ≥2 anemia ranged between 10% and 20% in the olaparib arm and ≤5% in the placebo group.
The rate of fatigue/asthenia was 66% with olaparib and 39% with placebo and reached grade 3/4 severity in 4% and 2%, respectively. Anemia occurred in 44% of the olaparib arm and 8% of the placebo group. The rate of grade 3/4 anemia was 19% with olaparib and 2% with placebo. Anemia resolved in 34% of the olaparib group, 17% required supportive treatment, and 17% required dose interruption.
Less common adverse events associated with olaparib were diarrhea (33% vs 20% in the placebo group), dysgeusia (27% vs 7%), and headache (25% vs 13%).
The rate of discontinuation because of adverse events was 11% with olaparib and 2% with placebo. Anemia and neutropenia were the only adverse events that led to discontinuation of more than 1% of patients.
“Overall, the safety profile of the olaparib tablet formulation in SOLO-2 was consistent with that previously observed in patients treated with olaparib capsules,” the investigators concluded.