nmCRPC and mHSPC

The recommended dose of NUBEQA is 600 mg (two 300 mg tablets) taken orally, twice daily, with food [see Clinical Pharmacology (12.3)].

Continue treatment until disease progression or unacceptable toxicity occurs.

Patients receiving NUBEQA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or have had a bilateral orchiectomy.

Advise patients to swallow tablets whole with food, to take any missed dose as soon as they remember prior to the next scheduled dose, and not to take two doses together to make up for a missed dose.

mHSPC

For patients with mHSPC treated with NUBEQA in combination with docetaxel, administer the first of 6 cycles of docetaxel within 6 weeks after the start of NUBEQA treatment. Refer to docetaxel prescribing information for additional dosing information, including dosage modifications.

Treatment with NUBEQA may be continued until disease progression or unacceptable toxicity, even if a cycle of docetaxel is delayed, interrupted, or discontinued [see Dosage and Administration (2.2)].

5.4 Embryo-Fetal Toxicity

The safety and efficacy of NUBEQA have not been established in females. Based on its mechanism of action, NUBEQA can cause fetal harm and loss of pregnancy when administered to a pregnant female [see Clinical Pharmacology (12.1)].

Advise males with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the last dose of NUBEQA [see Use in Specific Populations (8.1, 8.3)].

Non-Metastatic Castration Resistant Prostate Cancer

The safety of NUBEQA was evaluated in ARAMIS, a randomized (2:1), double-blind, placebo-controlled, multi-center clinical study, that enrolled patients who had non-metastatic castration-resistant prostate cancer (nmCRPC) [see Clinical Studies (14)]. Patients received either NUBEQA at a dose of 600 mg, or a placebo, twice a day. All patients in the ARAMIS study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. Among patients who received NUBEQA, the median duration of exposure was 14.8 months (range: 0 to 44.3 months).

Serious adverse reactions occurred in 25% of patients receiving NUBEQA and in 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia and hematuria. Fatal adverse reactions occurred in 3.9% of patients receiving NUBEQA and 3.2% of patients receiving placebo. Fatal adverse reactions in patients who received NUBEQA included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%).

Permanent discontinuation of NUBEQA due to adverse reactions occurred in 9% of patients receiving NUBEQA. The most common adverse reactions requiring permanent discontinuation in patients who received NUBEQA included cardiac failure (0.4%), and death (0.4%).

Dosage interruptions due to adverse reactions occurred in 13% of patients treated with NUBEQA. The most common adverse reactions requiring dosage interruption in patients who received NUBEQA included hypertension (0.6%), diarrhea (0.5%), and pneumonia (0.5%).

Dosage reductions due to adverse reactions occurred in 6% of patients treated with NUBEQA. The most common adverse reactions requiring dosage reduction in patients treated with NUBEQA included fatigue (0.7%), hypertension (0.3%), and nausea (0.3%).

The most common (>2% with a ≥2% increase compared to placebo) adverse reactions, including laboratory test abnormalities, were AST increased, neutrophil count decreased, fatigue, bilirubin increased, pain in extremity, and rash.

Table 1 summarizes the adverse reactions in ARAMIS.

Clinically relevant adverse reactions occurring in 2% or more of patients treated with NUBEQA included ischemic heart disease (4%) and heart failure (2.1%).

Table 2 summarizes the laboratory test abnormalities in ARAMIS.

Metastatic Hormone-Sensitive Prostate Cancer

The safety of NUBEQA, in combination with docetaxel, was evaluated in ARASENS, a randomized (1:1), double-blind, placebo-controlled, multi-center clinical study, that enrolled patients who had mHSPC [see Clinical Studies (14)]. Patients were to receive either NUBEQA at a dose of 600 mg, or a placebo, twice a day in combination with docetaxel at a dose of 75 mg/m2 every 21 days for 6 cycles. All patients in the ARASENS study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. Patients with a medical history of seizure were allowed to enter the study. Among patients who received NUBEQA, the median duration of exposure was 41 months (range: 0.1 to 56.5 months) vs. 16.7 months (range 0.3 to 55.8) with placebo. Eighty-eight percent and 86% of patients received the 6 planned cycles of docetaxel, in the NUBEQA with docetaxel arm and placebo with docetaxel arm, respectively.

