Phase 3 Study of Rucaparib as Switch Maintenance After Platinum in Relapsed High Grade Serous and Endometrioid Ovarian Cancer (ARIEL3)

Trial ID # NCT01968213; ARIEL3
Phase III
Drug Class DNA Damage Repair Pathway Inhibitors: PARP
Drug Name Rucaparib
Alternate Drug Names Rubraca, CO-338, PF 01367338, AG-014699
Drugs in Trial Rucaparib
Eligible Participant

Platinum sensitive recurrence and CR or PR in most recent platinum-based therapy, ≥ 2 platinum-based regimens

Patients Enrolled

564

Therapy Setting

Maintenance

Study Design

Double Blind, Randomized

Endpoints

PFS, PFS2, TFST, evaluated per RECIST

Biomarkers

Exploratory: BRCA1/2; LOH (by FoundationFocus CDx BRCA LOH), HRR gene alterations

Efficacy

Ruc maint vs Placebo (BICR):

All (n=564):
PFS: 13.7 vs 5.4 months, HR: 0.35 (0.28-0.45, p<0.0001)
BRCA MUT (n=196):
PFS: 26.8 vs 5.4 months, HR: 0.20 (0.13-0.32, p<0.0001)
BRCA MUT/BRCA WT LOH High (n=354):
PFS: 22.9 vs 5.5 months, HR: 0.34 (0.24-0.47, p<0.0001)

Exploratory analysis BRCA WT patients:
BRCA WT/LOH Low (n=161): PFS: 8.2 vs 5.3 months, HR: 0.47 (0.31-0.71, p=0.0002)
BRCA WT/LOH High (n=158): PFS: 11.1 vs 5.6 months, HR: 0.55 (0.35-0.89, p=0.0135)

Ruc maint vs Placebo (investigator review):

All (n=564):
PFS: 10.8 vs 5.4 months, HR: 0.36 (0.30-0.45, p<0.0001)
BRCA MUT (n=196):
PFS: 16.6 vs 5.4 months, HR: 0.23 (0.16-0.34, p<0.0001)
BRCA MUT/BRCA WT LOH High (n=354):
PFS: 13.6 vs 5.4 months, HR: 0.32 (0.24-0.42, p<0.0001)

Exploratory analysis BRCA status, patients w/ HRR alterations:
BRCA WT/LOH Low (n=161): PFS: 6.7 vs 5.4 months, HR: 0.58 (0.40-0.85, p=0.0049)
BRCA WT/LOH High (n=158): PFS: 9.7 vs 5.4 months, HR: 0.44 (0.29-0.66, p<0.001)
w/ HRR gene alterations (n=43):
PFS: 11.1 vs 5.5 months, HR: 0.21 (0.09-0.50); TFST: 16.9 vs 6.3 months, HR: 0.16 (0.06-0.40)
PFS2: 21.1 vs 17.3 months, HR: 0.30 (0.12-0.72); TSST: 24.4 vs 17.9 months, HR: 0.43 (0.18-1.04)
BRCA1 MUT (n=117):
TFST: 16.8 vs 8.1 months, HR: 0.41 (0.27-0.64); PFS2: 25.1 vs 21.8 month, HR: 0.84 (0.53-1.32); TSST: 25.9 vs 18.5 months, HR: 0.65 (0.41-1.04)
BRCA2 MUT (n=79):
TFST: 30.4 vs 7.1 months, HR: 0.17 (0.09-0.33); PFS2: 34.1 vs 18.4 month, HR: 0.51 (0.29-0.91); TSST: 34.2 vs 19.4 months, HR: 0.55 (0.31-0.96)

Exploratory analysis prior PFS interval, w/ or w/o prior Bev:
PFS interval >6 to ≤12 months:
8.2 vs 4.1 months, HR 0.33 (0.24-0.46, p<0.0001)
PFS interval >12 months: 
13.6 vs 5.6 months, HR 0.39 (0.30 to 0.52, p<0.0001)
w/ prior Bev:
10.3 vs 5.4 months, HR 0.42 (0.26 to 0.68, p=0.0004)
w/o prior Bev:
10.9 vs 5.4 months, HR 0.35 (0.28 to 0.45, p<0.0001)

Clinically Significant Adverse Events

Ruc vs Placebo:
Serious AE: any (21 vs 11%), AML/MDS (1 vs 0%) - two treatment related deaths in Ruc arm
Grade 3-4 AE: any (54 vs 14%), anemia (19 vs 1% ), elevated liver enzymes (11 vs 0%)

Conclusion

Improved PFS for all patients with rucaparib maintenance treatment

Reference

Coleman RL et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (2017) 390(10106): 1949-1961)
https://www.ncbi.nlm.nih.gov/pubmed/28916367

Ledermann JA et al. Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial. Lancet Oncol (2020) 21(5):710-722
https://pubmed.ncbi.nlm.nih.gov/32359490/

Kwan T et al. Clinical and molecular characteristics of ARIEL3 patients who derived exceptional benefit from rucaparib maintenance treatment for high-grade ovarian cancer (HGOC). J Clin Oncol (2021) 39 (suppl 15; abstr 5537)
https://meetinglibrary.asco.org/record/197247/abstract

Kwan T et al. Poster
https://www.clearityfoundation.org/wp-content/uploads/2021/06/ARIEL-3-Exceptional-benefit-poster-ASCO-2021-scaled.jpeg

Clamp A et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma: the effects of progression-free interval and prior therapies on efficacy and safety in the randomized phase III trial ARIEL3. Int J Gynecol Cancer (2021) 31(7):949-958
https://pubmed.ncbi.nlm.nih.gov/34103386/

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