A Phase I-II Study of the Oral Poly(ADP-ribose) Polymerase Inhibitor Rucaparib in Patients with Germline BRCA1/2-mutated Ovarian Carcinoma or Other Solid Tumors: Beyond the Abstract

The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib (CO-338; formerly known as AG-014447 and PF-01367338) has a high selectivity for PARP-1, -2, and -3 [1, 2], which play a key role in repair of single-strand DNA damage [3]. Inhibition of these enzymes can lead to accumulation of DNA double-strand breaks [4, 5]. PARP inhibitors have been shown to be selectively lethal to cells with mutations in other genes involved in DNA repair, such as BRCA1 and BRCA2 (BRCA1/2) [6-8]. Such mutations are common in various tumor types (eg, breast, ovarian), and in preclinical studies, rucaparib was cytotoxic to cells with a deleterious BRCA1/2 mutation or epigenetic silencing of BRCA1 [7, 9].

The phase 1 Study 1014 (NCT01009190) trial was the first-in-human trial of rucaparib (Table) and was initially designed to investigate the intravenous formulation in combination with chemotherapy in advanced solid tumors, including breast and ovarian cancer [10]. During the course of Study 1014, an oral formulation of rucaparib (rucaparib camsylate) was developed and studied in combination with carboplatin. The phase 1/2 Study 10 (NCT01482715) trial was the first clinical trial to fully evaluate the use of the oral formulation of rucaparib as monotherapy in patients with advanced solid tumors with or without a germline BRCA1/2 mutation and define the recommended Phase 2 dose (RP2D)[11].

The 3-part Study 10 trial was designed to examine the pharmacokinetic (PK) and safety profiles of rucaparib, establish the recommended phase 2 dose (RP2D) of rucaparib, and assess the clinical activity of rucaparib. Part 1 was a phase 1 dose escalation portion with the primary objective of characterizing PK and safety at multiple dose levels in patients with advanced solid tumors. Rucaparib was examined at dose levels of 40, 80, 160, 300, and 500 mg once daily and 240, 360, 480, 600, and 840 mg twice daily (BID). No maximum tolerated dose was identified according to prespecified criteria outlined in the protocol. The RP2D of 600 mg BID was selected based on consideration of the manageable safety and antitumor activity observed in patients in Part 1.

The RP2D was further evaluated in the Part 2A phase 2 expansion in patients with platinum-sensitive, relapsed, high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer associated with a germline BRCA1/2 mutation. The primary endpoint for Part 2A was investigator-assessed objective response rate per Response Evaluation Criteria In Solid Tumors version 1.1. A total of 42 patients were enrolled in this portion of the study, 25 (59.5%) of whom achieved an investigator-assessed confirmed response (4 [9.5%] complete responses; 21 [50.0%] partial responses). The median duration of response was 7.8 months. The most common treatment-emergent adverse events were asthenia/fatigue, nausea, anemia, elevated alanine transaminase (ALT) and/or aspartate transaminase (AST) levels, and vomiting. Adverse events were manageable; for example, gastrointestinal disorders and fatigue were successfully managed with supportive care and/or dose modification. Myelosuppression generally presented after several cycles of rucaparib and could be managed with supportive care and treatment modification. Elevations in ALT and AST were transient, were not accompanied by elevations in bilirubin, and resolved during treatment; the mechanism responsible for these elevations has not yet been identified. Elevations in creatinine (grade 1 or 2) were also observed in a third of patients. The renal transporters MATE1, MATE2-K, and OCT-1 play a role in secretion of creatinine into urine and are inhibited by rucaparib in vitro [12]; both olaparib and veliparib have shown similar inhibition of renal transporters in vitro [13, 14].

Part 2B is ongoing and aims to examine the efficacy of rucaparib in patients with platinum-sensitive, -resistant, or -refractory, relapsed high-grade ovarian cancer with a germline or somatic BRCA1/2 mutation; Part 3 is also ongoing and is assessing the PK and safety profile of a higher dose tablet of rucaparib in patients with solid tumors with a germline or somatic BRCA1/2 mutation.

As the first examination of oral rucaparib as a monotherapy, Study 10 provided clinical evidence for the activity of rucaparib in patients with solid tumors, including ovarian cancer. The robust antitumor activity in patients with platinum-sensitive ovarian cancer in Study 10 provided support for further clinical trials of rucaparib in ovarian cancer (Table). The phase 2 ARIEL2 study (NCT01891344) was designed to examine the efficacy of rucaparib monotherapy as treatment in patients with ovarian cancer and enrolled patients with and without a BRCA1/2 mutation in an effort to identify biomarkers associated with response to rucaparib. In Part 1 of ARIEL2, rucaparib provided a progression-free survival benefit to patients with platinum-sensitive ovarian cancer with a deleterious BRCA1/2 mutation (germline or somatic) or wild-type BRCA1/2 and a high degree of genomic loss of heterozygosity (LOH), a hallmark of DNA-repair defects, when compared to patients with ovarian cancer with wild-type BRCA1/2 and a low degree of genomic LOH [15]. Part 2 of ARIEL2 is ongoing and aims to examine the efficacy of rucaparib in patients with ovarian cancer who have received 3–4 prior chemotherapies [16].

