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Conference Correspondent  - ESMO Highlights

Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously shown clinical activity in subsets of patients with recurrent ovarian cancer.1 Based on the hypothesis that olaparib may complement the antitumor activity of immune checkpoint inhibitors like durvalumab, clinical trials have been undertaken to evaluate the safety and efficacy of the combination in recurrent ovarian cancer. In a previous phase 1 study, Lee and colleagues reported safety data and the recommended phase 2 dose of durvalumab + olaparib.2 Here, the same investigators report the safety data and clinical activity in the phase 2 cohort.3

Thirty-five patients with performance scores ranging from 0 to 1, good end-organ function, and biopsiable disease received at least 1 cycle of treatment. Each cycle consisted of the recommended phase 2 dose of 300 mg oral olaparib, twice daily, and 1500 mg intravenous durvalumab on day 1 of each 28-day cycle. The primary objective was to estimate clinical activity using Response Evaluation Criteria in Solid Tumors 1.1 objective response rate and a 2-stage design targeting 35 evaluable patients. Secondary objectives included progression-free survival and safety as assessed by Common Terminology Criteria for Adverse Events (version 4.0). Tissue and blood samples were collected both during pretreatment and on therapy, at cycle 1, day 15 and cycle 3, day 1.

The median age of patients in this study was 67 years (range 40-85 years), and 6 (17%) were germline BRCA mutation carriers (BRCAm), whereas 29 (83%) were BRCA wild type (BRCAwt). Thirty patients (86%) had platinum-resistant recurrent disease, and the median number of prior therapy regimens was 3.5 (range 1-16).

Of 34 evaluable patients (6 BRCAm, 28 BRCAwt), 5 partial responses (PRs) were observed (15% response rate, median 11 months [range 6.5-23 months]). Of those patients with PR, 2 patients were BRCAm (1 with platinum-resistant disease [8.5 months] and 1 with platinum-sensitive disease [11+ months]) and 3 patients were BRCAwt (2 with platinum-resistant disease [23 and 14+ months] and 1 with platinum-sensitive disease [6.5months]). Twenty patients (57%) had stable disease (SD) of ≥4 months (median 6.5 months [range, 4-12.5 months]), yielding a 37% clinical benefit rate (PR + SD ≥4 months).

High-grade (≥grade 3) adverse events included anemia (26%) and lymphopenia (14%). Three patients required a dose reduction of olaparib due to grade 3 anemia (n = 1), grade 3 atrial fibrillation (n = 1), and recurrent grade 2 nausea refractory to supportive care (n = 1). Biomarker analysis is ongoing, including tumor mutational burden, PD-L1/tumor-infiltrating lymphocyte expression, and STING pathway evaluation.

The results presented here suggest that the combination of durvalumab and the PARP inhibitor olaparib was well-tolerated and had clinical activity in a subgroup of heavily pretreated BRCAwt patients with ovarian cancer. Ongoing biomarker evaluation will further characterize the subset of patients who will benefit most from this combination.


References

  1. Lorusso D, et al. Drug Des Devel Ther. 2018;12:1501-1509.
  2. Lee J-M, et al. ASCO 2016. Abstract 3015.
  3. Lee J-M, et al. ESMO 2018. Abstract 936PD.
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