Serious adverse reactions occurred in 45% of patients receiving NUBEQA with docetaxel and in 42% of patients receiving placebo with docetaxel, respectively. Serious adverse reactions in ≥ 2% of patients who received NUBEQA with docetaxel included febrile neutropenia (6%), neutrophil count decreased (2.8%), musculoskeletal pain (2.6%) and pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients receiving NUBEQA with docetaxel and 4% of patients receiving placebo with docetaxel. Fatal adverse reactions in patients who received NUBEQA included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%).

Permanent discontinuation of NUBEQA due to adverse reactions occurred in 14% of patients treated in the NUBEQA with docetaxel arm. The most common adverse reactions which resulted in permanent discontinuation of NUBEQA were rash (1.1%), musculoskeletal pain (0.9%), and aspartate aminotransferase (AST) increased (0.9%).

Dosage interruptions of NUBEQA due to adverse reactions occurred in 23% of patients treated in the NUBEQA with docetaxel arm. The most common (>2%) adverse reactions requiring dosage interruption of NUBEQA were alanine aminotransferase (ALT) increased (3.2%), AST increased (3.1%) and febrile neutropenia (2.1%).

Dosage reductions of NUBEQA due to adverse reactions occurred in 9% of patients treated in the NUBEQA with docetaxel arm. The most common (>2%) adverse reactions requiring dosage reduction of NUBEQA were ALT increased (2.8%) and AST increased (2.5%).

The most common (>10% with a ≥2% increase over placebo with docetaxel) adverse reactions are constipation, decreased appetite, rash, hemorrhage, weight increased, and hypertension. The most common laboratory test abnormalities (≥30%) are anemia, hyperglycemia, lymphocyte count decreased, neutrophil count decreased, AST increased, ALT increased, and hypocalcemia.

Table 3 summarizes the adverse reactions in ARASENS.

Clinically relevant adverse reactions in < 10% of patients who received NUBEQA with docetaxel included fractures (8%), ischemic heart disease (3.2%), seizures (0.6%), and drug-induced liver injury (0.3%).

Table 4 summarizes laboratory test abnormalities in the ARASENS study.

Clinically relevant laboratory test abnormalities in < 30% of patients who received NUBEQA with docetaxel included blood bilirubin increased (all grades 20%, Grade 3-4 0.5%) compared to placebo with docetaxel (all grades 10%, grades 3-4 0.3%).

Combined P-gp and Strong or Moderate CYP3A4 Inducer

Concomitant use of NUBEQA with a combined P-gp and strong or moderate CYP3A4 inducer decreases darolutamide exposure which may decrease NUBEQA activity [see Clinical Pharmacology (12.3)]. Avoid concomitant use of NUBEQA with combined P-gp and strong or moderate CYP3A4 inducers.

Combined P-gp and Strong CYP3A4 Inhibitors

Concomitant use of NUBEQA with a combined P-gp and strong CYP3A4 inhibitor increases darolutamide exposure [see Clinical Pharmacology (12.3)] which may increase the risk of NUBEQA adverse reactions. Monitor patients more frequently for NUBEQA adverse reactions and modify NUBEQA dosage as needed [see Dosage and Administration (2.2)].

Breast Cancer Resistance Protein (BCRP) and Organic Anion Transporting Polypeptides (OATP) 1B1 and 1B3 Substrates

NUBEQA is an inhibitor of BCRP transporter. Concomitant use of NUBEQA increases the AUC and Cmax of BCRP substrates [see Clinical Pharmacology (12.3)], which may increase the risk of BCRP substrate-related toxicities.

Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more frequently for adverse reactions, and consider dose reduction of the BCRP substrate drug.

NUBEQA is an inhibitor of OATP1B1 and OATP1B3 transporters. Concomitant use of NUBEQA may increase the plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor patients more frequently for adverse reactions of these drugs and consider dose reduction while patients are taking NUBEQA [see Clinical Pharmacology (12.3)],

Review the prescribing information of the BCRP, OATP1B1 and OATP1B3 substrates when used concomitantly with NUBEQA.

Risk Summary

The safety and efficacy of NUBEQA have not been established in females. Based on its mechanism of action, NUBEQA can cause fetal harm and loss of pregnancy [see Clinical Pharmacology (12.1)]. Animal embryo-fetal developmental toxicology studies were not conducted with darolutamide. There are no human data on the use of NUBEQA in pregnant females.

