A Phase III Study Comparing Single-Agent Olaparib or the Combination of Cediranib and Olaparib to Standard Platinum-Based Chemotherapy in Women With Recurrent Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Trial ID # NCT02446600; NRG-GY004
Phase III
Drug Class DNA Damage Repair Pathway Inhibitors: PARP
Drug Name Olaparib
Alternate Drug Names AZD2281, Lynparza
Drugs in Trial Carboplatin, Cediranib, Gemcitabine, Liposomal doxorubicin, Olaparib, Paclitaxel
Eligible Participant

Platinum sensitive high grade serous or endometrioid ovarian cancer or germline BRCA1/2-mutated ovarian cancer, no prior PARP inhibitor

Patients Enrolled

565, median 1 prior therapy

Therapy Setting

Recurrence

Study Design

Open-Label, Randomized

Endpoints

ORR, PFS, OS, evaluated per RECIST

Biomarkers

Exploratory: BROCA-HR

Efficacy

Ola+Ced (n=189) vs Ola (n=189) vs Treatment of Physician's Choice (TPC) (CarboPt+Gem (27%)/PLD (48%)/Pac (25%)) (n=187):

ORR: 69.4 vs 52.4 vs 71.3%
PFS: 10.4 vs 8.2 vs 10.3 months, HR: 0.86 (0.66-1.11, p=0.077); HR: 1.20 (0.93-1.54)
OS: 30.5 vs 29.2 vs 31.3 months

Exploratory analysis, gBRCA status, HRR status, LOH status:
gBRCA MUT: ORR: 89 vs 90 vs 71%; PFS: 18.0 vs 12.7 vs 10.5 months, HR: 0.55 (0.32-0.94); HR: 0.63 (0.37-1.07)
gBRCA WT: ORR: 64 vs 40 vs 72%; PFS: 8.9 vs 6.6 vs 9.7 months, HR: 0.97 (0.73-1.30); HR: 1.41 (1.07-1.81)
HRR mut: PFS: 20.4 vs 13.1 vs 12.3 months, HR: 0.55 (0.32-0.95); HR0.78 (0.48-1.27)
HRR wt: PFS: 8.5 vs 6.4 vs 9 months, HR: 0.93 (0.68-1.27); HR1.56 (1.15-2.12) 
LOH high: PFS: 12.2 vs 8.5 vs 10.6 months
LOH low: PFS: 8.4 vs 6.3 vs 8.1 months

Clinically Significant Adverse Events

Ola+Ced vs Ola vs TPC:
Serious AE:
Grade 3-4 AE: neutropenia (3.8 vs 1.6 vs 31.8%), anemia (5.5 vs.15.0 vs 13.8%), thrombocytopenia (1.6 vs 1.0 vs 15.0%), leukopenia (1.1 vs 1.1 vs 14.4%), fatigue (17.5 vs 7.0 vs 1.8%), diarrhea (13.7 vs 1.0 vs 1.8%), hypertension (31.7 vs 5.3 vs 1.8%)

Conclusion

Cediranib+olaparib has similar activity to standard of care in relapsed platinum sensitive ovarian cancer but does not improve PFS

Reference

Lui JF et al. A phase III study comparing single-agent olaparib or the combination of cediranib and olaparib to standard platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer. J Clin Oncol (2020) 38: (suppl; abstr 6003)
https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.6003

Liu J et al. Association of homologous recombination deficiency (HRD) with clinical outcomes in a phase III study of olaparib or cediranib and olaparib compared to platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer (PSOC): Biomarker analyses from NRG-GY004. Annals of Oncology (2021) 32 (suppl_5): LBA34
https://oncologypro.esmo.org/meeting-resources/esmo-congress-2021/association-of-homologous-recombination-deficiency-hrd-with-clinical-outcomes-in-a-phase-iii-study-of-olaparib-or-cediranib-and-olaparib-compared

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