Compared to chemotherapy, treatment with the PARP inhibitor olaparib reduced the risk of disease progression or death by 38% in patients with platinum-sensitive, relapsed, germline <em>BRCA1/2</em>-mutated ovarian cancer who had received at least 2 prior chemotherapy regimens, based on topline findings from the confirmatory phase III SOLO3 trial.
Richard T. Penson, MD
Compared to chemotherapy, treatment with the PARP inhibitor olaparib (Lynparza) reduced the risk of disease progression or death by 38% in patients with platinum-sensitive, relapsed, germlineBRCA1/2-mutated ovarian cancer who had received at least 2 prior chemotherapy regimens, based on topline findings from the confirmatory phase III SOLO3 trial.
Results presented at the 2019 ASCO Annual Meeting showed that the median progression-free survival (PFS) per independent review was 13.4 months with olaparib compared with 9.2 months with chemotherapy (HR, 0.62; 95% CI, 0.43-0.91;P= .013). Among all patients, the overall response rate (ORR) by independent review was 72% with the PARP inhibitor compared with 51% with chemotherapy. The complete response (CR) and partial response (PR) rates were 9% versus 3% and 63% versus 49% with olaparib versus chemotherapy, respectively.
In patients with 2 prior lines of chemotherapy, the ORR was 85% (CR, 12%; PR, 73%) with olaparib compared with 62% (CR, 5%; PR, 56%) with chemotherapy. The ORR was 59% (CR, 7%, PR, 52%) versus 39% (all PRs), respectively, in patients who received ≥3 prior lines of chemotherapy.
“SOLO3 is the first phase III randomized trial of a PARP inhibitor versus nonplatinum based chemotherapy in women with platinum-sensitive, relapsed, germlineBRCAmutated ovarian cancer,” said lead study author Richard T. Penson, MD, Massachusetts General Hospital.
Olaparib was initially granted an accelerated approval in December 2014 for the treatment of patients with germlineBRCA-positive advanced ovarian cancer following treatment with 3 or more prior lines of chemotherapy. The SOLO3 trial is a confirmatory study intended to convert the accelerated approval to a full approval.
The multicenter, open-label, SOLO-3 trial enrolled 266 patients with relapsed high-grade serous or endometrioid ovarian, primary peritoneal, and/or fallopian tube cancer. Patients had germlineBRCAmutations, had received ≥2 prior lines of platinum-based chemotherapy, and were platinum sensitive.
Patient characteristics were well balanced between the treatment arms. In the olaparib arm, 67% of patients had aBRCA1mutation, 28% had aBRCA2mutation, and 4% were BRCA-negative or unknown status. Sixty-four percent of patient had progressed between 6 and 12 months after platinum-based chemotherapy, and 36% had progressed at more than 12 months after platinum-based chemotherapy.
Fifty-two percent of patients in the olaparib cohort had received 2 previous chemotherapy regimens, 23% had 3 prior regimens, and 25% had been treated with ≥4 chemotherapy regimens. The ECOG performance status (PS) was 0 for 76% of patients and 1 for 24% of patients. There was 1 patient with an ECOG PS of 2.
Patients were randomized in a 2:1 ratio to receive olaparib tablets (300 mg) twice daily (n = 178) or physician’s choice of single-agent, non-platinum chemotherapy (n = 88). Chemotherapy regimens included pegylated liposomal doxorubicin (PLD; n = 47), paclitaxel (n = 20), gemcitabine (n = 13), and topotecan (n = 8). The primary endpoint was ORR by blinded independent central review and key secondary endpoints included PFS, time to second disease progression or death (PFS2), overall survival, safety.
The investigator-assessed PFS data were comparable to the independent PFS findings. Investigators determined a median PFS of 13.2 months with olaparib compared to 8.5 months with chemotherapy (HR, 0.49; 95% CI, 0.35-0.70;P<.001). The investigator-assessed median PFS2 was 23.6 months with the PARP inhibitor compared with 19.6 months in the control arm (HR, 0.81; 95% CI, 0.52-1.26; P= 0.35). Overall survival data were immature at the time of the analysis.
At the data cutoff, 76% of patients in the olaparib arm and 85% of patients in the chemotherapy arm had discontinued treatment. Disease progression was the primary reason for discontinuation in both arms. The median treatment duration was 11.3 months (range, 0.1-39.5) with olaparib, 6.0 months (range, 0.9-15.4) with PLD, 5.1 months (range, 1.8-18.2) with paclitaxel, 3.3 months (range, 0.7-14.3) with gemcitabine, and 6.2 months (range, 2.3-9.7) with topotecan.
Fifty percent of patients receiving olaparib had a grade ≥3 adverse event (AE) compared with 47% of patients in the chemotherapy arm. The rates of serious AEs were 24% versus 18%, respectively. AE-related dose interruptions, dose reductions, and treatment discontinuation occurred in 48% versus 42%, 27% versus 33%, and 7% versus 20%, of the olaparib versus chemotherapy arms, respectively.
The most common grade ≥3 AEs in the olaparib arm were anemia (21.3% vs 0% in the chemotherapy arm), neutropenia (9.6% vs 15.8%, respectively), fatigue/asthenia (4.5% vs 1.3%), thrombocytopenia (3.9% vs 2.6%), nausea (1.1% vs 1.3%), vomiting (1.1% vs 2.6%), and abdominal pain (1.1% vs 0%).
Regarding AEs of special interest, MDS/AML was reported in 4 patients in the olaparib arm compared with 3 patients in the control arm. There were no new primary malignancies in the chemotherapy arm compared to the 3 in the olaparib arm (lung cancer, gastric cancer, and breast cancer). No cases of pneumonitis occurred on the study.
“This trial shows that Lynparza has the potential to provide a much-needed improvement and alternative over standard-of-care chemotherapy for certain patients with relapsedBRCA-mutated advanced ovarian cancer. This is the fourth positive phase II or phase III trial in advanced ovarian cancer for Lynparza across multiple lines of therapy. We look forward to discussing these results with regulatory authorities,” José Baselga, MD, PhD, executive vice president, Oncology R&D, AstraZeneca, the manufacturer of olaparib, said in a press release.
Penson RT, Valencia RV, Cibula D, et al. Olaparib monotherapy versus (vs) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial.J Clin Oncol.2019;37(suppl; abstr 5506).