Rucaparib Clinical Development Overview

Rucaparib is an oral, small molecule inhibitor of poly (ADP-ribose) polymerase (PARP)1, 2 and 3 is being developed in multiple tumor types, including ovarian and prostate cancers, as monotherapy and in combination with other anti-cancer agents.  Clovis holds global rights for rucaparib.

Ovarian Cancer

For rucaparib approved or authorized uses click here.

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. In June, the company announced the completion of enrollment of 1000 patients in the Clovis-sponsored Phase 3 ATHENA trial evaluating rucaparib as monotherapy and the combination of rucaparib and nivolumab as front-line maintenance treatment of newly-diagnosed advanced ovarian cancer. ATHENA is the first front-line switch maintenance study designed to evaluate PARP monotherapy and PARP/PD-1 combination therapy in one study design. 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 lucitanib, 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. Enrollment is complete for the Phase 1b portion.

Prostate Cancer

Rucaparib is in clinical development for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients.

  • Rucaparib is being studied in the Phase 3 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. This trial is open for enrollment.
  • The Phase 3 CASPAR study is evaluating the benefit of adding rucaparib to enzalutamide for men with mCRPC that has become resistant to testosterone-deprivation therapy.  This trial is currently planned and is sponsored by the Alliance for Clinical Trials in Oncology which is part of the National Cancer Institute.

Other Studies

The Phase 2 LODESTAR study is a pan-tumor study in patients with solid tumors associated with deleterious mutations in homologous recombination repair genes.

Exploratory studies in other tumor types are also underway. 

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, exploratory studies in multiple tumor types are also underway.

Rucaparib Scientific Presentations 

Clinical Activity of Rucaparib in Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC) and <i>BRCA1</i> or <i>BRCA2</i> Mutations Identified by FoundationOne® Liquid CDx (F1L CDx)

Virtual Presentation 2020 PCF Scientific Retreat

Timing of adverse events during maintenance treatment with rucaparib for recurrent ovarian cancer in the phase 3 ARIEL3 study

Poster Presentation 2020 ESMO Virtual Meeting

Rucaparib population pharmacokinetics and exposure-response analyses in patients with metastatic castration-resistant prostate cancer (mCRPC) in TRITON2

Poster Presentation 2020 ESMO Virtual Meeting

Rucaparib + sacituzumab govitecan: initial data from the phase 1b/2 SEASTAR study (NCT03992131)

Poster Presentation 2020 ESMO Virtual Meeting

Postprogression Efficacy Outcomes From the Phase 3 ARIEL3 Study of Rucaparib in Patients With Platinum-Sensitive Recurrent Ovarian Carcinoma Associated With Either <i>BRCA1</i> or <i>BRCA2</i> Mutations

Virtual Presentation 2020 ICGS Digital Annual Global Meeting​

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