Maintenance olaparib monotherapy for platinum-sensitive relapsed ovarian cancer in patients without a germline BRCA1/BRCA2 mutation: Secondary safety results from the phase IIIb OPINION study (128)

Objectives: The Phase IIIb, single-arm OPINION study (NCT03402841) is the largest dataset to evaluate maintenance olaparib in patients (pts) without a deleterious or suspected deleterious germline BRCA1/BRCA2 mutation (non-gBRCAm) who had platinum-sensitive relapsed ovarian cancer (PSR OC) and had received ≥2 prior lines of platinum-based chemotherapy (PBC). In the primary analysis, safety and tolerability were consistent with those observed in prior olaparib studies (Poveda et al. J Clin Oncol 2021). Here, we report prespecified and post hoc secondary safety analyses to characterize more completely the safety profile of maintenance olaparib in this setting. Methods: Pts with high-grade serous or endometrioid OC with incomplete or partial response to PBC received olaparib (300 mg bid) until disease progression or unacceptable toxicity. Safety and tolerability were assessed in all pts receiving ≥1 dose. Treatment-emergent adverse events (TEAEs; CTCAE v5.0) were defined as having onset between the first dose and 30 days after the last dose or worsening of a pre-existing AE. AEs of special interest (AESIs; myelodysplastic syndrome [MDS] or acute myeloid leukemia [AML], new primary malignancy, or pneumonitis) occurring after 30 days were also reported. Anemia, neutropenia, and thrombocytopenia were analyzed as grouped terms. Results: All 279 enrolled pts received olaparib and were included in safety analyses. At the primary data cut-off (October 2, 2020; ~18 months after the last pt was enrolled), 208 (74.6%) pts had discontinued olaparib, mostly due to disease progression (175 pts, 62.7%). Median (range) total and actual (excluding dose interruptions) durations of treatment were 9.4 (0-31.9) and 9.2 (0-31.9) months, respectively. TEAEs are presented in the Table. While most were grade 1-2, grade ≥3 occurred in 29.0% of pts. Serious TEAEs and AEs leading to discontinuation and dose modification occurred in 19.7%, 7.5%, and 49.1% of pts, respectively. For the five most common TEAEs (nausea [48.4%], fatigue/asthenia [44.1%], anemia [39.1%], vomiting [16.1%], and neutropenia [15.8%]), median time (interquartile range) to first occurrence was 6 (2-29), 29 (6-77), 57 (29-86), 28 (8-81), and 56 (29-156) days, respectively, and median duration of first event was 64, 336, 57, 2, and 21.5 days, respectively. There were seven AESIs reported in 6 pts: two new primary malignancies (breast cancer and rectal adenocarcinoma), two cases of MDS, two pneumonitis, and one lung infiltration. One fatal TEAE (aspiration pneumonia; not considered related to olaparib) was reported. Conclusions: In the largest olaparib dataset in non-gBRCAm PSR OC pts who had received ≥2 prior lines of PBC, maintenance olaparib was well tolerated, and the safety profile was consistent with that observed in prior olaparib studies. Most TEAEs were low grade, and only one grade ≥3 TEAE (anemia) was reported in >10% of pts. In almost half of pts, TEAEs were managed via dose modification; the discontinuation rate due to TEAEs was low. Objectives: The Phase IIIb, single-arm OPINION study (NCT03402841) is the largest dataset to evaluate maintenance olaparib in patients (pts) without a deleterious or suspected deleterious germline BRCA1/BRCA2 mutation (non-gBRCAm) who had platinum-sensitive relapsed ovarian cancer (PSR OC) and had received ≥2 prior lines of platinum-based chemotherapy (PBC). In the primary analysis, safety and tolerability were consistent with those observed in prior olaparib studies (Poveda et al. J Clin Oncol 2021). Here, we report prespecified and post hoc secondary safety analyses to characterize more completely the safety profile of maintenance olaparib in this setting. Methods: Pts with high-grade serous or endometrioid OC with incomplete or partial response to PBC received olaparib (300 mg bid) until disease progression or unacceptable toxicity. Safety and tolerability were assessed in all pts receiving ≥1 dose. Treatment-emergent adverse events (TEAEs; CTCAE v5.0) were defined as having onset between the first dose and 30 days after the last dose or worsening of a pre-existing AE. AEs of special interest (AESIs; myelodysplastic syndrome [MDS] or acute myeloid leukemia [AML], new primary malignancy, or pneumonitis) occurring after 30 days were also reported. Anemia, neutropenia, and thrombocytopenia were analyzed as grouped terms. Results: All 279 enrolled pts received olaparib and were included in safety analyses. At the primary data cut-off (October 2, 2020; ~18 months after the last pt was enrolled), 208 (74.6%) pts had discontinued olaparib, mostly due to disease progression (175 pts, 62.7%). Median (range) total and actual (excluding dose interruptions) durations of treatment were 9.4 (0-31.9) and 9.2 (0-31.9) months, respectively. TEAEs are presented in the Table. While most were grade 1-2, grade ≥3 occurred in 29.0% of pts. Serious TEAEs and AEs leading to discontinuation and dose modification occurred in 19.7%, 7.5%, and 49.1% of pts, respectively. For the five most common TEAEs (nausea [48.4%], fatigue/asthenia [44.1%], anemia [39.1%], vomiting [16.1%], and neutropenia [15.8%]), median time (interquartile range) to first occurrence was 6 (2-29), 29 (6-77), 57 (29-86), 28 (8-81), and 56 (29-156) days, respectively, and median duration of first event was 64, 336, 57, 2, and 21.5 days, respectively. There were seven AESIs reported in 6 pts: two new primary malignancies (breast cancer and rectal adenocarcinoma), two cases of MDS, two pneumonitis, and one lung infiltration. One fatal TEAE (aspiration pneumonia; not considered related to olaparib) was reported. Conclusions: In the largest olaparib dataset in non-gBRCAm PSR OC pts who had received ≥2 prior lines of PBC, maintenance olaparib was well tolerated, and the safety profile was consistent with that observed in prior olaparib studies. Most TEAEs were low grade, and only one grade ≥3 TEAE (anemia) was reported in >10% of pts. In almost half of pts, TEAEs were managed via dose modification; the discontinuation rate due to TEAEs was low.