Type of information: Acceptation for review of a sNDA
Product name: Rubraca®
Therapeutic area: Cancer - Oncology
- enzyme inhibitor/PARP inhibitor. Rucaparib is an orally-available, small molecule PARP 1 (poly ADP-ribose polymerase), PARP2 and PARP3 inhibitor being developed for the treatment of platinum-sensitive ovarian cancer, specifically in patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA, commonly referred to as “BRCA-like” or “BRCAness.”
- BRCA genes are involved with repairing damaged DNA and normally work to prevent tumor development. However, mutations of these genes may lead to certain cancers, including ovarian cancers. By blocking PARP enzyme, DNA inside the cancerous cells with damaged BRCA genes may be less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth.
Company: Clovis Oncology UK - Clovis Oncology (USA)
- platinum-sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with two or more prior lines of platinum based chemotherapy, and who are unable to tolerate further platinum based chemotherapy.
- maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum based chemotherapy
• On July 5, 2018
, Clovis Oncology announced that the European Medicines Agency (EMA) has validated the application for a Type II variation to the marketing authorization for Rubraca® (rucaparib) to include maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum based chemotherapy. This validation confirms the submission is complete and begins the EMA’s centralized review process.
This submission is based on the positive results from the phase 3 ARIEL3
study, which evaluated rucaparib in the ovarian cancer maintenance treatment setting among three populations: 1) BRCA mutant (BRCAmut+) 2) HRD positive inclusive of BRCAmut+ and, 3) all patients treated in ARIEL3. ARIEL3 successfully achieved its primary endpoints, extending investigator assessed progression-free survival (PFS) versus placebo in all patients treated, regardless of BRCA status. Safety findings from the ARIEL3 trial were consistent with previous clinical trials. 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.
• On June 4, 2018
, Clovis Oncology announced the submission of a regulatory application to the European Medicines Agency (EMA), as part of a type II variation seeking to expand the marketing authorization for Rubraca® (rucaparib) to include maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum based chemotherapy.
• On May 24, 2018
, the European Commission (EC) has authorized Rubraca® (rucaparib) as monotherapy treatment of adult patients with platinum-sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with two or more prior lines of platinum based chemotherapy, and who are unable to tolerate further platinum based chemotherapy. Certain confirmatory post-marketing commitments are required as part of this conditional authorization. The EC approval was based on data from two multicenter, single-arm, open-label clinical trials, Study 10 (NCT01482715) and ARIEL2
(NCT01891344), in women with advanced BRCA-mutant ovarian cancer who had progressed after two or more prior chemotherapies. All patients received Rubraca® orally 600 mg twice daily as monotherapy. Treatment continued until disease progression or unacceptable toxicity. The primary efficacy outcome measure of both studies was objective response rate (ORR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Based on investigator assessment of response, rucaparib showed an objective response rate (ORR) of 54.7% (95% CI [44.8, 64.4], in the primary efficacy population (N=106) and 64.6% (95% CI [53.0, 75.0], in the platinum sensitive population (N=79). The independent radiology review response rate reported was consistent with the investigator assessed response rate reported.
• On April 6, 2018
, Clovis Oncology announced that the FDA has approved Rubraca®
(rucaparib) tablets for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. FDA granted regular approval for Rubraca in this second, broader and earlier-line indication on a priority review timeline based on positive data from the phase 3 ARIEL3 clinical trial. Biomarker testing is not required for patients to be prescribed Rubraca in this maintenance treatment indication. Warnings and precautions include Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), and embryo-fetal toxicity. Please see warnings and precautions and additional Select Important Safety Information below.
In addition to granting Rubraca®
approval in this second indication, the FDA converted the approval of the initial treatment indication from accelerated to regular approval.
• On 22 March 2018
, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a conditional marketing authorisation for Rubraca®, intended for the treatment of relapsed or progressive ovarian cancer. Rubraca® was designated as an orphan medicinal product on 10 October 2012. The drug will be available as 200 mg, 250 mg and 300 mg film-coated tablet. The full indication is: “monotherapy treatment of adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with two or more prior lines of platinum based chemotherapy, and who are unable to tolerate further platinum based chemotherapy”.
- The European Marketing Authorization application for the treatment indication was based on objective response rate and duration of response results from two multicenter, single-arm, open-label clinical trials, Study 10 and ARIEL2, in women with advanced BRCA mutant ovarian cancer who had progressed after two or more prior chemotherapies. Pending approval for the treatment indication, Clovis plans to submit the variation to the MA based on data from the phase 3 ARIEL3 clinical trial, which found that rucaparib significantly improved progression-free survival in all ovarian cancer patient populations studied. ARIEL3 is a double-blind, placebo-controlled trial of rucaparib that enrolled 564 women with platinum-sensitive, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The primary efficacy analysis evaluated three prospectively defined molecular sub-groups in a step-down manner: 1) BRCA mutant (BRCAmut+); 2) HRD positive (HRD+) inclusive of BRCA mutant; and finally, 3) the intent-to-treat population, or all patients treated in ARIEL3. The study achieved its primary endpoint of improved PFS by investigator review in each of three populations. The variation to the MA will be directed at the broader intent-to-treat or “all comers” population.
