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Overview

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed for advanced ovarian cancer and metastatic castration-resistant prostate cancer.

The first indication for which rucaparib is being developed is monotherapy treatment of advanced ovarian cancer in patients with a deleterious BRCA-mutation. Rucaparib’s Marketing Authorization Application (MAA) to the European Medicines Agency for the proposed treatment indication was submitted in November 2016.

Rucaparib is also being developed as maintenance treatment for advanced ovarian cancer in the ARIEL3 trial. In June 2017, topline data from the ARIEL3 trial was announced. The ARIEL3 trial successfully achieved the primary endpoint of improved progression-free survival (PFS) by investigator review in each of the three populations studied: BRCA-mutant, HRD-positive and the overall intent-to-treat population. PFS was also improved in the rucaparib group compared with placebo by blinded independent central review (BICR), a key secondary endpoint. Based on these findings, the Company submitted a supplemental New Drug Application (sNDA) on October 9, 2017 for a maintenance treatment indication for women with platinum-sensitive recurrent ovarian cancer.

Two additional ovarian cancer studies are ongoing or expected to begin enrolling patients before the end of 2017. The ARIEL4 confirmatory study in the treatment setting is currently enrolling relapsed ovarian cancer patients with BRCA mutations who have failed two prior lines of therapy. The pivotal ATHENA study in the first-line maintenance treatment setting is expected to begin enrolling patients before the end of 2017, and will evaluate rucaparib plus the cancer immunotherapy nivolumab; anti-PD1, rucaparib, nivolumab and placebo in newly-diagnosed patients who have completed platinum-based chemotherapy. This study is part of a broad clinical collaboration with Bristol-Myers Squibb.

Additionally, rucaparib is in clinical development for the treatment of metastatic castration-resistant prostate cancer patients in the TRITON2 trial for patients with BRCA mutations and ATM mutations or other deleterious mutations in other HR repair genes and the TRITON3 trial for patients with BRCA mutations and ATM mutations who have progressed on AR-targeted therapy and who have not yet received chemo in the castrate-resistant setting. Both trials are open for enrollment.

Exploratory studies in other tumor types are also underway. Clovis holds global rights for rucaparib.

ABOUT RUCAPARIB CLINICAL DEVELOPMENT

The ARIEL (Assessment of Rucaparib in Ovarian Cancer Trial) program is a novel, integrated translational-clinical program designed to accurately and prospectively identify ovarian cancer patients with tumor genotypes associated with benefit from rucaparib therapy.

  • The ARIEL3 (NCT 01968213) pivotal study is a randomized, double-blind study comparing the effects of rucaparib against placebo to evaluate whether rucaparib given as a maintenance treatment to platinum-sensitive patients can extend the period of time for which the disease is controlled after a positive outcome with platinum-based chemotherapy. Patients are randomized 2:1 to receive either rucaparib or placebo and the primary endpoint of the study is PFS. Target enrollment in ARIEL3 was completed during the second quarter of 2016 and the comprehensive results of the study were presented and published in September 2017. The study successfully achieved its primary endpoint of improved PFS by investigator review in all three primary efficacy analyses: BRCA-mutant, HRD positive, and overall intent to treat patients.
  • The ARIEL4 confirmatory study (NCT 02855944) is a Phase 3 multicenter, randomized study of rucaparib versus chemotherapy in relapsed ovarian cancer patients with BRCA mutations who have failed two prior lines of therapy. The primary endpoint of the study is PFS. The study is currently open for enrollment.
  • For more information, please visit www.arielstudy.com.

The TRITON (Trial of RucaparIb in ProsTate IndicatiONs) program is a novel, integrated translational-clinical development program but it is designed to accurately and prospectively identify prostate cancer patients with metastatic & castration-resistant disease that have tumor genotypes associated with benefit from rucaparib therapy.

  • The TRITON2 (NCT02952534) study is a single-arm open-label Phase 2 study of men with mCRPC and specific gene alterations including BRCA, ATM and other HRD gene alterations. As part of this study, genetic testing results will be provided. Eligible patients must have progressed on at least one, but no more than two prior next-generation hormonal (also known as androgen-receptor targeted) therapies and one prior taxane-based chemotherapy for the treatment of mCRPC. The primary endpoint of the study is response rate. The study is currently open for enrollment.
  • The TRITON3 (NCT02975934) study is a randomized open-label Phase 3 study evaluating the effects of rucaparib compared to physician’s choice of therapy for patients with mCRPC with specific gene alterations including BRCA and ATM. Not all patients will receive rucaparib. As part of this study, genetic testing results will be provided. Eligible patients must have progressed on one prior androgen-receptor targeted therapy and must not have received prior chemotherapy for castration-resistant prostate cancer. The primary endpoint of the study is progression-free survival. The study is currently open for enrollment.
  • For more information, please visit www.tritontrials.com.

