Nubeqa darolutamide 300 mg Tablet, Film Coated, 120-count — NDC 50419-395-01 (Billing 50419-0395-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Darolutamide is an androgen receptor (AR) inhibitor. Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. A major metabolite, ketodarolutamide, exhibited similar in vitro activity to darolutamide.

In addition, darolutamide functioned as a progesterone receptor (PR) antagonist in vitro (approximately 1% activity compared to AR). Darolutamide decreased prostate cancer cell proliferation in vitro and tumor volume in mouse xenograft models of prostate cancer.

12.2Pharmacodynamics PSA reduction was observed in CRPC patients receiving darolutamide doses of 100-900 mg twice a day, reaching a plateau of PSA reduction at the 600 mg twice daily dose. Twice daily dosing of 600 mg darolutamide in nmCRPC patients resulted in undetectable PSA levels in 24% of patients at 12 months compared to 0.4% of patients in the placebo arm. Twice daily dosing of 600 mg darolutamide in mCSPC patients resulted in undetectable PSA levels (<0.2 ng/mL) in 63% of patients compared to 19% of patients in the placebo arm.

Twice daily dosing of 600 mg darolutamide in combination with docetaxel in mCSPC patients resulted in undetectable PSA levels in 60% of patients at 12 months compared to 26% of patients in the placebo with docetaxel arm. 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.

12.3Pharmacokinetics Following administration of 600 mg twice daily, darolutamide mean (%CV) steady-state peak plasma concentration (C max ) is 4.79 mg/L (30.9%) and area under the plasma concentration-time curve from time 0 to 12 hours (AUC 12h ) is 52.82 h∙µg/mL (33.9%). Steady-state is reached 2–5 days after repeated dosing with food, with an approximate 2-fold accumulation. The exposure (C max and AUC 12 ) of the darolutamide and the active metabolite ketodarolutamide increase in a nearly dose-proportional manner in the dose range of 100 to 700 mg (0.17 to 1.17 times the approved recommended dosage).

No further increase in darolutamide exposure was observed at 900 mg twice daily (1.5 times the approved recommended dosage). Absorption Darolutamide C max 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/1.73m 2 ), or mild hepatic impairment.… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Darolutamide is an androgen receptor (AR) inhibitor. Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. A major metabolite, ketodarolutamide, exhibited similar in vitro activity to darolutamide.

In addition, darolutamide functioned as a progesterone receptor (PR) antagonist in vitro (approximately 1% activity compared to AR). Darolutamide decreased prostate cancer cell proliferation in vitro and tumor volume in mouse xenograft models of prostate cancer.

12.3Pharmacokinetics Following administration of 600 mg twice daily, darolutamide mean (%CV) steady-state peak plasma concentration (C max ) is 4.79 mg/L (30.9%) and area under the plasma concentration-time curve from time 0 to 12 hours (AUC 12h ) is 52.82 h∙µg/mL (33.9%). Steady-state is reached 2–5 days after repeated dosing with food, with an approximate 2-fold accumulation. The exposure (C max and AUC 12 ) of the darolutamide and the active metabolite ketodarolutamide increase in a nearly dose-proportional manner in the dose range of 100 to 700 mg (0.17 to 1.17 times the approved recommended dosage).

No further increase in darolutamide exposure was observed at 900 mg twice daily (1.5 times the approved recommended dosage). Absorption Darolutamide C max 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/1.73m 2 ), or mild hepatic impairment.

In non-cancer subjects with severe renal impairment (eGFR 15–29 mL/min/1.73 m 2 ) 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 m 2 ) 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 AUC 0-72 by 72% and C max 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 AUC 0-72 by 1.7- and C max by 1.4-fold. CYP3A4 substrates Concomitant use of darolutamide decreased the mean AUC and C max 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 C max 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 mCSPC patients.… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics PSA reduction was observed in CRPC patients receiving darolutamide doses of 100-900 mg twice a day, reaching a plateau of PSA reduction at the 600 mg twice daily dose. Twice daily dosing of 600 mg darolutamide in nmCRPC patients resulted in undetectable PSA levels in 24% of patients at 12 months compared to 0.4% of patients in the placebo arm. Twice daily dosing of 600 mg darolutamide in mCSPC patients resulted in undetectable PSA levels (<0.2 ng/mL) in 63% of patients compared to 19% of patients in the placebo arm.

Twice daily dosing of 600 mg darolutamide in combination with docetaxel in mCSPC patients resulted in undetectable PSA levels in 60% of patients at 12 months compared to 26% of patients in the placebo with docetaxel arm. 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.

