Akeega Niraparib Tosylate Monohydrate and Abiraterone Acetate 100 mg; 500 mg Tablet, Film Coated, 60-count — NDC 57894-100-60 (Billing 57894-0100-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Niraparib is an inhibitor of PARP enzymes, including PARP-1 and PARP-2, that play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death. Increased niraparib‑induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2 .

Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient‑derived xenograft tumor models with homologous recombination deficiency (HRD) that had either mutated or wild-type BRCA1/2 . Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.

CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals [see Warnings and Precautions (5.9) ] .

Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor. Abiraterone decreased serum testosterone and other androgens in patients in the placebo-controlled clinical trial.

It is not necessary to monitor the effect of abiraterone on serum testosterone levels. Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients. In mouse xenograft models of prostate cancer, the combination of niraparib and abiraterone acetate increased anti-tumor activity when compared to either drug alone.

12.2Pharmacodynamics The exposure-response relationship and time-course of pharmacodynamic response for the safety and effectiveness of AKEEGA have not been fully characterized. Hypertension and Cardiovascular Effects Niraparib has the potential to cause effects on pulse rate and blood pressure in patients, which may be related to pharmacological inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT) [see Nonclinical Toxicology (13.2) ] . Niraparib increased mean pulse rate by 22.4 to 24.1 beats/min, mean systolic blood pressure by 24.5 mmHg, and mean diastolic pressure by 16.5 mmHg relative to 14.0 to 15.8 beats per min, 18.3 to 19.6 mmHg, and 11.6 mmHg in the placebo arm.

Cardiac Electrophysiology No large (>20 ms) increases in the mean QTc interval were detected following the treatment of niraparib 300 mg once daily or 1,000 mg of abiraterone acetate once daily.

12.3Pharmacokinetics Niraparib Following the administration of AKEEGA, the mean (coefficient of variation [CV%]) C max, ss was 831 ng/mL (32%) and AUC 0–24h, ss was 13,616 ng∙h/mL (36%). The accumulation ratio following daily administration of AKEEGA was 3.5-, and 2.6-fold for niraparib AUC 0–24h and C max . Niraparib exhibits dose proportional increase in C max and AUC in the dose range of 30 mg (0.15 times the recommended dosage) to 400 mg (2 times the recommended dosage).

Abiraterone Acetate Following the administration of AKEEGA, the mean (CV%) C max,ss was 151 ng/mL (59%) and AUC 0–24h,ss was 707 ng∙h/mL (59%) for abiraterone. The accumulation ratio following daily administration of AKEEGA was 2-, and 1.8-fold for abira… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Niraparib is an inhibitor of PARP enzymes, including PARP-1 and PARP-2, that play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death. Increased niraparib‑induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2 .

Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient‑derived xenograft tumor models with homologous recombination deficiency (HRD) that had either mutated or wild-type BRCA1/2 . Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.

CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals [see Warnings and Precautions (5.9) ] .

Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor. Abiraterone decreased serum testosterone and other androgens in patients in the placebo-controlled clinical trial.

It is not necessary to monitor the effect of abiraterone on serum testosterone levels. Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients. In mouse xenograft models of prostate cancer, the combination of niraparib and abiraterone acetate increased anti-tumor activity when compared to either drug alone.

12.3Pharmacokinetics Niraparib Following the administration of AKEEGA, the mean (coefficient of variation [CV%]) C max, ss was 831 ng/mL (32%) and AUC 0–24h, ss was 13,616 ng∙h/mL (36%). The accumulation ratio following daily administration of AKEEGA was 3.5-, and 2.6-fold for niraparib AUC 0–24h and C max . Niraparib exhibits dose proportional increase in C max and AUC in the dose range of 30 mg (0.15 times the recommended dosage) to 400 mg (2 times the recommended dosage).

