On April 29, 2019 The Janssen Pharmaceutical Companies of Johnson & Johnson reported the submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) seeking approval of a new indication for ERLEADA (apalutamide) for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC) (Press release, Johnson & Johnson, APR 29, 2019, View Source [SID1234535449]). The sNDA is based on findings from the Phase 3 TITAN study, whose dual primary endpoints, overall survival (OS) and radiographic progression-free survival (rPFS), were both achieved. These data will be presented at the upcoming American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting during an oral abstract session on Friday, May 31st.
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The sNDA is being reviewed by the FDA through the Real-Time Oncology Review (RTOR) program, which for certain applications allows the FDA to review data before the applicant formally submits the complete application. The program aims to explore a more efficient review process to help ensure treatments are available for patients as soon as possible. Selection into the RTOR program does not guarantee or influence approvability of the application.
"This submission marks an important step in providing a potential treatment option for patients with metastatic castration-sensitive prostate cancer, regardless of prior treatment or the extent of their disease," said Craig Tendler, M.D., Vice President, Oncology Clinical Development and Medical Affairs, Janssen Research & Development, LLC. "We look forward to closely collaborating with the FDA through the efficient Real-Time Oncology Review pilot program with the goal of bringing ERLEADA to an earlier population of patients with metastatic prostate cancer as soon as possible."
About the TITAN Study1
TITAN (NCT02489318) is a Phase 3 randomized, placebo-controlled, double-blind study in patients with mCSPC regardless of extent of disease, and prior treatment with docetaxel or treatment of localized disease. More than 1,050 patients with mCSPC were randomized to receive either ERLEADA plus androgen deprivation therapy (ADT), or placebo plus ADT. The TITAN study included mCSPC patients with both low and high-volume disease, those who were newly diagnosed or those who have received prior definitive local therapy, or prior treatment with up to six cycles of docetaxel. Participants were treated until disease progression or the occurrence of unacceptable treatment related toxicity, or end of treatment. The dual primary endpoints of the study are OS and rPFS. Secondary endpoints include time to chemotherapy, time to pain progression, time to chronic opioid use and time to skeletal related event.1 For additional study information, visit ClinicalTrials.gov.
About ERLEADA
ERLEADA (apalutamide) is an androgen receptor (AR) inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC). It became the first treatment to receive FDA approval for this disease state on February 14, 2018.2 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer include apalutamide as a treatment option for patients with non-metastatic (M0) CRPC with a category 1 recommendation for those with a PSA doubling time ≤10 months*.3 Additionally, the American Urological Association (AUA) Guidelines for Castration-Resistant Prostate Cancer (CRPC) were updated to include apalutamide (ERLEADA) with continued ADT as a treatment option that clinicians should offer to patients with asymptomatic nmCRPC. It is included as one of the options clinicians should offer to patients with nmCRPC who are at high-risk for developing metastatic disease (Standard; Evidence Level Grade A)**.4
*Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer V.2.2019. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed April 23, 2019. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application, and disclaims any responsibility for their application or use in any way.
**Standard: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade A or B evidence.
**Evidence Level: A designation indicating the certainty of the results as high, moderate, or low (A, B, or C, respectively) based on AUA nomenclature and methodology.
About Metastatic Castration-Sensitive Prostate Cancer
Metastatic prostate cancer is cancer that has spread to another part of the body.5 Metastatic castration-sensitive prostate cancer (mCSPC), refers to prostate cancer that still responds to androgen deprivation therapy (ADT).5 Patients with mCSPC tend to have a poor prognosis, with a median OS of less than five years, underscoring the need for new treatment options.6,7,8
ERLEADA IMPORTANT SAFETY INFORMATION2
CONTRAINDICATIONS
Pregnancy — ERLEADA (apalutamide) can cause fetal harm and potential loss of pregnancy.
WARNINGS AND PRECAUTIONS
Falls and Fractures — In a randomized study (SPARTAN), falls and fractures occurred in 16% and 12% of patients treated with ERLEADA compared to 9% and 7% treated with placebo, respectively. Falls were not associated with loss of consciousness or seizure. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone targeted agents.
Seizure — In a randomized study (SPARTAN), 2 patients (0.2%) treated with ERLEADA experienced a seizure. Permanently discontinue ERLEADA in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA. Advise patients of the risk of developing a seizure while receiving ERLEADA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.
ADVERSE REACTIONS
Adverse Reactions — The most common adverse reactions (≥10%) were fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.
Laboratory Abnormalities — All Grades (Grade 3-4)
Hematology — anemia ERLEADA 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA 41% (2%), placebo 21% (2%)
Chemistry — hypercholesterolemia ERLEADA 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA 70% (2%), placebo 59% (1%); hypertriglyceridemia ERLEADA 67% (2%), placebo 49% (0.8%); hyperkalemia ERLEADA 32% (2%), placebo 22% (0.5%)
Rash — Rash was most commonly described as macular or maculo-papular. Adverse reactions were 24% with ERLEADA versus 6% with placebo. Grade 3 rashes (defined as covering > 30% body surface area [BSA]) were reported with ERLEADA treatment (5%) versus placebo (0.3%).
The onset of rash occurred at a median of 82 days. Rash resolved in 81% of patients within a median of 60 days (range: 2 to 709 days) from onset of rash. Four percent of patients treated with ERLEADA received systemic corticosteroids. Rash recurred in approximately half of patients who were re-challenged with ERLEADA.
Hypothyroidism was reported for 8% of patients treated with ERLEADA and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA and 7% of patients treated with placebo. The median onset was day 113. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted.
DRUG INTERACTIONS
Effect of Other Drugs on ERLEADA — Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA dose based on tolerability [see Dosage and Administration (2.2)].
Effect of ERLEADA on Other Drugs — ERLEADA is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA and evaluate for loss of activity.
P-gp, BCRP or OATP1B1 substrates — Apalutamide is a weak inducer of P-glycoprotein (P- gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with ERLEADA and evaluate for loss of activity if medication is continued.