14 CLINICAL STUDIES Non-Metastatic Castration Resistant Prostate Cancer ARAMIS (NCT02200614) was a multicenter, double-blind, placebo-controlled clinical trial in 1509 patients with non-metastatic castration resistant prostate cancer with a prostate-specific antigen doubling time (PSADT) of ≤ 10 months. Randomization was stratified by PSADT and use of bone-targeted therapy at study entry. Patients with pelvic lymph nodes less than 2 cm in short axis below the aortic bifurcation were eligible to enter the study.

Absence or presence of metastasis was assessed by blinded independent central review (BICR). PSA results were not blinded and were not used for treatment discontinuation. Patients were randomized 2:1 to receive either 600 mg NUBEQA orally twice daily (n=955) or matching placebo (n=554).

Treatment continued until radiographic disease progression as assessed by CT, MRI, 99m Tc bone scan by BICR, unacceptable toxicity or withdrawal. All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a bilateral orchiectomy. The median age was 74 years (range 48–95) and 9% of patients were 85 years of age or older.

The racial distribution included 79% White, 13% Asian, 3% Black or African American, while ethnicity included 3.1% Hispanic or Latino patients. A majority of patients (73%) had a Gleason score of 7 or higher at diagnosis. The median PSADT was 4.5 months.

Forty-two percent of patients in both treatment arms had prior surgery or radiotherapy to the prostate. Eleven percent of patients had enlarged pelvic lymph nodes less than 2 cm at study entry. Six percent of patients were retrospectively identified by BICR as having metastases at baseline.

Seventy-three percent of patients received prior treatment with an anti-androgen (bicalutamide or flutamide). All patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry. At baseline, 47% of patients reported no pain on the Brief Pain Inventory-Short Form (a 7-day diary average of the daily worst pain item).

There were 12 patients (1.3%) enrolled on the NUBEQA arm with a history of seizure. The major efficacy endpoint was metastasis free survival (MFS), defined as the time from randomization to the time of first evidence of BICR-confirmed distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first. Distant metastasis was defined as new bone or soft tissue lesions or enlarged lymph nodes above the aortic bifurcation.

Overall survival (OS), time to pain progression, and time to initiation of cytotoxic chemotherapy, were additional efficacy endpoints. Treatment with NUBEQA resulted in a statistically significant improvement in MFS compared to placebo. At the protocol-specified final analysis of OS, treatment with NUBEQA resulted in a statistically significant improvement in OS compared to placebo.

The final analysis of OS and time to initiation of cytotoxic chemotherapy was event-driven and conducted after 254 OS events had occurred. The efficacy results from ARAMIS are summarized in Table 7 and Figure 1. Table 7: Efficacy Results from the ARAMIS Study NUBEQA (N=955) Placebo (N=554) NR: not reached Metastasis-free survival Locoregional-only progression occurred in 6% of patients overall.

Distant Metastasis or Death (%) 221 (23) 216 (39) Median, months (95% CI) Based on Kaplan-Meier estimates 40.4 (34.3, NR) 18.4 (15.5, 22.3) Hazard Ratio (95% CI) Hazard ratio is based on a stratified Cox regression model. Hazard ratio < 1 favors NUBEQA. 0.41 (0.34, 0.50) P-value The pre-specified final OS analysis was event-driven and occurred 14 months after the MFS analysis <0.0001 Overall survival Deaths (%) 148 (15) 106 (19) Median, months (95% CI) NR (56.1, NR) NR (46.9, NR) Hazard Ratio (95% CI) 0.69 (0.53, 0.88) P-value P-value is based on a log-rank test stratified by PSADT (≤ 6 months vs. > 6 months) and use of osteoclast-targeted therapy (yes vs. no) 0.003 F… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Oral administration of darolutamide to male and female RasH2 transgenic mice for 26 weeks did not show carcinogenic potential at doses up to 1000 mg/kg/day. Darolutamide was clastogenic in an in vitro chromosome aberration assay in human peripheral blood lymphocytes. Darolutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in the in vivo combined bone marrow micronucleus assay and the Comet assay in the liver and duodenum of the rat.

Fertility studies in animals have not been conducted with darolutamide. In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), tubular dilatation of testes, hypospermia, and atrophy of seminal vesicles, testes, prostate gland and epididymides were observed at doses ≥ 100 mg/kg/day in rats (0.6 times the human exposure based on AUC) and ≥ 50 mg/kg/day in dogs (approximately 1 times the human exposure based on AUC).