Abiraterone Acetate Following the administration of AKEEGA, the mean (CV%) C max,ss was 151 ng/mL (59%) and AUC 0–24h,ss was 707 ng∙h/mL (59%) for abiraterone. The accumulation ratio following daily administration of AKEEGA was 2-, and 1.8-fold for abiraterone AUC 0–24h and C max . No major deviation from dose proportionality was observed for abiraterone acetate in the dose range of 250 mg (0.25 times the recommended dosage) to 1,000 mg (the recommended dosage).

Absorption Niraparib The median T max was 3 hours after dosing. The absolute bioavailability of niraparib is approximately 73%. Abiraterone Acetate The median T max of abiraterone was 1.5 hours after dosing.

Administration of abiraterone acetate with food, compared with administration in a fasted state, results in up to a 10-fold (AUC) and up to a 17-fold (C max ) increase in mean systemic exposure of abiraterone, depending on the fat content of the meal. Given the normal variation in the content and composition of meals, taking abiraterone acetate with meals has the potential to result in increased and highly variable exposures. Distribution Niraparib The apparent volume of distribution of niraparib was 1,117 L.

Niraparib is 83% bound to human plasma proteins. Abiraterone Acetate The apparent volume of distribution of abiraterone was 25,774 L. Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein.

Elimination Niraparib The mean t ½ of niraparib when given in combination was approximately 62 hours (CV%: 42%) and apparent CL/F was

16.7L/h (CV%: 27%). Abiraterone Acetate The mean t ½ of abiraterone when given in combination was approximately 20 hours (CV%: 7.8%) and apparent CL/F was 1673 L/h (CV%: 24%). Metabolism Niraparib Niraparib is metabolized by carboxylesterases.

Abiraterone Acetate Abiraterone acetate is rapidly converted in vivo to abiraterone. CYP3A4 and SULT2A1 are the enzymes involved in the metabolism of abiraterone. Excretion Niraparib About 48% (33% to 60%) of the radiolabeled dose was recovered in urine and 39% (28% to 47%) in feces.

Unchanged niraparib accounted for 11% and 19% of the administered dose recovered in urine and feces, respectively. Abiraterone Acetate Approximately 88% of the radiolabeled dose is recovered in feces and 5% in urine. Unchanged abiraterone acetate and abiraterone accounted for 55% and 22% of the administered dose recovered in the feces, respectively.

Specific Populations No clinically significant effects on the PK of niraparib and abiraterone were observed based on body weight (43.3–165 kg for niraparib and 46–165 kg for abiraterone), age (45–90 years for niraparib and 43–90 years for abiraterone), race/ethnicity (White, Asian, and Hispanic) and mild to moderate renal impairment (CLcr: 30–90 mL/min). Severe renal impairment (CLcr: 15–30 mL/min) has not been studied. Hepatic Impairment Niraparib Mild hepatic impairment did not affect the exposure of niraparib.

Moderate hepatic impairment (Total bilirubin > 1.5 to 3 × ULN and any aspartate aminotransferase value) increased niraparib AUC by 56% compared to that of patients with normal hepatic function. Abiraterone Acetate Mild (Child-Pugh score of 5 to 6; Child-Turcotte-Pugh Class A) hepatic impairment increased abiraterone (AUC) by 1.1-fold and moderate (Child-Pugh score of 7 to 9; Child-Turcotte-Pugh Class B) hepatic impairment increased abiraterone (AUC) by 3.6-fold compared to subjects with normal hepatic function. Severe (Child-Pugh score of 10 to 15; C… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics The exposure-response relationship and time-course of pharmacodynamic response for the safety and effectiveness of AKEEGA have not been fully characterized. Hypertension and Cardiovascular Effects Niraparib has the potential to cause effects on pulse rate and blood pressure in patients, which may be related to pharmacological inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT) [see Nonclinical Toxicology (13.2) ] . Niraparib increased mean pulse rate by 22.4 to 24.1 beats/min, mean systolic blood pressure by 24.5 mmHg, and mean diastolic pressure by 16.5 mmHg relative to 14.0 to 15.8 beats per min, 18.3 to 19.6 mmHg, and 11.6 mmHg in the placebo arm.

