FDA Accepts Clovis Oncology’s New Drug Application for Rucaparib for Priority Review for the Treatment of Advanced Mutant BRCA Ovarian Cancer
- Seeking approval for mutant BRCA patients treated with two or more prior therapies
- FDA Grants Priority Review Status
Assigns PDUFA Date of
February 23, 2017
“The acceptance of the rucaparib NDA submission represents an important
milestone for rucaparib, and for Clovis,” said
“Recurrent ovarian cancer remains a very difficult disease to treat,
even among women who carry, or whose tumors have a mutation in the BRCA
genes. Despite the available treatment options, few effective therapies
are at our disposal. Thus, the opportunity to treat women with germline
or somatic BRCA mutations with rucaparib after two prior lines of
platinum-based therapy, represents a meaningful step forward for our
About the Submission: Efficacy
The efficacy of rucaparib was assessed in 106 patients from two multicenter, single-arm, open-label clinical trials, Study 1 (Study 10, NCT01482715) and Study 2 (ARIEL2 Parts 1 and 2, NCT01891344), in patients with advanced BRCA-mutant ovarian cancer who had progressed after two or more prior chemotherapies. Median age was 59 years and median number of prior chemotherapy regimens was three.
Study 1 was limited to platinum sensitive patients; Study 2 included platinum sensitive, platinum resistant and platinum refractory patients.
All 106 patients received the starting dose of rucaparib 600 mg twice daily. The major efficacy outcome measure of both trials was objective response rate (ORR) and duration of response (DOR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. All responses were confirmed.
Efficacy results from Study 1 and Study 2 in all patients treated are summarized in the table below:
Overall Response and Duration of Response in Patients with BRCA-mutant Ovarian Cancer Who Received 2 or More Chemotherapies in Study 1 and Study 2
Activity by RECIST 1.1 per Investigator Assessment
|Objective Response Rate (95% CI)||60% (43, 74)||50% (37, 63)||54% (44, 64)|
Median Duration of Response in months (95% CI)
|7.8 (5.6, 10.5)||11.6 (5.5, 18.2)||9.2 (6.6, 11.6)|
1 Pooled analysis of Study 1 and Study 2
Confidence Interval (CI)
Nine (9%) of the 106 patients overall had progressive disease as best response. The ORR was similar for patients with germline BRCA-mutant ovarian cancer or somatic BRCA-mutant ovarian cancer and for patients with a BRCA1 gene mutation or BRCA2 gene mutation.
About the Submission: Safety
The safety population is comprised of the 377 ovarian cancer patients treated with starting dose of rucaparib 600 mg twice daily in Study 1 and Study 2.
The Grade 3/4 treatment emergent adverse events (AEs) reported in ≥10% of patients were anemia/decreased or low hemoglobin (25%), fatigue/asthenia (11%) and increased ALT/AST (11%).
The increases in aspartate (AST) and alanine (ALT) aminotransferase levels that were observed were asymptomatic, reversible and were rarely associated with increases in bilirubin. The elevations normalized over time with continued rucaparib treatment.
The discontinuation rate for ovarian cancer patients due to rucaparib-related AEs was 8%.
Myelodysplastic syndrome (MDS) was reported in 1 of 377 (0.3%) patients with ovarian cancer.
In addition, in the ongoing ARIEL3 maintenance trial, a blinded, randomized trial evaluating rucaparib versus placebo, acute myeloid leukemia (AML) was reported in 2 (<0.5%) patients with ovarian cancer. One case of AML was fatal. Both of these patients had received prior treatment with platinum and other DNA damaging agents.
Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed for advanced ovarian 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 (as detected by an
Additionally, rucaparib is being developed as maintenance therapy in the ARIEL3 trial (NCT01968213) for patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA (commonly referred to as homologous recombination deficiencies, or HRD). Data from ARIEL3 are expected in Q4 2017, which is expected to be followed by the submission of a supplemental NDA for second-line maintenance therapy.
Clovis is also exploring rucaparib in other solid tumor types with BRCA and HRD populations, including prostate, breast and gastroesophageal 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.
ARIEL2 is a two-part single-arm open label study designed to identify
pre-specified tumor characteristics that predict sensitivity to
rucaparib using DNA sequencing to evaluate each patient’s tumor. Part
1 enrolled 204 platinum-sensitive patients and updated results were
June 2016. Part 2 enrolled 286 patients with advanced ovarian cancer who have received at least three prior chemotherapy regimens and includes platinum-sensitive, -resistant and -refractory patients. ARIEL2 is evaluating clinical response in patients classified into molecularly-defined subgroups, including germline BRCA-mutant, somatic BRCA-mutant and HRD by a prospectively defined genomic signature.
- The phase 2 portion of Study 10, the initial dose finding study, enrolled patients with relapsed, high-grade ovarian cancer associated with a deleterious germline BRCA mutation who received 2-4 prior lines of chemotherapy.
The ARIEL3 pivotal study is a randomized, double-blind study comparing
the effects of rucaparib against placebo to evaluate whether rucaparib
given as a maintenance therapy 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 to receive either placebo or rucaparib 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
Targetenrollment in ARIEL3 was completed during the second quarter of 2016.
- The ARIEL4 confirmatory study (NCT 02855944), expected to begin during the second half of 2016, 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.
In addition to the ARIEL program in ovarian cancer, the Company is exploring rucaparib in other solid tumor types with BRCA and HRD populations, including two monotherapy prostate cancer studies as well as multiple combination studies, including with inhibitors of PD-L1, are planned to initiate in late 2016 and early 2017.
An abstract based on the ovarian NDA dataset has been accepted for an
oral presentation at the ESMO 2016
About Ovarian Cancer
According to the
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descriptions of historical facts regarding