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

person Stephanie Lheureux Princess Margaret, University Health Network, Toronto, ON, Canada info_outline Stephanie Lheureux, Taymaa May, Michelle K. Wilson, Diane M. Provencher, Susie Lau, Prafull Ghatage, Johanne I Weberpals, Susana N. Banerjee, Iain A. McNeish, Neesha C. Dhani, Sarah Ferguson, Genevieve Bouchard-Fortier, Trevor John Pugh, Xiang Y Ye, Sarah Garisto, Judy Quintos, Janelle Ramsahai, Horace Wong, Valerie Bowering, Amit M. Oza

Authors person Stephanie Lheureux Princess Margaret, University Health Network, Toronto, ON, Canada info_outline Stephanie Lheureux, Taymaa May, Michelle K. Wilson, Diane M. Provencher, Susie Lau, Prafull Ghatage, Johanne I Weberpals, Susana N. Banerjee, Iain A. McNeish, Neesha C. Dhani, Sarah Ferguson, Genevieve Bouchard-Fortier, Trevor John Pugh, Xiang Y Ye, Sarah Garisto, Judy Quintos, Janelle Ramsahai, Horace Wong, Valerie Bowering, Amit M. Oza Organizations Princess Margaret, University Health Network, Toronto, ON, Canada, University Health Network, Toronto, ON, Canada, Auckland City Hospital, Auckland, New Zealand, Centre Hospitalier de l'Université de Montréal (CHUM)-Notre Dame, Montreal, QC, Canada, McGill, Montreal, QC, Canada, Tom Baker Cancer Centre, Calgary, AB, Canada, Ottawa Hospital Research Institute, Ottawa University, Ottawa, ON, Canada, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, United Kingdom, Imperial College London, London, United Kingdom, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, Ontario Cancer Institute, Toronto, ON, Canada, Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, ON, Canada, Ozmosis, Toronto, ON, Canada, Princess Margaret Cancer Centre, Toronto, ON, Canada Abstract Disclosures Research Funding OICR Astra-Zeneca 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 wtBRCA1/2) 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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