Cardiac Electrophysiology No large (>20 ms) increases in the mean QTc interval were detected following the treatment of niraparib 300 mg once daily or 1,000 mg of abiraterone acetate once daily.

14 CLINICAL STUDIES

14.1BRCA2 -mutated Metastatic Castration-Sensitive Prostate Cancer (mCSPC) The efficacy of AKEEGA was investigated in AMPLITUDE (NCT04497844), a randomized double-blind, placebo-controlled, multi-cohort, multi-center study in which 696 patients with homologous recombination repair (HRR) gene-mutated (HRRm) mCSPC were randomized (1:1) to receive niraparib 200 mg and abiraterone acetate 1,000 mg (N=348) or placebo and abiraterone acetate (N=348). All patients received prednisone 5 mg daily and were required to have androgen deprivation therapy (ADT) (medical or surgical) >14 days prior to randomization.

The only allowable prior systemic therapy in the mCSPC setting, was up to 45 days of abiraterone acetate, up to 6 cycles of docetaxel, and up to 6 months of ADT. Randomization was stratified by HRR gene alteration ( BRCA2 versus CDK12 versus all other pathogenic alterations), prior docetaxel use (yes versus no), and volume of disease at screening (high versus low). Of the 696 patients enrolled, 323 were randomized as having BRCA2 gene mutation ( BRCA2 m).

Mutation status was determined prospectively using the Foundation One CDx tissue assay or other clinical trial assays. Among the 323 patients with BRCA2 m the median age was 66 years (range 41; 92); 68% were White, 25% Asian, 4% Black, and 3% other or not reported; 10% were Hispanic or Latino; and baseline ECOG performance status was 0 (68%), 1 (30%) or 2 (1.2%). 16% had received prior docetaxel and 11% received prior abiraterone acetate for up to 45 days for mCSPC.

40% had bone-only metastases and 15% had visceral metastases, 10% had BRCA 2 mutations in combination with mutations in other HRR genes. The major efficacy outcome measure was radiographic progression free survival (rPFS) determined by investigator-assessed radiographic progression by bone scan (according to PCWG3 criteria) or soft tissue lesions by CT or MRI (according to RECIST 1.1 criteria) or death, whichever occurred first. Overall Survival (OS) and Time to Symptomatic Progression (TSP) were additional efficacy outcome measures.

A statistically significant improvement in rPFS for niraparib and abiraterone acetate compared to placebo and abiraterone acetate was observed in the overall population of patients with HRRm. In an exploratory analysis in the subgroup of 373 patients with non- BRCA2 mutations, the investigator-assessed rPFS hazard ratio was 0.88 (95% CI: 0.63, 1.24), indicating that the improvement in the overall population was primarily attributed to the results seen in the subgroup of patients with BRCA2 mutation. The efficacy results are presented in Table 6 and Figure 1 for patients with BRCA2 mutations in AMPLITUDE.

Table 6: Efficacy Results from the BRCA2m Subgroup of the AMPLITUDE Study Endpoints AKEEGA (N=162) Placebo +Abiraterone Acetate (N=161) NE = not estimable Radiographic Progression-free Survival Investigator-assessed Events 48 (30%) 82(51%) Median (95% CI) time to event (months) NE (41, NE) 26 (18, 28) Hazard Ratio (95% CI) Calculated using an unstratified Cox proportional hazards model 0.46 (0.32, 0.66) At the first interim analysis for OS, 91 deaths occurred in the BRCA2 m population, 36 [22%] in the AKEEGA arm) and 55 [34%] in the placebo and abiraterone acetate arm.

