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.
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