Rechallenge with the poly (ADP-­ribose) polymerase (PARP) inhibitor olaparib in patients with platinum-sensitive ovarian cancer led to significant improvement in progression-free survival, in patients with either BRCA1/2-mutated or nonmutated (ie, wild-type) disease compared with placebo, according to the results of the phase IIIb OReO/ENGOT OV-38 trial presented during the European Society for Medical Oncology (ESMO) Congress 2021.¹ 

In patients with BRCA1/2-mutated disease, median progression-free survival was 4.3 months vs 2.8 months with olaparib and placebo, respectively; in the non–BRCA1/2-mutated cohort, it was 5.3 months vs 2.8 months, respectively. The benefit of olaparib was similar in patients with tumors characterized by homologous recombination repair deficiency (HRD) and in those who were HRD-negative. 

In both BRCA-mutated and non–BRCA-mutated cohorts, a proportion of patients derived a clinically relevant long-term benefit from maintenance olaparib rechallenge.

— Eric Pujade-Lauraine, MD, PhD

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“In a heavily pretreated ovarian cancer population, rechallenge with maintenance olaparib following response to platinum-based chemotherapy provided a statistically significant improvement in progression-free survival compared with placebo, regardless of BRCA mutation status. In both BRCA-mutated and non–BRCA-mutated cohorts, a proportion of patients derived a clinically relevant long-term benefit from maintenance olaparib rechallenge. In the non–BRCA-mutated cohort, patients appeared to benefit regardless of HRD status,” said lead author Eric ­Pujade-Lauraine, MD, PhD, of the GINECO cooperative group in France.

PARP inhibitor maintenance therapy is standard of care for newly diagnosed patients with ovarian cancer and patients with platinum-sensitive relapse who have not received previous PARP inhibitor therapy. The majority of patients, however, will ultimately experience disease progression. 

The OReO/ENGOT OV-38 study was designed to address the unresolved issue of whether patients who are platinum-sensitive and who relapse can benefit from PARP inhibitor rechallenge. It is the first phase III study to evaluate PARP inhibitor maintenance retreatment in platinum-sensitive patients, and results should inform treatment selection.

Study Details

OReO/ENGOT OV-38 enrolled 220 patients with platinum-sensitive, nonmucinous epithelial ovarian cancer who had received one prior line of PARP inhibitor maintenance therapy and who were responsive to their most recent platinum-based chemotherapy. They were randomly assigned 2:1 to receive olaparib at 300 mg twice daily (or a lower dose of 250 mg twice daily if tolerability was an issue previously) or placebo until disease progression. There were two cohorts: BRCA1/2-mutated (n = 112) and non–BRCA1/2-mutated (n = 108).

Eligibility criteria included at least 18 months of PARP inhibitor maintenance as part of first-line therapy in the BRCA1/2-mutated group or at least 12 months in later lines of therapy. In the non–BRCA1/2-mutated group, criteria were 12 months of first-line therapy and at least 6 months in later lines. There was no limit on number of previous lines of any chemotherapy, but patients had to have had a response to their most recent platinum-based chemotherapy. The primary endpoint was investigator-assessed progression-free survival.

Accrual was completed in the BRCA1/2-mutated arm about 1 year earlier than in the non–BRCA1/2-mutated arm. The two cohorts were analyzed separately.

At baseline, both arms and both cohorts were well balanced for demographic and disease characteristics, with the exception of more younger patients assigned to olaparib in the BRCA1/2-mutated arm than in the non–BRCA1/2-mutated arm: median of 58.5 years vs 66.5 years, respectively. These patients were heavily pretreated: 93% in the BRCA1/2-mutated arm and 86% in the non–BRCA1/2-mutated arm had received at least three prior lines of chemotherapy. The median duration of previous PARP inhibitor therapy was longer for those with BRCA-mutated disease than for those with non–BRCA-mutated disease.

Both cohorts of these poor-prognosis patients met the primary endpoint. In the BRCA1/2-mutated group, olaparib rechallenge achieved a 43% increase in progression-free survival vs placebo (P = .022). The 6-month rate of progression-free survival was 35% for olaparib vs 13% for placebo in patients with BRCA1/2-mutated disease; the 12-month progression-free survival was 19% vs 0% for placebo.

In the non–BRCA1/2-mutated group, olaparib maintenance was associated with a 57% reduction in the risk of disease progression or death (P = .0023). The 6-month progression-free survival was 30% with olaparib vs 7% with placebo; the 12-month progression-free survival rate was 14% vs 0%, respectively.

Subgroup Analyses

An exploratory analysis of the non–BRCA1/2-mutated cohort found that olaparib rechallenge was of similar benefit in patients with HRD-positive and HRD-negative tumors (about 5.3 months for olaparib vs 2.8 months for placebo in both groups), suggesting the benefit of olaparib was not driven by the presence of HRD in 40% of these patients, Dr. Pujade-Lauraine noted.

On subgroup analysis, a consistent benefit of olaparib rechallenge was seen regardless of prior bevacizumab treatment, the number of prior platinum-based regimens, the type of response to most recent chemotherapy, or the duration of PARP inhibitor maintenance therapy. “These [subgroups] are small numbers of patients and have to be interpreted with caution,” Dr. Pujade-­Lauraine said. “We can’t make treatment decisions based on this.”

Safety analysis showed that olaparib was well tolerated, although as expected, adverse events were more common in olaparib-treated patients than in the placebo group. In the BRCA1/2-mutated group, grade 3 or higher adverse events occurred in 15% of the olaparib group vs 5% of placebo-treated patients. In the non–BRCA1/2-mutated group, the rate was 21% vs 8%, respectively. Three olaparib recipients discontinued treatment because of adverse events. 

DISCLOSURE: Dr. Pujade-Lauraine reported financial relationships with AstraZeneca, Tesaro, Roche, Clovis Oncology, Incyte, Pfizer, and ARCAGY.

REFERENCE

1. Pujade-Lauraine E, Selle F, Scambia G, et al: Maintenance olaparib rechallenge in patients with ovarian carcinoma previously treated with a PARP inhibitor. Phase IIIb OReO/ENGOT OV-38 trial. ESMO Congress 2021. Abstract LBA33. Presented September 18, 2021.