Figure 1: Kaplan-Meier Plot of Radiographic Progression-Free Survival in the BRCA2 m Population (AMPLITUDE) Treatment with AKEEGA resulted in a delay in TSP (HR = 0.41, 95% CI= 0.26, 0.65). TSP was defined as the time from randomization to the time of symptomatic progression, which included use of external beam radiation for skeletal or pelvic symptoms, cancer-related morbid events, initiation of new systemic anti-cancer therapy, and other cancer-related procedures. Chemical Structure

14.2BRCA -mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC) The efficacy of AKEEGA was investigated in Cohort 1 of MAGNITUDE (NCT03748641), a randomized double-blind, placebo-controlled, multi-cohort, multi… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Niraparib Carcinogenicity studies have not been conducted with niraparib. Niraparib was clastogenic in an in vitro mammalian chromosomal aberration assay and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of niraparib and indicates potential for genotoxicity in humans.

Niraparib was not mutagenic in a bacterial reverse mutation assay (Ames) test. Fertility studies in animals have not been conducted with niraparib. In repeat-dose oral toxicity studies, niraparib was administered daily for up to 3 months' duration in rats and dogs.

Reduced sperm, spermatids, and germ cells in epididymides and testes were observed at doses ≥10 mg/kg and ≥1.5 mg/kg in rats and dogs, respectively. These dose levels resulted in systemic exposures approximately 0.5 and 0.02 times, respectively, the human exposure (AUC 0–24h ) at the dose of 200 mg daily. There was a trend toward reversibility of these findings 4 weeks after dosing was stopped.

Abiraterone Acetate A two-year carcinogenicity study was conducted in rats at oral abiraterone acetate doses of 5, 15, and 50 mg/kg/day for males and 15, 50, and 150 mg/kg/day for females. Abiraterone acetate increased the combined incidence of interstitial cell adenomas and carcinomas in the testes at all dose levels tested. This finding is considered to be related to the pharmacological activity of abiraterone.

Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Abiraterone acetate was not carcinogenic in female rats at exposure levels up to 0.8 times the human clinical exposure (1,000 mg daily) based on AUC. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse.

Abiraterone acetate and abiraterone were not mutagenic in an in vitro microbial mutagenesis (Ames) assay or clastogenic in an in vitro cytogenetic assay using primary human lymphocytes or an in vivo rat micronucleus assay. In repeat-dose toxicity studies in male rats (13- and 26-weeks) and monkeys (39-weeks), atrophy, aspermia/hypospermia, and hyperplasia in the reproductive system were observed at ≥50 mg/kg/day in rats and ≥250 mg/kg/day in monkeys and were consistent with the antiandrogenic pharmacological activity of abiraterone.

These effects were observed in rats at systemic exposures similar to humans and in monkeys at exposures approximately 0.6 times the AUC in humans at 1,000 mg daily. In a fertility study in male rats, reduced organ weights of the reproductive system, sperm counts, sperm motility, altered sperm morphology and decreased fertility were observed in animals dosed for 4 weeks at ≥30 mg/kg/day orally. Mating of untreated females with males that received 30 mg/kg/day oral abiraterone acetate resulted in a reduced number of corpora lutea, implantations and live embryos and an increased incidence of pre-implantation loss.

Effects on male rats were reversible after 16 weeks from the last abiraterone acetate administration. In a fertility study in female rats, animals dosed orally for 2 weeks until day 7 of pregnancy at ≥30 mg/kg/day had an increased incidence of irregular or extended estrous cycles and pre-implantation loss (300 mg/kg/day). There were no differences in mating, fertility, and litter parameters in female rats that received abiraterone acetate.

Effects on female rats were reversible after 4 weeks from the last abiraterone acetate administration. The dose of 30 mg/kg/day in rats is approximately 0.3 times the recommended dose of 1,000 mg/day based on body surface area. In 13- and 26-week studies in rats and 13- and 39-week studies in monkeys, a reduction in circulating testosterone levels occurred with abiraterone acetate at approximately one half the human clinical exposure based on AUC.

As a result, decreases in organ weights and toxicities were o… [Excerpted — this section continues on DailyMed.]