- • On December 19, 2016, the FDA granted accelerated approval to Rubraca® (rucaparib) to treat women with a certain type of ovarian cancer. Rubraca® is approved for women with advanced ovarian cancer who have been treated with two or more chemotherapies and whose tumors have a specific gene mutation (deleterious BRCA) as identified by an FDA-approved companion diagnostic test. The FDA also approved the FoundationFocus CDxBRCA companion diagnostic for use with Rubraca®, which is the first next-generation-sequencing (NGS)-based companion diagnostic approved by the agency. The NGS test detects the presence of deleterious BRCA gene mutations in the tumor tissue of ovarian cancer patients. If one or more of the mutations are detected, the patient may be eligible for treatment with Rubraca®.
- The safety and efficacy of Rubraca® were studied in two, single-arm clinical trials ( Study 10 and ARIEL2 Parts 1 and 2) involving 106 participants with BRCA-mutated advanced ovarian cancer who had been treated with two or more chemotherapy regimens. BRCA gene mutations were confirmed in 96 percent of tested trial participants with available tumor tissue using the FoundationFocus CDxBRCA companion diagnostic. The trials measured the percentage of participants who experienced complete or partial shrinkage of their tumors (overall response rate). Fifty-four percent of the participants who received Rubraca® in the trials experienced complete or partial shrinkage of their tumors lasting a median of 9.2 months.
- Common side effects of Rubraca® include nausea, fatigue, vomiting, low levels of red blood cells (anemia), abdominal pain, unusual taste sensation (dysgeusia), constipation, decreased appetite, diarrhea, low levels of blood platelets (thrombocytopenia) and trouble breathing (dyspnea). Rubraca® is associated with serious risks, such as bone marrow problems (myelodysplastic syndrome), a type of cancer of the blood called acute myeloid leukemia and fetal harm.
- The FDA approved Rubraca® under its accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease or condition based on clinical data showing the drug has an effect on a surrogate (substitute) endpoint that is reasonably likely to predict clinical benefit. The sponsor is continuing to study this drug in patients with advanced ovarian cancer who have BRCA gene mutations and in patients with other types of ovarian cancer. The ARIEL3 maintenance confirmatory study has completed enrollment and the ARIEL4 treatment confirmatory study is open for enrollment.
- The FDA also granted the Rubraca® application breakthrough therapy designation and priority review status. Rubraca® also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs intended to treat rare diseases.
- * On October 7, 2016, Clovis Oncology announced that the company is actively preparing for a European submission during the fourth quarter of 2016.
- * On August 23, 2016, Clovis Oncology announced that the FDA has accepted Clovis’ New Drug Application (NDA) for accelerated approval of rucaparib and granted priority review status to the application with a Prescription Drug User Fee Act (PDUFA) date of February 23, 2017. In late June 2016, Clovis completed its NDA submission of rucaparib to the FDA for the treatment of advanced ovarian cancer in patients with deleterious BRCA-mutated tumors inclusive of both germline and somatic BRCA mutations (as detected by an FDA-approved test), and who have been treated with two or more chemotherapies. Rucaparib was granted Breakthrough Therapy Designation for the proposed indication by the FDA in April 2015. Foundation Medicine, Clovis’ companion diagnostic partner, has submitted a Premarket Approval (PMA) application for its FoundationFocus CDxBRCA to the FDA in June 2016. The test is designed to identify tumor BRCA mutations, including germline and somatic BRCA mutations. The timing of the submission is expected to allow for regulatory approval of the companion diagnostic in a similar timeframe.
- 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. 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.
- 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.
- * On April 6, 2015, Clovis Oncology announced that the FDA has granted Breakthrough Therapy designation for the Company’s investigational agent rucaparib as monotherapy treatment of advanced ovarian cancer in patients who have received at least two lines of prior platinum-containing therapy, with BRCA-mutated tumors, inclusive of both germline BRCA (gBRCA) and somatic BRCA (sBRCA) mutations. The Breakthrough Therapy designation was granted based on interim efficacy and safety results from two ongoing Phase 2 studies of rucaparib in ovarian cancer, including a Phase 2 study in women with gBRCA mutations, and the ARIEL2 treatment study. A clinical data update from the ARIEL2 study presented at the 2015 Annual Meeting on Women’s Cancer® demonstrated that seventy percent (16/23) of evaluable BRCA-mutant patients achieved a RECIST and/or CA-125 response, and 65% (15/23) achieved a RECIST response. Responses were observed in both germline and somatic BRCA-mutant tumors.
- * On September 5, 2012, the COMP has adopted a positive opinion recommending rucaparib for designation as orphan medicinal products for the treatment of ovarian cancer.
