Rucaparib Clinical Development Overview
Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in ovarian cancer as well as several additional solid tumor indications. Studies open for enrollment or under consideration include ovarian, prostate, breast, gastroesophageal, pancreatic, and lung cancers.
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.
- SEASTAR is a Phase 1b/2 study comprised of multiple single-arm rucaparib combination studies which currently includes the following planned combinations:
- Rucaparib and luctanib, Clovis' investigational inhibitor of multiple tyrosine kinases including VEGFR, for the treatment of ovarian cancer, is currently enrolling patients with locally advanced or metastatic solid tumors into the Phase 1b portion
- Rucaparib and sacituzumab govitecan, an antibody drug conjugate, for the treatment of advanced metastatic triple-negative breast cancer, relapsed platinum-resistant ovarian cancer and advanced metastatic urothelial cancer, is enrolling patients into the Phase 1b portion
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.
The U.S. Food and Drug Administration (FDA) has accepted the company’s supplemental New Drug Application (sNDA) for Rubraca® (rucaparib) and granted priority review status to the application with a Prescription Drug User Fee Act (PDUFA) date of May 15, 2020. Clovis submitted the sNDA submission for rucaparib as a monotherapy treatment of adult patients with BRCA1/2-mutant recurrent, metastatic castrate-resistant prostate cancer in November 2019.
The Phase 2 LODESTAR study is a pan-tumor study in patients with solid tumors associated with deleterious mutations in homologous recombination repair genes.
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.
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, gastroesophageal and lung cancers.
Rucaparib Scientific Presentations
Evaluation of Brain Pharmacokinetics (PK) and Tumor Growth Inhibition of PARP Inhibitors in Mouse Xenograft Models Using Semi-Mechanistic PK/Pharmacodynamic (PD) Modeling
Poster Presentation 2020 AACR Virtual Meeting II
Characterization of Patients With Long-term Responses to Rucaparib in Recurrent Ovarian Cancer
Virtual Presentation 2020 ASCO
Postprogression Outcomes in Patients With Ovarian Carcinoma Associated With a Mutation in a Non-<i>BRCA</i>Homologous Recombination Repair Gene Receiving Rucaparib Maintenance Treatment: Results From the Phase 3 Study ARIEL3
Webinar Presentation 2020 SGO
Population Exposure-Safety and Exposure-Efficacy Analyses for Rucaparib in Patients With Recurrent Ovarian Carcinoma From Study 10 and ARIEL2
Poster Presentation 2020 SGO
Rucaparib for recurrent, locally advanced or metastatic urothelial carcinoma: results from ATLAS, a phase 2, open-label trial
Presented at 2020 ASCO GU
Genomic characteristics associated with clinical activity of rucaparib in patients (pts) with <i>BRCA1</i> or <i>BRCA2</i> (<i>BRCA</i>)-mutated metastatic castration-resistant prostate cancer (mCRPC)
Presented at 2020 ASCO GU
ATHENA (GOG-3020/ENGOT-ov45): A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of the Poly(ADP-Ribose) Polymerase (PARP) Inhibitor Rucaparib + the PD-1 Inhibitor Nivolumab Following Frontline Platinum-Based Chemotherapy in Ovarian Cancer
Presented at 2019 ASGO
Integrated safety analysis of the poly(ADP-ribose) polymerase inhibitor rucaparib in patients with ovarian cancer in the treatment and maintenance settings
Presented at 2019 ESMO
Effect of response to last platinum-based chemotherapy in patients (pts) with platinum-sensitive, recurrent ovarian carcinoma in the phase 3 study ARIEL3 of rucaparib maintenance treatment
Presented at 2019 ESMO
Preliminary results from the TRITON2 study of rucaparib in patients (pts) with DNA damage repair (DDR)-deficient metastatic castration-resistant prostate cancer (mCRPC): updated analyses
Presented at 2019 ESMO
ARIES: A Phase 2, Open-Label Study to Evaluate Rucaparib (PARP Inhibitor) in Combination with Nivolumab (Anti-PD-1 Antibody) in Patients with Ovarian Cancer
Presented at 2019 ICGS