Randomized, Double-Blind, Phase III Trial Olaparib vs. Placebo Patients With Advanced FIGO Stage IIIB-IV High Grade Serious or Endometrioid Ovarian, Fallopian Tube, or Peritoneal Cancer Treated Standard First-Line Treatment

Stage III or IV, high grade serous or endometrioid, with CR or PR after first-line chemotherapy+bevacizumab

806

Maintenance

Double Blind, Randomized

PFS, OS, PFS2, evaluated per RECIST

Exploratory: BRCA status, HRD status

Ola (n=537) vs Placebo (n=269):

All patients:
PFS: 22.1 vs 16.6 months, H
R: 0.59 (0.49-0.72, p<0.001)
PFS2: 36.5 vs 32.6 months, HR: 0.78 (0.64-0.95, p=0.0125)
TSST: 38.2 vs 31.5 months, HR: 0.78 (0.64 -0.95, p=0.0115)
OS: 56.5 vs 51.6 months, HR: 0.92 (0.76-1.12, p=0.41)

HRD+ (incl. BRCA MUT) (n=387):
PFS: 37.2 vs 17.7 months, HR: 0.33 (0.25-0.45)
OS: 75.2 vs 57.3 months, HR: 0.62 (0.45-0.85)
OS (5 years): 65.5 vs 48.4%

Exploratory analyses:
BRCA MUT (n=237):
PFS: 37.2 vs 21.7 months, HR: 0.31 (0.20-0.47); PFS2: NR vs 45.0 months, HR: 0.53 (0.34-0.83); OS: 75.2 vs 66.9 months, HR: 0.60 (0.39-0.54)
HRD+ (excl. BRCA MUT) (n=152):
PFS: 28.1 vs 16.6 months, HR: 0.43 (0.28-0.66); PFS2: 50.3 vs 30.1 months, HR: 0.60 (0.38-0.96); OS: NR vs 52.0 months, HR: 0.71 (0.45-1.13)
non-BRCA MUT (n=569):
PFS: 18.9 vs 16.0 months,  HR: 0.71 (0.58-0.88)
HRD- (n=419):
PFS: 16.9 vs 16.0 months, HR: 0.92 (0.72-1.17); PFS2: 24.4 vs 26.4 months, HR: 1.04 (0.77-1.42); OS: 36.8 vs 40.4 months, HR: 1.19 (0.88-1.63)
Upfront surgery and no residual disease (n=245): PFS: 39.3 vs 22.1 months, HR: 0.47 (0.29-0.75)
Interval surgery and no residual disease (n=238): PFS: 22.1 vs 17.7 months, HR: 0.61 (0.41-0.91)
Upfront surgery with residual disease (n=164): PFS: 17.6 vs 13.0 months, HR: 0.74 (0.48-1.15)
Interval surgery with residual disease (n=100): PFS: 18.7 vs 12.3 months, HR: 0.70 (0.41-1.2)
Higher risk (stage III w/ upfront surgery and residual disease or who received neoadjuvant chemotherapy, or stage IV, n=595):
PFS: 20.3 vs 14.7 months, HR: 0.60 (0.49-0.79)
Higher risk and BRCA MUT: PFS: 36.0 vs 19.4 months, HR: 0.37 (0.23-0.59)
Higher risk and HRD+:
PFS: 31.3 vs 15.9 months, HR: 0.46 (0.34-0.61); PFS at 5 years: 35 vs 15%
OS: NR vs 54.0 months, HR: 0.70 (0.50-1.00); OS at 5 years: 55 vs 42%
Higher risk and HRD-: PFS: 16.6 vs 13.9 months, HR: 0.83 (0.64-1.08)
Lower risk (stage III w/ upfront surgery and no residual disease, n=211): PFS: 39.3 vs 22.9 months, HR: 0.46 (0.30-0.72)
Lower risk and BRCA MUT: PFS: NR vs 22.2 months, HR: 0.11 (0.03-0.31)
Lower risk and HRD+:
PFS: NR vs 22.3 months, HR: 0.26 (0.13-0.45); PFS at 5 years: 72 vs 28%
OS: NR vs NR, HR: 0.31 (0.14-0.66); OS at 5 years: 88 vs 61%
Lower risk and HRD-: PFS: 23.8 vs 22.9 months, HR: 1.18 (0.65-2.25)

Median time from first subsequent therapy (FST) to second subsequent therapy (SST):
Progression during Ola maint vs Progression after Ola maint vs Placebo:
Treatment with any chemo:
All patient: 6.1 vs 11.4 vs 11.9 months
HRD+: 7.2 vs 12.7 vs 13.9 months
HRD-: 6.0 vs 10.6 vs 10.8 months
Treatment with Pt-based chemo:
All patients: 7.3 vs 12.0 vs 12.9 months
HRD+: 7.3 vs 12.7 vs. 14.3 months
HRD-: 6.6 vs. 12.9 vs.11.8 months

Ola vs Placebo:
Serious AE: MDS, AML or aplastic anemia (1.7 vs 2.2%), hypertension (9 vs 13%), anemia (6 vs <1%)
Grade 3-4 AE: all (57 vs 51%), hypertension (19 vs 30%), anemia (17 vs 1%)

Dual maintenance therapy with olaparib and bevacizumab improves PFS and OS compared with bevacizumab maintenance alone for BRCA MUT and HRD+ high and low clinical risk patients

Ray-Coquard I et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med (2019) 381(25):2416-2428
https://www.ncbi.nlm.nih.gov/pubmed/31851799

Harter P et al. Efficacy of maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed, advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial. Gynecol Oncol (2022) 164(2):254-264
https://pubmed.ncbi.nlm.nih.gov/34952708/

Gonzalez-Martin A et al. Maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced high-grade ovarian cancer: Main analysis of second progression-free survival in the phase III PAOLA-1/ENGOT-ov25 trial. Eur J Cancer (2022) 174:221-231
https://pubmed.ncbi.nlm.nih.gov/36067615/

Ray-Coquard I et al. Final overall survival (OS) results from the phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib (ola) plus bevacizumab (bev) in patients (pts) with newly diagnosed advanced ovarian cancer (AOC). Ann Oncol (2023) 34(8):681-692
https://pubmed.ncbi.nlm.nih.gov/37211045/

Ray-Coquard I et al. Slide from presentation
https://www.clearityfoundation.org/wp-content/uploads/2022/10/PAOLA-1-Slide-from-presentation-ESMO-2022.pdf

Sabatier R et al. Efficacy and safety of maintenance olaparib and bevacizumab in ovarian cancer patients aged > = 65 years from the PAOLA-1/ENGOT-ov25 trial. Eur J Cancer (2023) 181:42-52
https://pubmed.ncbi.nlm.nih.gov/36634389/

Harter P et al. Efficacy of subsequent therapies in patients (pts) with advanced ovarian cancer (AOC) in the phase III PAOLA-1/ENGOT-ov25 trial according to whether disease progression occurred during or after the end of olaparib (ola) maintenance. J Clin Oncol 41, 2023 (suppl 16; abstr 5550)
https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.5550

Harter P et al. Poster
https://www.clearityfoundation.org/wp-content/uploads/2023/08/PAOLA-1-poster-ASCO-2023-scaled.jpeg

Lorusso D et al. Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial. Int J Gynecol Cancer (2024) 34(4):550-558
https://pubmed.ncbi.nlm.nih.gov/38129136/