- • On December 4, 2018, Clovis Oncology announced after opposition proceedings at The Hague, Netherlands, that the European Patent Office upheld claims of European Patent 2534153 in amended form covering certain crystalline forms of rucaparib camsylate, including rucaparib S-camsylate Form A, the crystalline form in Rubraca®.In its oral decision announced at the hearing, the Opposition Division upheld claims, narrowed from the originally granted patent, to certain crystalline forms of rucaparib camsylate. These forms include, but are not limited to, the commercial product. The European Opposition Division found patentability of the claimed forms based on the inventiveness of these crystalline forms and a constellation of unexpected properties. The European patent was opposed by two opponents. Clovis and/or either opponent have an opportunity to appeal the decision of the European Opposition Division within two months of the written decision, which is expected in the next few months. If appealed, all claims in the originally granted patent will remain in force until the Technical Board of Appeal issues its decision.
- In addition to the rucaparib camsylate patent protection through at least 2031 confirmed here, the commercial form of Rubraca® is also entitled to European regulatory exclusivity until at least 2028 (and 2029 if an indication in a second tumor type is approved). Also, Clovis has filed for supplementary protection certificate (SPC) extension on this rucaparib camsylate patent in various European countries, which if approved, would provide extension of protection until 2033 under this patent.
- • On November 20, 2018, Clovis Oncology announced that the United States Patent and Trademark Office issued United States Patent 10,130,636 with claims directed to methods of treating cancer with high dosage strength rucaparib camsylate formulations. The patent claims cover methods of treating cancer with commercial Rubraca® product, including all commercial dosage strengths (200, 250 and 300mg). The high dosage strength rucaparib formulation patent expires in 2035, and will join multiple patents directed to rucaparib, rucaparib camsylate, and methods of treatment as the 11th Orange Book-listed patent for rucaparib.
- • On March 8, 2018, Clovis Oncology announced that the company has received a Notice of Allowance from the United States Patent and Trademark Office in United States Patent Application 14/828,065 with claims directed to high dosage strength rucaparib camsylate formulations. The patent is expected to issue shortly with claims that cover the commercial Rubraca® product, including all commercial dosing strengths (200, 250 and 300mg). Upon issuance, the high dosage strength rucaparib formulation patent will expire in 2035, and will have the longest term of the multiple patents directed to rucaparib, rucaparib camsylate, and methods of treatment. This will be the 10th Orange Book-listed patent for rucaparib.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2016-12-19/2018-04-06
UE authorization: 2018-05-24
Favourable opinion UE: 2018-03-22
Favourable opinion USA:
Orphan status USA: 2012-07-31
Orphan status UE: 2012-10-10/2018-04-06
Pediatric exclusivit _USA:
Pediatric exclusivity UE:
- • On March 23, 2018, Clovis Oncology announced the initiation of an early access program in Europe for rucaparib for treatment and as maintenance therapy in recurrent ovarian cancer. The program will be overseen and implemented by Caligor Coghlan, which specializes in early access to medicines. The program, to be known as the Rucaparib Access Program (RAP), will enable participation from certain countries in Europe, where permitted by applicable rules, procedures and regulatory authorities. The RAP protocol allows for rucaparib treatment of an individual patient with third-line or greater BRCA mutant epithelial, fallopian tube, or primary peritoneal ovarian cancer who has platinum-sensitive disease and is unable to tolerate further platinum-based chemotherapy or has platinum-resistant disease and needs treatment with single agent rucaparib.
- The RAP protocol will also provide access to rucaparib for maintenance therapy of an individual patient with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who has received at least two prior platinum-based treatment regimens, has platinum-sensitive disease, and is in a complete or partial response to the most recent platinum-based regimen. In all cases, the patient must have a special clinical need that cannot be met by current licensed available medicines. Patients must be ineligible for Clovis’ ARIEL4 clinical trial or unable to access a participating ARIEL4 site to qualify for Clovis’ early access program.
- On February 28, 2018, Rubraca® was added to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology Ovarian Cancer, as maintenance therapy for patients with platinum-sensitive epithelial ovarian, fallopian tube and primary peritoneal cancer who are in partial or complete response after completion of two or more lines of platinum-based therapy. The NCCN designated Rubraca® as a category 2A treatment.
- • On April 27, 2017, Myriad Genetics and Clovis Oncology announced a companion diagnostic collaboration to support a post-marketing regulatory commitment related to Clovis' PARP inhibitor, Rubraca® (rucaparib). Under the agreement, Myriad will submit a supplementary premarket approval (sPMA) application under its existing PMA for BRACAnalysis CDx to include Rubraca®. The Myriad sPMA submission will fulfill a post-approval regulatory commitment by Clovis Oncology to the FDA for Rubraca®. In December 2016, Rubraca® was approved for women with advanced ovarian cancer who have been treated with two or more chemotherapies and whose tumors have a deleterious BRCA mutation as identified by an FDA-approved companion diagnostic test. The companion diagnostic test approved with Rubraca® does not discriminate between germline and somatic mutations. Knowledge of germline status is important to provide patients appropriate counseling.