Olaparib Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer and a Germline BRCA1/2 Mutation (SOLO3): A Randomized Phase III Trial

Abstract

Purpose: A phase II study (ClinicalTrials.gov identifier: NCT00628251) showed activity of olaparib capsules versus pegylated liposomal doxorubicin in patients with germline BRCA-mutated platinum-resistant or partially platinum-sensitive relapsed ovarian cancer. We conducted a phase III trial (SOLO3) of olaparib tablets versus nonplatinum chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy.

Patients and methods: In this randomized, open-label trial, patients were randomly assigned 2:1 to olaparib 300 mg twice a day or physician's choice single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). The primary end point was objective response rate (ORR) in the measurable disease analysis set assessed by blinded independent central review (BICR). The key secondary end point was progression-free survival (PFS) assessed by BICR in the intent-to-treat population.

Results: Of 266 randomly assigned patients, 178 were assigned to olaparib and 88 to chemotherapy. In patients with measurable disease (olaparib, n = 151; chemotherapy, n = 72), the BICR-assessed ORR was significantly higher with olaparib than with chemotherapy (72.2% v 51.4%; odds ratio [OR], 2.53 [95% CI, 1.40 to 4.58]; P = .002). In the subgroup who had received 2 prior lines of treatment, the ORR was 84.6% with olaparib and 61.5% with chemotherapy (OR, 3.44 [95% CI, 1.42 to 8.54]). BICR-assessed PFS also significantly favored olaparib versus chemotherapy (hazard ratio, 0.62 [95% CI, 0.43 to 0.91]; P = .013; median, 13.4 v 9.2 months). Adverse events were consistent with the established safety profiles of olaparib and chemotherapy.

Conclusion: Olaparib resulted in statistically significant and clinically relevant improvements in ORR and PFS compared with nonplatinum chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy.

Trial registration: ClinicalTrials.gov NCT00628251 NCT02282020.

Figures

FIG 1.

Trial profile. The primary analysis was conducted in the measurable disease analysis set (olaparib, n = 151; placebo, n = 72). Six of the patients in the chemotherapy group did not receive chemotherapy because of early withdrawal. (*) Other reasons for discontinuation included clinical progression (n = 4, olaparib; n = 4, chemotherapy), investigator decision (n = 6, chemotherapy), and chemotherapy complete (n = 7, chemotherapy).

FIG 2.

Best response for target lesions by patient in the olaparib and single-agent chemotherapy groups based on investigator assessment. (A) Best change from baseline in target lesion size in the olaparib group. (B) Best change from baseline in target lesion size in the single-agent chemotherapy group, with the accompanying table showing best response by chemotherapy agent. The best change from baseline in target lesion size is based on investigator assessment (RECIST version 1.1) in the measurable disease analysis set (olaparib, n = 160; chemotherapy; n = 78). Eleven patients in the olaparib group and 19 patients in the chemotherapy group were not evaluable. The dashed line represents the threshold for progressive disease (a ≥ 20% increase in the sum of diameters of target lesions), and the solid line represents the threshold for partial response (a ≥ 30% decrease in the sum of diameters of target lesions). CR, complete response; PD, disease progression, PR, partial response; SD, stable disease.

FIG 3.

Subgroup analysis of objective response rate. Objective response was assessed in the measurable disease analysis set on the basis of blinded independent central review. The analysis was performed using unadjusted logistic regression, including in all patients. For the odds ratios, the size of the circle is proportional to the number of responses, the vertical gray band represents the 95% CI for all patients, and the dashed line indicates the point of no effect. ECOG, Eastern Cooperative Oncology Group; NC, not calculated.

FIG 4.

Kaplan-Meier estimates of progression-free survival. (A) Kaplan-Meier estimates of blinded independent central review-assessed disease progression or death in the olaparib group and the chemotherapy group. The median duration of follow-up for censored patients was 13.8 months (interquartile range [IQR], 7.51-22.08 months) in the olaparib group and 3.9 months (IQR, 0.03-12.75 months) in the chemotherapy group. (B) Kaplan-Meier estimates of investigator-assessed disease progression or death in the olaparib group and the chemotherapy group.