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PR072/#1519  Effort: clinical and molecular features associated with clinical benefit from adavosertib with or without olaparib in recurrent ovarian cancer following progression on PARP inhibition (NCT03579316)
  1. Naomi Adjei1,
  2. Robert Coleman2,
  3. Bryan Fellman3,
  4. Sarah Tran1,
  5. Ying Yuan3,
  6. Tugba Yildiran Ozmen4,
  7. Furkan Ozmen4,
  8. Anil Sood1,
  9. Pamela Soliman1,
  10. Alexi A Wright5,
  11. Neil Horowitz6,
  12. Susana Campos7,
  13. Panagiotis Konstantinopoulos6,
  14. David Gershenson1,
  15. Karen Lu1,
  16. Ami Patel1,
  17. Charnelle Ruben1,
  18. Alexis Rabbitt6,
  19. Lone Ottesen8,
  20. Dana Ghiorghiu9,
  21. Robert Godin10,
  22. Joyce Liu6,
  23. Gordon Mills4 and
  24. Shannon Westin1
  1. 1The University of Texas MD Anderson Cancer Center, Gynecologic Oncology, Houston, USA
  2. 2US Oncology, Texas Oncology, Houston, USA
  3. 3The University of Texas MD Anderson Cancer Center, Department of Biostatistics, Houston, USA
  4. 4Oregon Health and Sciences University, Precision Oncology, Portland, USA
  5. 5Dana-Farber Cancer Institute, Medical Oncology, Boston, USA
  6. 6Dana-Farber Cancer Institute, Division of Gynecologic Oncology, Boston, USA
  7. 7Dana Farber Cancer Institute, Medicine, Boston, USA
  8. 8Adcendo Aps, Adcendo Aps, Copenhagen, Denmark
  9. 9AstraZeneca, Late Oncology Randd, Cambridge, UK
  10. 10AstraZeneca, Oncology External Randd, Waltham, USA


Introduction EFFORT, a randomized noncomparative phase II study of adavosertib (WEE1 inhibitor) +/- olaparib [poly (ADP-ribose) polymerase inhibitor (PARPi)] in patients with PARPi-resistant ovarian cancer (OC), demonstrated efficacy and moderate toxicity. We report updated progression-free survival (PFS) and clinical/molecular features associated with clinical benefit from adavosertib (A) +/- olaparib (O).

Methods Eligible patients had recurrent OC after progression on PARPi, measurable disease, and adequate end-organ function. Primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included PFS and clinical benefit (ORR/stable disease > 4 months) based on BRCA status, homologous recombination deficiency (HRD), platinum sensitivity, and intervening alternate therapy after prior PARPi before trial enrollment. Replication stress and HRD are being assessed using novel pRPA32 and Rad51 foci.

Results There were 35 evaluable patients on each arm. Patients received a median of 4 prior therapies (range 1–11), including olaparib (41%). Median PFS was 5.5 months (95% CI, 3.9–6.9) from A and 6.8 months (95% CI, 4.3–8.3) from A/O. Table 1 demonstrates clinical benefit based on clinical/molecular features. Clinical benefit was observed on both arms regardless of BRCA status, platinum sensitivity, or use of intervening therapy after PARPi. Figure 1 demonstrates clinical benefit based on platinum sensitivity, with intriguing activity in platinum-resistant disease.

Conclusion/Implications Efficacy of adavosertib +/- olaparib was retained across multiple clinical cohorts of PARPi-resistant OC, including BRCAwt and platinum-resistant disease. Ongoing analysis using a novel functional HRD assay consisting of concordant measurement of Rad51, gH2AX and geminin foci will elucidate the role of HRD in clinical benefit.

Abstract PR072/#1519 Table 1

The efficacy of adavosertib with or without olaparib in the treatment of PARPi-resistant recurrent ovarian cancer based on various clinical and molecular features

Abstract PR072/#1519 Figure 1

Swimmer plots illustrating response to therapy among patients who received adavosertib alone (Arm 1) vs adavosertib in combination with olaparib (Arm 2) by platinum sensitivity and BRCA mutation status. Abbreviations: PD (progression of disease), PR (partial response), AZD1775 (adavosertib), BRCA- (BRCA wildtype), BRCA1/BRCA2 (Breast Cancer gene 1 and 2)

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