Rucaparib: the past, present, and future of a newly approved PARP inhibitor for ovarian cancer

Figures & data

Figure 1 Chemical structure of rucaparib.

Table 1 Pharmacokinetics of rucaparib

Pharmacokinetic parameter	Mean T1/2	Median Tmax	Clearance	Mean SS Cmax	AUC0–12 h	Mean bioavailability	References
Fasted	17–19 h	1.9 h	15.3–79.2 L/h	1,940 ng/mL	16,900 h⋅ng/mL	36% (30%–45%)	^Citation28
After high-fat meal		Delayed by 2.5 h		Increased by 20%	AUC0–24 h increased by 38%		^Citation28

Notes: Mean T_1/2, mean terminal half-life; median T_max, median time to maximal concentration; mean SS C_max, mean peak serum concentration.

Abbreviation: AUC, area under the curve.

Figure 2 ARIEL3 schema.

Notes: N=540; primary end point: PFS; secondary end points: OS, health-related quality of life, and safety and tolerability; analysis will evaluate the three separate groups defined in ARIEL2. Clovis Oncology. A Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer (ARIEL3). Available from https://clinicaltrials.gov/ct2/show/NCT01968213?term=NCT01968213&rank=1. NLM identifier: NCT01968213.⁴⁸
Abbreviations: b.i.d., twice daily; CR, complete response; PFS, progression-free survival; p.o., by mouth; PR, partial response; OS, overall survival; R, randomized.

Table 2 Rucaparib in epithelial ovarian cancer clinical trials

Study	Phase	Patient population	Treatment arms	Primary end points	HR classification	Findings	References
A4991002	I	Advanced solid tumors or malignant melanoma	Open-label, dose escalation using IV rucaparib and temozolomide	Safety and efficacy, pharmacokinetics and pharmacodynamics	N/A	PARP inhibitory dose of 12 mg/m^2. No toxicity attributed to rucaparib alone. Mean tumor PARP inhibition at 5 h was 92%	^Citation31
CO-338-010 (NCT01482715)	I/II	Part 1: solid tumors (breast, ovary, pancreas) with progression on prior treatment. Part 2A: recurrent platinum- sensitive ovarian cancer, two to four prior lines of chemotherapy. Part 2B: recurrent ovarian cancer, three to four prior lines of chemotherapy. Part 3: solid tumors	Part 1: open-label dose escalation, p.o. rucaparib Parts 2A, 2B, and 3: 600 mg p.o. b.i.d. of rucaparib	Part 1: Recommended Phase II dose, incidence of grade 3/4 AE and laboratory abnormalities. Parts 2A and 2B: ORR by RECIST criteria Part 3: pharmacokinetics	Part 1: N/A Part 2A: germline BRCA mutation Parts 2B and 3: germline or somatic BRCA mutation	Part 1: recommended Phase II dose 600 mg p.o. b.i.d. Grade 2/3 myelosuppression in 50% of patients. Grade 1/2 fatigue, nausea in 30% of patients. Part 2A: ORR 74%, disease control rate 77%. Parts 2B and 3 are ongoing	^Citation32,Citation33
ARIEL2 (NCT01891344)	II	Part 1: recurrent, platinum- sensitive high-grade serous or endometrioid ovarian cancer, ≥1 prior platinum therapy. Part 2: recurrent, platinum- sensitive, platinum-resistant, or platinum-refractory ovarian cancer, three to four prior lines of chemotherapy	Parts 1 and 2: open- label, rucaparib 600 mg p.o. b.i.d.	Part 1: disease progression by RECIST criteria. Part 2: ORR by RECIST criteria	Known germline BRCA1/2 mutation capped at n=15. Three tumor HRD groups: BRCA^mut; BRCA^wt/LOH^high; BRCA^wt/LOH^low	Part 1: median PFS by HRD subgroup: significantly longer in BRCA^mut (12.8 months HR 0.27, 95% CI 0.16–0.44) and BRCA^wt/LOH^high (5.7 months, HR 0.62, 95% CI 0.42–0.90) than in BRCA^wt/LOH^low (5.2 months) Part 2: N/A	^Citation20
ARIEL3 (NCT01968213)	III	Recurrent, platinum-sensitive high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, ≥2 prior lines of platinum-based chemotherapy	Double-blind, randomized (2:1), controlled trial evaluating rucaparib maintenance therapy 600 mg p.o. b.i.d. versus placebo	PFS	HRD stratification at the time of enrollment (BRCA^mut; BRCA^wt/LOH^high; BRCA^wt/LOH^low)	N/A	^Citation40
ARIEL4 (NCT02855944)	III	Recurrent or progressive ovarian, fallopian tube, or primary peritoneal cancer, ≥2 prior lines of chemotherapy	Arm 1: rucaparib monotherapy Arm 2: platinum-based therapy (monotherapy or doublet; investigator’s choice)	PFS by RECIST criteria	Germline BRCA mutation	N/A	^Citation41

Abbreviations: AE, adverse event; b.i.d., twice daily; HRD, homologous recombination deficiency; HR, hazard ratio; IV, intravenous; LOH, loss of heterozygosity; mut, mutated; N/A, not available; ORR, overall response rate; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; p.o., by mouth.

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