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.
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 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.
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 firstname.lastname@example.org.
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.
ARIEL4: An International, Randomized Phase 3 Study of the PARP Inhibitor Rucaparib vs Chemotherapy for the Treatment of BRCA-Mutated, Relapsed, High-Grade Ovarian Cancer — Presented at ESMO 2017
The TRITON Clinical Trial Programme: Evaluation of the PARP Inhibitor Rucaparib in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Associated with Homologous Recombination Deficiency (HRD) — Presented at ESMO 2017
A PHASE3, Randomized, Double-Blind Study OF Rucaparib vs Placebo Following Response to Platinum-Based Chemotherapy for Recurrent Ovarian Carcinoma (OC) — Presented at ESMO 2017
Trial of RucaparIb in ProsTate IndicatiONs 3 (TRITON3): An International, Multicenter, Randomized, Open-Label Phase 3 Study of Rucaparib vs Physician’s Choice of Therapy for Patients (Pts) with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Associated with Homologous Recombination Deficiency (HRD) — Presented at ASCO 2017
An open-label, phase II study of rucaparib, a PARP inhibitor, in HER2- metastatic breast cancer patients with high genomic loss of heterozygosity: RUBY — Presented at ASCO 2017
ARIEL4: An International, Multicenter Randomized Phase 3 Study of the PARP Inhibitor Rucaparib vs Chemotherapy in Germline or Somatic BRCA1- or BRCA2-Mutated, Relapsed, High-Grade Ovarian Carcinoma — Presented at ASCO 2017
DNA repair protein expression and response of homologous recombination deficient ovarian cancer to the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib in the ARIEL2 Part 1 study — Presented at AACR 2017
Preclinical evaluation of the PARP inhibitor rucaparib in combination with PD-1 and PD-L1 inhibition in a syngeneic BRCA1 mutant ovarian cancer model — Presented at AACR 2017
In vitro and in vivo assessment of the mechanism of action of the PARP inhibitor rucaparib — Presented at AACR 2017
Preclinical assessment of the PARP inhibitor rucaparib in homologous recombination deficient prostate cancer models — Presented at AACR 2017
Population Pharmacokinetics (PK) of Rucaparib (CO-338) in Patients with Advanced Ovarian Cancer (AOC) or Other Solid Tumors — Presented at the 2017 ASCPT Annual Meeting
BRCA1 and RAD51C Promoter Hypermethylation Confer Sensitivity to the PARP Inhibitor Rucaparib in Patients with Relapsed, Platinum Sensitive Ovarian Carcinoma in ARIEL2 Part 1 — Presented at the 2017 SGO Annual Meeting on Women’s Cancer
Rucaparib in Patients with Relapsed, Primary Platinum-Sensitive High-Grade Ovarian Carcinoma with Germline or Somatic BRCA Mutations: Integrated Summary of Efficacy and Safety from the Phase 2 Study ARIEL2 — Presented at the 2017 SGO Annual Meeting on Women’s Cancer
Integrated Efficacy and Safety Analysis of the Poly (ADP-Ribose) Polymerase (PARP) Inhibitor Rucaparib in Patients with High-Grade Ovarian Carcinoma (HGOC)—Presented at 2017 ECCO Annual Meeting
Secondary mutations in RAD51C and RAD51D as a mechanism of resistance to PARP inhibition in high-grade serous ovarian cancer—28th EORTC-NCI-AACR Symposium 2016
Feasibility of Monitoring Response to the PARP Inhibitor Rucaparib with Targeted Deep Sequencing of Circulating Tumor DNA (ctDNA) in Women With High-Grade Serous Carcinoma on the ARIEL2 Trial—28th EORTC-NCI-AACR Symposium 2016
Trial of RucaparIb in ProsTate IndicatiONs 2 (TRITON2): A Multicenter, Open-Label Phase 2 Study of the PARP Inhibitor Rucaparib in Patients with Metastatic Castration-Resistant Prostate Cancer Associated with Homologous Recombination Deficiencies—23rd Annual PCF Scientific Retreat 2016
Clinical activity of the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with high grade ovarian carcinoma (HGOC) and a BRCA mutation (BRCAmut): Analysis of pooled data from Study 10 (parts 1, 2a, and 3) and ARIEL2 (parts 1 and 2)—Presented at ESMO 2016