Phase II randomized multi-centre study of neoadjuvant olaparib in patients with platinum sensitive relapsed high grade serous ovarian cancer: The NEO trial.

5506 Background: Recurrent Platinum sensitive (PS) high grade serous ovarian cancer (HGSOC) can be managed in selected patients (pts) with secondary cytoreductive surgery and systemic therapy. NEO [NCT02489006] is a window of opportunity study with the PARP inhibitor (PARPi) olaparib given prior to secondary cytoreductive surgery in PS HGSOC to assess potential for de-escalation therapy post surgery. Methods: This was a phase II, open label, randomized study in PARPi naïve pts with recurrent HGSOC ≥6 months following previous platinum therapy. Pts were suitable for secondary cytoreductive surgery and underwent tumor biopsy before neo-adjuvant therapy with olaparib 300mg po bid for 6 ± 2 weeks. Post-operatively, pts were randomized 1:1 to 6 cycles of platinum chemotherapy followed by maintenance olaparib (arm A) or olaparib alone 28 days cycle (arm B). The primary clinical efficacy endpoint was PFS with OS a secondary endpoint, estimated using the KM method and compared between the two treatment groups using the log-rank test. Response was assessed by RECIST 1.1. AEs were assessed with CTCAE v4.03. Translational studies include paired tumor tissue analyses by WGTS and longitudinal circulating tumor DNA. Results: 44 pts were enrolled from Feb 2017 to Sep 2021 and 36 pts randomized (arm A: n=19 - arm B: n=17).Two pts withdrew and 6 pts (all wt BRCA1/2) were assigned to arm A because of disease progression during neo-adjuvant olaparib. Median (IQR) FU of the study was 3.96 (2.23-5.29) years. Median age was 59 (53-66) years and 31% had known deleterious germline BRCA1/2 mutation. The median duration of neo-adjuvant was 40 (34-48) days, ranging from 20 to 120 days. Of 36 pts proceeded to surgery, 31 (86%) were surgically cytoreduced to no visible residual disease. Median cycles of all adjuvant therapy was similar in the two arms (21.5 cycles arm A and 18 cycles in Arm B, p=0.60). The median time on adjuvant olaparib was 13.8 and 14.7 months for arm A and B respectively. The PFS and OS rates at 3 years are the same and were 84.2 % (69.3% - 100%) and 75.1% (56.6%-99.7%) for arm A and arm B respectively (HR: 0.90 (0.28, 2.83)). No difference in PFS or OS was observed between the two arms (p=0.85). Subjects with no visible residual disease had better OS (HR=0.23, p=0.0097). No cases of MDS/AML were reported. There were no grade >3 AEs during neoadjuvant therapy and reported in 16% and 4% pts in arms A and B respectively during first 6 months of adjuvant therapy. Conclusions: Neo-adjuvant olaparib followed by cytoreductive surgery was feasible and safe in PS HGSOC. In pts with resectable disease at secondary cytoreduction, olaparib alone post-surgery was as effective as chemotherapy followed by olaparib and less toxic, suggesting the potential for a chemo-free approach in this selected population. Translational research is on-going to assess biomarkers of response/resistance. Clinical trial information: NCT02489006 .

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