In addition to the ARIEL program and the TRITON program, the Company is exploring rucaparib in combination with inhibitors of PD-1 and PD-L1.

In July 2017, Bristol-Myers Squibb Company (BMS) and Clovis Oncology, Inc. announced the companies have entered into a clinical collaboration agreement to evaluate the combination of Bristol-Myers Squibb’s immunotherapy nivolumab and Clovis Oncology’s rucaparib in pivotal phase 3 clinical trials in:

  • Advanced ovarian cancer: First-line maintenance treatment study to evaluate rucaparib + nivolumab, rucaparib, nivolumab and placebo in newly diagnosed patients with stage III/IV high-grade ovarian, fallopian tube or primary peritoneal cancer who have completed platinum-based chemotherapy. The ATHENA study is expected to begin before the end of 2017.
  • Advanced triple-negative breast cancers (TNBC): First-line maintenance treatment study to evaluate rucaparib + nivolumab, rucaparib, nivolumab and chemotherapy in patients with stage IV or recurrent locally advanced inoperable TNBC associated with a homologous recombination deficiency (HRD).

The collaboration will also include a Phase 2 study to evaluate the safety and efficacy of nivolumab in combination with rucaparib in patients with mCRPC. The nivolumab + rucaparib combination in mCRPC will be conducted as an arm of a larger BMS-sponsored study.

Also currently enrolling is a Phase 1B combination study sponsored by Genentech of the cancer immunotherapy atezolizumab and rucaparib for the treatment of solid tumors and gynecological cancers, with a focus on ovarian cancer (NCT03101280).

To participate in a Clovis Oncology Clinical Trial, please contact the Clovis Oncology Clinical Trial Navigation Service at 1-855-262-3040 (USA) or +1-303-625-5160 (ex-USA) or clovistrials@emergingmed.com.

DNA Repair and PARP

Cells in the human body are under constant attack from environmental factors that can cause damage to DNA, as well as DNA-binding chemicals that can cause changes in the composition of DNA. Since DNA is the vehicle by which fundamental information is passed on when a cell divides, it is critical that DNA damage be repaired. A fundamental principle of cancer therapy is to damage cells profoundly with radiation or DNA-binding drugs, for example, alkylating agents or platinums, and induce apoptosis in those cells, thus killing the cancer cells. DNA repair mechanisms may reduce the activity of these anti-cancer therapies, but, conversely, inhibition of DNA repair processes may enhance the effects of DNA-damaging anti-cancer therapies.

PARP initiates a process which quickly repairs DNA during the early stage of damage. In the absence of PARP, cells are unusually sensitive to DNA damage when exposed to radiation or DNA-alkylating agents. Additionally, tumors that are defective in BRCA are particularly prone to DNA damage, as BRCA is involved in DNA repair as well.

There are two major forms of PARP that are involved in DNA repair in this way, PARP-1 and PARP-2. We believe that a drug that inhibits both PARP-1 and PARP-2 may have enhanced activity in preventing DNA repair in tumor cells, particularly those tumors that have defective BRCA. Defects, or mutations, in BRCA1 and BRCA2 are associated with an increased risk of ovarian, breast, prostate, and pancreatic cancers.

The hypothesis that some tumors might have defective DNA repair function for reasons other than germ-line (hereditary) or somatic (acquired) BRCA1 and BRCA2 gene mutations has also been explored. Homologous recombination deficiency (HRD) drives genome-wide loss of heterozygosity (LOH) which results in a BRCA-like phenotype. The notion is that a “BRCA-like” phenotype also sensitizes a tumor cell to PARP inhibition. Subsequent work has shown that BRCA-like tumors exist, and that cancer patients with normal BRCA genes but with LOH can also respond to monotherapy with rucaparib.

Work is underway to identify a molecular HRD signature for BRCA and BRCA-like tumors that could enable patient selection for therapy.

rucaparib Scientific Presentations