On October 2, 2018 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for Rubraca (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 (Press release, Clovis Oncology, OCT 2, 2018, View Source [SID1234529714]).
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Breakthrough Therapy designation is granted by the FDA to investigational agents intended to treat a serious or life-threatening disease or condition and whose preliminary clinical evidence may demonstrate substantial improvement on at least one clinically significant endpoint over available therapy. The FDA previously granted Breakthrough Therapy designation to Rubraca for the monotherapy treatment of certain advanced ovarian cancer patients and then in December 2016 approved Rubraca for the treatment of certain adult patients with deleterious BRCA mutation (germline and/or somatic) associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. The FDA subsequently approved Rubraca in a second indication, 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, in April 2018.
"We are committed to the rapid development of Rubraca in mCRPC and we are obviously pleased to receive Breakthrough Therapy designation. We look forward to presenting the data that served as the basis of our BTD application at the ESMO (Free ESMO Whitepaper) conference later this month," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We hope the decision by the FDA to grant this Breakthrough Therapy designation for Rubraca offers encouragement to the prostate cancer community, and we will do our best to make Rubraca available to eligible prostate cancer patients as quickly as possible."
This most recent Breakthrough Therapy designation was granted to Rubraca based on initial efficacy and safety results from TRITON2, the Phase 2 study of Rubraca in men with advanced prostate cancer with BRCA 1/2 mutations (germline or somatic) and deleterious mutations of other homologous recombination (HR) repair genes, in the metastatic castration-resistant setting.
Initial data from the TRITON2 clinical study, which served as the basis for BTD, will be presented for the first time at the 2018 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress taking place October 19-23, 2018, in Munich, Germany.
"We are pleased the FDA has granted Breakthrough Therapy designation to Rubraca in mCRPC," said Howard R. Soule, Ph.D., Executive Vice President and Chief Scientific Officer of the Prostate Cancer Foundation. "There is tremendous need for new therapeutic options in advanced prostate cancer. In particular, we are enthusiastic about the potential for targeted therapies that may provide more meaningful benefit to patients with specific genetic mutations."
Data from the TRITON2 clinical study will also be presented in an oral presentation at the 25th Annual Prostate Cancer Foundation Scientific Retreat, taking place October 26-28, 2018, in Carlsbad, CA.
About Breakthrough Therapy Designation
The Breakthrough Therapy designation was enacted as part of the 2012 FDA Safety and Innovation Act and is intended to expedite development and review of drugs intended to treat serious or life-threatening medical conditions when preliminary clinical evidence demonstrates that the drug may have substantial improvement over existing therapies on at least one clinically significant endpoint. Breakthrough Therapy designation includes all the features of the Fast Track designation, as well as more intensive guidance from the FDA on a drug’s clinical development program. The standard for breakthrough therapy designation is not the same as the standard for drug approval and not all drugs receiving breakthrough therapy designation will receive approval for marketing.
About Prostate Cancer
The American Cancer Society estimates that more than 164,000 men in the United States will be diagnosed with prostate cancer in 2018, and the GLOBOCAN Cancer Fact Sheets estimated that approximately 345,000 men in Europe were diagnosed with prostate cancer in 2012. Castration-resistant prostate cancer has a high likelihood of developing metastases. Metastatic castration-resistant prostate cancer, or mCRPC, is an incurable disease, usually associated with poor prognosis. According to the American Cancer Society, the five-year survival rate for mCRPC is approximately 29%. Approximately 12% of mCRPC patients have a deleterious mutation in BRCA1 or BRCA2, according to an article published in the Journal of Clinical Oncology in 2017. These molecular markers may be used to select patients for treatment with a PARP inhibitor.
About Rubraca
Rubraca is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian, metastatic castration-resistant prostate, and bladder cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway. Clovis holds worldwide rights for Rubraca. Rubraca is an unlicensed medical product outside of the U.S. and Europe.
Rubraca U.S. FDA Approved Indications and Important Safety Information
Rubraca is indicated as monotherapy 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.
Rubraca is indicated as monotherapy for the treatment of adult patients with deleterious BRCA mutations (germline and/or somatic) associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies and selected for therapy based on an FDA-approved companion diagnostic for Rubraca.
Select Important Safety Information
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur uncommonly in patients treated with Rubraca and are potentially fatal adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long-term follow-up. Of these, 5 occurred during treatment or during the 28-day safety follow-up (0.5%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA-damaging agents. Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1).
Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose (see Dosage and Administration [2.2] in full Prescribing Information) and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample cytogenetic analysis. If MDS/AML is confirmed, discontinue Rubraca.
Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca.
Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1–4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%) and neutropenia (20%).
Most common laboratory abnormalities in ARIEL3 (≥ 25%; Grade 1–4) were increase in creatinine (98%), decrease in hemoglobin (88%), increase in cholesterol (84%), increase in alanine aminotransferase (ALT) (73%), increase in aspartate aminotransferase (AST) (61%), decrease in platelets (44%), decrease in leukocytes (44%), decrease in neutrophils (38%), increase in alkaline phosphatase (37%) and decrease in lymphocytes (29%).
Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%; Grade 1–4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%) and thrombocytopenia (21%).
Most common laboratory abnormalities in Study 10 and ARIEL2 (≥ 35%; Grade 1–4) were increase in creatinine (92%), increase in alanine aminotransferase (ALT) (74%), increase in aspartate aminotransferase (AST) (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%) and decrease in absolute neutrophil count (35%).
Co-administration of Rubraca can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring. Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose. You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Clovis Oncology, Inc. at 1-844-258-7662.