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

Trial ID # NCT02477644; PAOLA-1
Phase III
Drug Class DNA Damage Repair Pathway Inhibitors: PARP
Drug Name Olaparib
Alternate Drug Names Lynparza, AZD2281
Drugs in Trial Bevacizumab, Carboplatin, Olaparib, Paclitaxel
Eligible Participant

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

Patients Enrolled

806

Therapy Setting

Maintenance

Study Design

Double Blind, Randomized

Endpoints

PFS, PFS2, evaluated per RECIST

Biomarkers

Exploratory: BRCA status, HRD status

Efficacy

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

All patients:
PFS: 22.1 vs 16.6 months, HR: 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)

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)
HRD+ (incl. BRCA MUT) (n=387): PFS: 37.2 vs 17.1 months, HR: 0.33 (0.25-0.45)
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)
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)
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=596):
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: 36.0 vs 16.0 months, HR: 0.39 (0.28-0.54)
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=210): PFS: 39.3 vs 22.9 months, HR: 0.46 (0.30-0.72)
Lower risk and BRCA MUTPFS: NR vs 22.2 months, HR: 0.11 (0.03-0.31)
Lower risk and HRD+: PFS: NR vs 22.1 months, HR: 0.15 (0.07-0.30)
Lower risk and HRD-: PFS: 23.8 vs 22.9 months, HR: 1.18 (0.65-2.25)

Clinically Significant Adverse Events

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

Conclusion

Dual maintenance therapy with olaparib and bevacizumab significantly improves PFS compared with bevacizumab maintenance alone for BRCA MUT and HRD+ patients

Reference

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

Grimm C et al. Maintenance olaparib plus bevacizumab (bev) after platinum-based chemotherapy plus bev in patients (pts) with newly diagnosed advanced high-grade ovarian cancer (HGOC): Efficacy by timing of surgery and residual tumor status in the Phase III PAOLA-1 trial. SGO (2020) abstract 34
https://sgo.confex.com/sgo/2020/meetingapp.cgi/Paper/16928

Harter P et al. Efficacy of maintenance olaparib plus bevacizumab by biomarker status in clinical higher- and lower-risk patients with newly diagnosed, advanced ovarian cancer in the PAOLA-1 trial. IGCS (2020) Plenary session V, abstract 18
https://www.clearityfoundation.org/wp-content/uploads/2020/09/PAOLA-IGCS-2020-abstract.pdf

Harter P et al. Figure 2 from abstract
https://www.clearityfoundation.org/wp-content/uploads/2020/09/PAOLA-IGCS-2020-Figure-2.pdf

Gonzalez Martin A et al. Maintenance olaparib plus bevacizumab (bev) in patients (pts) with newly diagnosed advanced high‐grade ovarian carcinoma (HGOC): Final analysis of second progression-free survival (PFS2) in the phase III PAOLA-1/ENGOT-ov25 trial. Annals Oncol (2020) 31 (suppl_4): abstract LBA33
https://www.clearityfoundation.org/wp-content/uploads/2020/10/PAOLA-ESMO-2020-PFS2-abstract.pdf