Risk Summary

The safety and efficacy of NUBEQA have not been established in females. There are no data on the presence of darolutamide or its metabolites in human milk, the effect on the breastfed child, or the effect on milk production.

Contraception

Infertility

Cardiac Electrophysiology

The effect of darolutamide (600 mg twice daily) on the QTc interval was evaluated in a subgroup of 500 patients in the ARAMIS study. No large mean increase in QTc (i.e., > 20 ms) was detected.

Absorption

Darolutamide Cmax is reached approximately 4 hours after administration of a single 600 mg oral dose.

The absolute bioavailability is approximately 30% following oral administration of a NUBEQA tablet containing 300 mg darolutamide under fasted conditions.

Food Effect

Bioavailability of darolutamide increased by 2.0 to 2.5‑fold when administered with food. A similar increase of exposure was observed for the active metabolite ketodarolutamide.

Distribution

The apparent volume of distribution of darolutamide after intravenous administration is 119 L.

Protein binding is 92% for darolutamide and 99.8% for the active metabolite, ketodarolutamide. Serum albumin is the main binding protein for darolutamide and ketodarolutamide.

Elimination

The effective half-life of darolutamide and ketodarolutamide is approximately 20 hours in patients. The clearance (%CV) of darolutamide following intravenous administration is 116 mL/min (39.7%).

Metabolism

Darolutamide is primarily metabolized by CYP3A4, as well as by UGT1A9 and UGT1A1. Ketodarolutamide total exposure in plasma is 1.7‑fold higher compared to darolutamide.

Excretion

After a single radiolabeled dose as an oral solution, a total of 63.4% of darolutamide‑related material is excreted in the urine (approximately 7% unchanged) and 32.4% (approximately 30% unchanged) in the feces. More than 95% of the dose was recovered within 7 days after administration.

Specific Populations

No clinically significant differences in the pharmacokinetics of darolutamide were observed based on age (41-95 years), race (White, Asian, Black or African American), mild to moderate renal impairment (eGFR 30–89 mL/min/1.73m2), or mild hepatic impairment.

In non-cancer subjects with severe renal impairment (eGFR 15–29 mL/min/1.73 m2) not receiving dialysis or with moderate hepatic impairment (Child-Pugh Class B), NUBEQA exposure increased by about 2.5- and 1.9-fold, respectively, compared to healthy subjects.

The effect of end-stage renal disease (eGFR <15 mL/min/1.73 m2) or severe hepatic impairment (Child-Pugh C) on darolutamide pharmacokinetics has not been studied.

Drug Interaction Studies

Clinical Studies

Combined P-gp and Strong CYP3A4 Inducers

Concomitant use of rifampicin (a combined P-gp and strong CYP3A4 inducer) decreased mean darolutamide AUC0-72 by 72% and Cmax by 52%. The decrease of darolutamide exposure by moderate CYP3A4 inducers is expected to be in the range of 36% – 58%.

Combined P-gp and Strong CYP3A4 Inhibitors

Itraconazole (a strong combined CYP3A4 and P-gp inhibitor) increased mean darolutamide AUC0-72 by 1.7- and Cmax by 1.4-fold.

CYP3A4 substrates

Concomitant use of darolutamide decreased the mean AUC and Cmax of midazolam (CYP3A4 substrate) by 29% and 32%, respectively. No clinically relevant differences in the pharmacokinetics of midazolam were observed when used concomitantly with darolutamide.

BCRP, OATP1B1 and OATP1B3 Substrates

Concomitant use of darolutamide increased the mean AUC and Cmax of rosuvastatin (BCRP, OATP1B1 and OATP1B3 substrate) by approximately 5-fold.

Docetaxel

Administration of darolutamide in combination with docetaxel resulted in no clinically relevant changes in the pharmacokinetics of docetaxel in mHSPC patients. There were no clinically relevant changes in the pharmacokinetics of darolutamide, when used in combination with docetaxel.

P-gp Substrates

No clinically relevant differences in the pharmacokinetics of dabigatran (P-gp substrate) were observed when used concomitantly with darolutamide.

In vitro, darolutamide did not inhibit the major CYP enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) or transporters (MRP2, BSEP, OATs, OCTs, MATEs, OATP2B1, and NTCP) at clinically relevant concentrations.