Rucaparib was recently approved by the United States Food and Drug Administration for use as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with ≥2 chemotherapies [12]. Approval in the United States was based on partial results from Study 10 and ARIEL2, which were pooled for an analysis of efficacy in patients with ovarian cancer and a BRCA1/2 mutation who had received ≥2 chemotherapies (Study 10 Part 2A, n=42; ARIEL2 Parts 1 and 2, n=64) and an analysis of safety in patients with ovarian cancer from these studies who had received rucaparib 600 mg BID (Study 10, n=62; ARIEL2, n=315) [17].

The ongoing phase 3 ARIEL3 study (NCT01968213) aims to assess the efficacy of rucaparib as maintenance therapy following a response to platinum-based chemotherapy in patients with ovarian cancer. Topline data from ARIEL3 are expected in mid-2017. The ongoing phase 3 ARIEL4 study (NCT02855944) aims to assess the benefit-risk profile of rucaparib versus current standard-of-care chemotherapy as monotherapy treatment for patients with BRCA1/2-mutated, relapsed, high-grade ovarian cancer. Rucaparib is under investigation in various other tumor types, including prostate and breast cancer (TRITON2 [NCT02952534], TRITON3 [NCT02975934], RUBY [NCT02505048], and BRE09-146 [NCT01074970]).

Written by: Rebecca Kristeleit, Research Department of Oncology, UCL Cancer Institute, London, United Kingdom

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Acknowledgements:
Study was funded by Clovis Oncology. R. Kristeleit is supported by the UCH/UCL Biomedical Research Centre and UCL Experimental Cancer Medicine Centre. Medical writing and editorial support was funded by Clovis Oncology, and provided by Nathan Yardley, PhD and Shannon Davis of Ashfield Healthcare Communications.

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RUCAPARIB CLINICAL TRIALS
Study and Phase

Tumor Type

Intervention

Status

Study 1014 (NCT01009190), phase 1

Advanced solid tumors (including breast and ovarian cancer)

IV rucaparib (various) + chemotherapy (carboplatin, carboplatin/paclitaxel, cisplatin/pemetrexed, or epirubicin/cyclophosphamide); oral rucaparib (dose escalation) + carboplatin

Completed

Study 10 (NCT01482715), phase 1/2

Part 1: advanced solid tumors

Part 2A: platinum-sensitive ovarian cancer with a germline BRCA1/2 mutation

Part 2B: platinum-sensitive, -resistant, or -refractory ovarian cancer with a germline/somatic BRCA1/2 mutation

Part 3: advanced solid tumors with a germline/somatic BRCA1/2 mutation

Part 1: oral rucaparib (dose escalation)

Parts 2A, 2B, and 3: oral rucaparib 600 mg BID

Parts 1 and 2A: Completed

Parts 2B and 3: Ongoing, not enrolling patients

ARIEL2 (NCT01891344), phase 2

Part 1: platinum-sensitive ovarian cancer

Part 2: platinum-sensitive, -resistant, or -refractory ovarian cancer

Oral rucaparib 600 mg BID

Part 1: Completed

Part 2: Ongoing, not enrolling patients

ARIEL3 (NCT01968213), phase 3

Platinum-sensitive[i] ovarian cancer

Maintenance therapy; oral rucaparib 600 mg BID vs placebo

Ongoing, not enrolling patients

ARIEL4 (NCT02855944), phase 3

Ovarian cancer with a germline/somatic BRCA1/2 mutation

Oral rucaparib 600 mg BID vs standard-of-care chemotherapy

Enrolling patients

TRITON2 (NCT02952534), phase 2

Metastatic castration-resistant prostate cancer with HRD

Oral rucaparib 600 mg BID

Enrolling patients

TRITON3 (NCT02975934), phase 3

Metastatic castration-resistant prostate cancer with a germline/somatic BRCA1/2 or ATM mutation

Oral rucaparib 600 mg BID vs physician’s choice (abiraterone acetate, enzalutamide, or docetaxel)

Enrolling patients

RUBY (NCT02505048),
phase 2

Metastatic breast cancer with high genomic LOH or a somatic BRCA1/2 mutation

Oral rucaparib 600 mg BID

Enrolling patients

BRE09-146 (NCT01074970), phase 2

Triple-negative breast cancer with a germline/somatic BRCA1/2 mutation

Low-dose IV rucaparib (dose escalation) + cisplatin vs cisplatin alone

Ongoing, not enrolling patients

BID, twice daily; HRD, homologous recombination deficiency; IV, intravenous; LOH, loss of heterozygosity.