Olaparib Maintains Acceptable Safety Profile in Platinum-Sensitive, Relapsed Ovarian Cancer

Olaparib (Lynparza), when used in patients with platinum-sensitive relapsed ovarian cancer who had a known BRCA mutation and homologous recombination deficiency (HRD) status, demonstrated adverse effects (AEs) that proved to be consistent with the established safety profile of the PARP inhibitor, according to data from the phase 2 LIGHT trial (NCT02983799).¹

Results from the trial, which were presented during the 2021 SGO Virtual Annual Meeting on Women’s Cancer, showed that the treatment-emergent adverse effects (TEAEs) reported with the agent were low grade, namely Common Terminology Criteria for Adverse Events (CTCAE) grade 1/2. Forty-four percent of patients on olaparib required dose modifications in the form of interruptions or reductions to manage toxicities, while 4% of patients discontinued therapy because of TEAEs. 

The most frequently reported effects with olaparib included nausea, fatigue/asthenia, vomiting, and anemia, which generally presented early on in treatment. However, over the first year of treatment with the agent, investigators noted decreases in the prevalence of nausea and vomiting, as well as in CTCAE grade 2 or higher effects of nausea, vomiting, and fatigue/asthenia; the same was true for anemia that was grade 3 or higher in severity.

LIGHT was the first prospective trial to examine olaparib in the treatment of patients with platinum-sensitive, relapsed ovarian cancer in subgroups of patients with known BRCA mutation and HRD status. To be eligible for enrollment, patients must have received at least 1 previous line of platinum-based chemotherapy. 

A total of 272 participants were assigned to 1 of 4 study cohorts, which included those with germline BRCA mutations (cohort 1; n = 75), those with somatic BRCA mutations (cohort 2; n = 26), those with HRD positivity without BRCA mutations (cohort 3; n = 68) and those with HRD negativity (cohort 4; n = 90).2 Patients received olaparib at a twice-daily dose of 300 mg until either progressive disease or intolerable toxicity.

The primary end point of the trial was objective response rate (ORR), while key secondary end points included disease control rate (DCR) and investigator-assessed progression-free survival (PFS) per RECIST v1.1 criteria, as well as safety and tolerability.

Results from the primary analysis indicated that olaparib induced a greater magnitude of benefit in patients who harbored BRCA mutations or had HRD positivity compared with those who were HRD negative. The ORR with olaparib was 69% (95% CI, 58%-80%) in cohort 1, 64% (95% CI, 43%-82%) in cohort 2, 29% (95% CI, 19%-42%) in cohort 3, and 10% (95% CI, 5%-18%) in cohort 4.

Additionally, the DCRs in cohorts 1 through 4 were 96% (95% CI, 89%-99%), 100% (95% CI, 86%-100%), 79% (95% CI, 68%-88%), and 75% (95% CI, 65%-84%), respectively. The median PFS in these subgroups was 11.0 months (95% CI, 8.3-12.2), 10.8 months (95% CI, 7.3–not evaluable), 7.2 months (95% CI, 5.3-7.6), and 5.4 months (95% CI, 3.7-5.6), respectively.

At the August 27, 2019 data cutoff for the primary analysis, 76% of patients had discontinued treatment; 81% had done so because of progressive disease. The median total duration of treatment was 7.3 months (range, 0.5-22.2), while the median actual duration, with the exception of dose interruptions, was 7.1 months (range, 0.1-21.9). The median relative dose intensity was 100%, while the mean relative dose intensity was 91%.

Additional safety data from the trial presented during the 2021 SGO Virtual Annual Meeting on Women’s Cancer indicated that at 12 months, 70% of patients who were still receiving treatment with olaparib continued to receive the starting dose of twice-daily 300 mg. 

Regarding AEs of special interest, 1 case of CTCAE grade 2 pneumonitis was reported; this occurred 57 days following treatment initiation with the agent and it resolved following discontinuation of the drug. Subsequently, the patient had CTCAE grade 3 pneumonitis that presented 108 days following the last dose of the agent.

Another patient on the trial previously reported a CTCAE grade 2 AE that presented 22 days following the last dose of the olaparib was received; however, the effect was reclassified as pneumonia by a study investigator later. In both of these cases, effects were determined to be causally related to the agent per the investigator.

Moreover, another patient reported CTCAE grade 2 pulmonary fibrosis that presented 110 days following initiation of olaparib; this was also considered to be causally associated with the agent per the study investigator.

Notably, no cases of either myelodysplastic syndrome or acute myeloid leukemia were observed with the agent.

Additionally, 2 toxicities were linked with fatal outcomes, although they were not determined to be related to olaparib. One of these patients had a history of recurring atrial fibrillation and experienced the effect 46 days following the start of treatment with olaparib, while another patient experienced intestinal perforation which happened 32 days following the last dose of olaparib.

Once olaparib was initiated, the most frequently reported TEAEs presented early on in treatment. The median time to first occurrence of nausea was 5 days, while the median duration of the first event was 57 days. For fatigue/asthenia, 15 days was the median time to the first occurrence, while the median duration of the first event had not been reached. The median time to first occurrence of vomiting was 21 days and the median duration was 2 days, while it took a median of 52 days for anemia to present with a median duration of 305 days.

The majority of the nausea, vomiting, and fatigue/asthenia events reported with olaparib were CTCAE grade 1 in severity and they were mostly well tolerated. The prevalence of events that were CTCAE grade 2 or higher were found to decrease over time. Cases of anemia ranged from grade 1 to grade 3 in severity, but the overall severity of this effect also decreased over time. Moreover, the prevalence of nausea and vomiting was found to decrease over time, while the prevalence of fatigue/asthenia and anemia plateaued shortly after start of treatment with olaparib.

References

1. Cadoo K, Simpkins F, Mathews C, et al. Olaparib treatment in patients with platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: secondary safety results from the phase II LIGHT study. Presented at: 2021 SGO Virtual Annual Meeting on Women’s Cancer; March 19-26, 2021; virtual.
2. Cadoo KA, Simpkins F, Mathews CA, et al. Olaparib treatment in patients (pts) with platinum-sensitive relapsed (PSR) ovarian cancer (OC) by BRCA mutation (BRCAm) and homologous recombination deficiency (HRD) status: phase II LIGHT study. J Clin Oncol. 2020;38(suppl 15):6013. doi:10.1200/JCO.2020.38.15_suppl.6013