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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.

Specifically, rucaparib is being developed as monotherapy treatment of advanced ovarian cancer in patients with deleterious BRCA-mutated tumors inclusive of both germline and somatic BRCA mutations. 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: tumor 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 plans to submit a supplemental New Drug Application (sNDA) by October 2017 for a second-line and later maintenance treatment indication for all women with platinum-sensitive ovarian cancer who have responded to their most recent platinum therapy.

Additionally, rucaparib is in clinical development for the treatment of metastatic castration-resistant prostate cancer patients in the TRITON2 trial for patients with tumor BRCA mutations and ATM mutations (both inclusive of germline and somatic) or other deleterious mutations in other HR repair genes and the TRITON3 trial for patients with tumor BRCA mutations and ATM mutations (both inclusive of germline and somatic) 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.

Clovis is also exploring rucaparib in other solid tumor types with BRCA and HRD populations, including, breast, pancreatic, gastroesophageal, bladder and lung cancers.

Clovis holds worldwide 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. The primary efficacy analysis will evaluate, in a step-down process, BRCA-mutant patients, all patients with a HRD signature (including BRCA and non-BRCA), followed by all patients. Target enrollment in ARIEL3 was completed during the second quarter of 2016 and data are expected by the end of June 2017.
  • The ARIEL4 confirmatory study (NCT 02855944), which is currently enrolling, 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.
  • 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 an open-label Phase 2 study evaluating the effects of rucaparib in patients with metastatic castration-resistant prostate cancer who have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM or other prespecified homologous recombination repair gene as determined by central or local test. Eligible patients must have progressed on at least one but no more than two prior androgen-receptor targeted therapies and one prior taxane-based chemotherapy. 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 metastatic castration-resistant prostate cancer who have a deleterious germline or somatic mutation in BRCA1, BRCA2, or ATM as determined by central or local test. Eligible patients must have progressed on at least one but no more than two prior androgen-receptor targeted therapies 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.

In addition to the ARIEL program in ovarian cancer and the TRITON program in metastatic castration-resistant prostate cancer, the Company is exploring rucaparib in other solid tumor types with BRCA and HRD populations, including multiple combination studies, as well as with inhibitors of PD-L1, are planned to initiate in early 2017.

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.

The hypothesis that some tumors might have defective DNA repair function for reasons other than germ-line (hereditary) or somatic (acquired) BRACA1 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. If successful, this work has the potential to increase the percentage of high-grade serous ovarian cancer patients eligible for rucaparib therapy from the approximately 20% to 25% typically found to have germ-line or somatic BRCA mutations to an estimated 50%, which includes those patients whose tumors have certain DNA repair deficiencies, and thus may be considered a BRCA-like population.

rucaparib Scientific Presentations