Updated SOLO1 Safety Data Show Olaparib Maintenance is Safe in BRCA-Positive Ovarian Cancer

Olaparib (Lynparza) maintenance in newly diagnosed patients with BRCA-positive advanced ovarian cancer demonstrated a predictable and manageable adverse event (AE) profile, according to an analysis of timing duration, and grade of most common hematologic and non-hematologic AEs in the phase 3 SOLO1 trial published in Gynecologic Oncology.

Women with newly diagnosed, advanced ovarian cancer who are in response to first-line platinum-based chemotherapy are eligible to receive maintenance therapy with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib. This patient population is planned to receive olaparib for 2 years in the setting of no or minimal residual disease, meaning that it’s important the agent dose not add a significant toxicity or safety burden.

The phase 3 SOLO1 trial enrolled 457 participants. The primary end point of the study was progression-free survival (PFS). Secondary end points include overall survival, time to first progression, time to second progression, health-related quality of life, time to first subsequent therapy or death, and time to second subsequent therapy or death.

Patients were randomized 2:1 into an experimental or control arm. During the experimental arm, patients were given 300 mg of olaparib twice daily for 2 years, with the option to continue beyond that if it is in the patient’s best interest for an additional year. In the control arm, patients were administered a matching placebo twice a day.

Between September 2013 and March 2015, 391 patients were randomized into either the experimental (n = 260) or the control arm (n = 130). Baseline characteristics were well balanced between the 2 groups.

In the olaparib arm, 81.9% had a complete clinical response after platinum-based chemotherapy and 18.1% had a partial clinical response. Most patients, 76.9%, had an ECOG score of 0. Primary tumor location included ovary (84.6%), fallopian tubes (8.5%), primary peritoneal (5.8%), and other (1.2%). A FIGO stage of 3 was seen in 84.6% of patients and 94.6% of patients had a serous histology. BRCA mutations included BRCA1 (73.5%), BRCA2 (25.4%), and both (1.2%). Adverse events (AEs) at baseline included nausea (5.8%), fatigue (16.5%), asthenia (4.6%), anemia (19.2%), neutropenia (0.8%), and thrombocytopenia (0.4%). 

In the placebo arm, 81.7% had a complete clinical response to platinum-based chemotherapy and 18.3% had a partial clinical response. The majority, 80.2%, had an ECOG score of 0and 80.2% had a FIGO score of 3. Primary tumor location included the ovary (86.3%), the fallopian tubes (8.4%), and the primary peritoneal (5.3%). A serous histology was seen in 99.2% of patients. BRCA mutations observed included BRCA1 (69.5%) and BRCA2 (30.5%). Adverse events at baseline included nausea (6.9%), fatigue (19.8%), asthenia (3.1%), vomiting (0.8%), anemia (10.7%), and neutropenia (3.1%).

In terms of efficacy, the median duration of follow-up for the olaparib arm was 40.7 months (range, 34.9-42.9) and 41.2 months for the placebo arm (range, 32.2-41.6). The median duration of treatment was 24.6 months in the experimental group and 13.9 months for the placebo group, which is consistent with the median PFS of 13.8 months in the placebo group. Nearly half, 47.3%, completed treatment for at least 2 years and 10% completed treatment beyond 2 years in the experimental group. In the placebo group, 26.9% completed 2 years of treatment and 2.3% continued treatment beyond 2 years. 

AEs were predominantly grade 1-2 in both arms. Common all-grade hematologic AEs included anemia (38.8% in the experimental arm versus 10% in the control arm), neutropenia (23.1% vs 11.5%), and thrombocytopenia (11.2% vs. 3.8%). Grade ≥ 3 hematologic events included anemia (21.5% vs 1.5%), neutropenia (8.5% vs. 4.6%), and thrombocytopenia (0.4% vs 0.8%). Nonhematologic any-grade AEs included nausea (77.3% vs 37.7%), fatigue (63.5% vs 41.5%), and vomiting (40% vs 14.6%). Grade ≥ 3 nausea occurred in 0.8% of patients in the experimental arm, grade ≥ 3 fatigue occurred in 3.8% of patients in the experimental arm and 1.5% of patients in the placebo arm, and ≥ 3 vomiting occurred in 0.4% of patients in the experimental arm versus 0.8% of patients in the placebo arm.

AEs led to dose interruptions in 51.9% of patients in the olaparib arm versus 16.9% of patients in the placebo arm. No incidences of increases in blood creatinine lead to study discontinuation. Dose reductions were seen in 28.5% of patients in the experimental arm and 3.1% of patients in the placebo arm. The rate of discontinuation was 11.5% in the experimental group and 2.3% in the control group. The median duration dose interruption was 15.5 days (range, 7-36) in the experimental arm versus 13 days (range, 7-17) in the placebo arm.

Acute myeloid leukemia (AML) was reported in 1.2% of patients in the olaparib arm. All cases resulted in death. No cases of AML were reported in the placebo arm. New primary malignancies were reported in 2.7% of patients in the olaparib arm and 3.8% of patients in the placebo arm.

“Although similarities are evident in the tolerability profiles of the different PARP inhibitors, with olaparib, niraparib [Zejula], rucaparib [Rubraca] and veliparib all associated with nausea, vomiting, fatigue/asthenia and anemia, distinct differences are also observed. For example, the frequency and severity of hematologic AEs differs between PARP inhibitors,” wrote study authors.

_REFERENCES:

_{Colombo N, Moore K, Scambia G, et al. Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial. Gynecol Oncol.2021;163:41-49. doi: 10.1016/j.ygyno.2021.07.016}