Rucaparib Clinical Development Overview

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed for ovarian, prostate and bladder cancers.

Ovarian Cancer

For rucaparib approved or authorized uses click here. Rucaparib is also being developed as maintenance treatment for advanced ovarian cancer in the ARIEL3 trial. Data from the ARIEL3 study were presented and published in September 2017. 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. Centered on these findings, Clovis submitted in June 2018 an application to EMA to expand use of rucaparib to include maintenance treatment for women with recurrent ovarian cancer. Based on the timing of this submission, the company anticipates an opinion from the Committee for Medicinal Products for Human Use (CHMP) by end of 2018.

Three additional studies enrolling women with ovarian cancer are ongoing or planned:

  • The ARIEL4 Phase 3 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 Phase 3 ATHENA study in 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. This Clovis sponsored study is part of a broad clinical collaboration with Bristol-Myers Squibb.
  • The Phase 2, open-label, multi-cohort ARIES study to evaluate the combination of rucaparib and nivolumab in patients with relapsed, BRCA wild-type ovarian cancer and in patients with locally advanced or metastatic bladder carcinoma who are ineligible for treatment with cisplatin. This study is sponsored by Clovis and is expected to begin in the first quarter of 2019.

Prostate Cancer

Rucaparib is in clinical development for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients in the TRITON2 trial for patients with BRCA mutations (inclusive of germline and somatic) and also enrolling patients with deleterious mutations of other HR repair genes, including ATM, 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.

On October 2, 2018 Clovis Oncology announced that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for rucaparib as a monotherapy treatment of adult patients with BRCA1/2-mutated mCRPC who have received at least one prior androgen receptor (AR)-directed therapy and taxane-based chemotherapy.

Bladder Cancer

Clovis is sponsoring the Phase 2, open-label, multi-cohort ARIES study to evaluate the combination of rucaparib and nivolumab in patients with relapsed, BRCA wild-type ovarian cancer and in patients with locally advanced or metastatic bladder carcinoma who are ineligible for treatment with cisplatin. This study is expected to begin in the first quarter of 2019.

Other Studies

The Phase 1 RUCA-J study, sponsored by Clovis, initiated during the quarter with the first patient dosed with rucaparib in Japan. The Phase 1 study seeks to identify the recommended dose of rucaparib in Japanese patients, which will enable development of a bridging strategy and potential inclusion of Japanese sites in planned or ongoing global studies.

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

The Role of PARP Inhibition in Cancer Therapy

Cells in the human body are under constant attack from agents that can cause damage to DNA, including sunlight and other forms of radiation, as well as DNA-binding chemicals that can cause changes in the composition of DNA. Cells have evolved multiple mechanisms to enable such DNA repair, and these mechanisms are complementary to each other, each driving repair of specific types of DNA damage. If a cell’s DNA damage repair system is overwhelmed, then the cell will die undergoing a form of suicide termed apoptosis. A fundamental principle of cancer therapy is to damage cells profoundly with radiation or DNA-binding drugs, such as alkylating agents or platinums, to induce apoptosis and, subsequently, cancer cell death. Multiple DNA repair mechanisms active in the cell may reduce the activity of these anti-cancer therapies.

The PARP family comprises 17 structurally related proteins that have been identified on the basis of sequence similarity. PARP1, PARP2, and PARP3 play a central role in DNA repair. They are rapidly recruited to the sites of DNA damage and catalyze the recruitment of additional proteins that initiate the repair of damaged DNA. The breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes also have important roles in DNA repair pathways such as homologous recombination. According to the National Cancer Institute, BRCA1 and BRCA2 mutations are associated with an increased risk of ovarian, breast, prostate, and pancreatic cancers.

Rucaparib is an inhibitor of BRCA enzymes, including PARP1, PARP2, and PARP3. PARP inhibitors have shown activity in BRCA 1/2 mutant and homologous recombination (“HR”) repair deficient cancer cell lines through a mechanism known as synthetic lethality in which the loss of two genes/pathways is required for cell death. The inhibition/inactivation of repair pathways by administration of a PARP inhibitor in the context of an underlying genetic defect such as a BRCA mutation results in tumor cell death through accumulation of unrepaired DNA damage. Alterations in DNA repair genes other than BRCA1/2 have been observed in, and contribute to the hereditary risk of, ovarian, breast, prostate and pancreatic cancers. PARP inhibitors have shown evidence of nonclinical and clinical activity in tumors with alterations in non-BRCA HR genes. DNA repair deficiencies resulting from genetic and epigenetic alterations can result in a “BRCA-like” phenotype that may also render tumor cells sensitive to PARP inhibitors. One approach to identify patients with DNA repair deficiencies due to mechanisms other than a mutation in BRCA or other non-BRCA HR genes is to assess loss of heterozygosity (“LOH”), or the loss of one normal copy of a gene, which arises from error-prone DNA repair pathways when HR is compromised.

On the basis of these scientific observations, Clovis initially developed rucaparib in ovarian cancer patients with tumors having BRCA mutations or other homologous recombination deficiencies (“HRD”). These molecular markers also may be used to select patients with other tumors for treatment with rucaparib. Thus, in addition to ovarian trials, studies open for enrollment or under consideration to further evaluate rucaparib, either alone or in combination with other agents, include prostate, breast, pancreatic, bladder, gastroesophageal and lung cancers

Rucaparib Scientific Presentations