Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents
ATC code: L01XK
Akeega is a combination of niraparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), and abiraterone acetate (a prodrug of abiraterone), a CYP17 inhibitor targeting two oncogenic dependencies in patients with mCRPC and HRR gene mutations.
Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which 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.
Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor. Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in, and is required for, androgen biosynthesis in testicular, adrenal and prostatic tumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosterone precursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage of the C17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals (see section 4.4).
Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with luteinising hormone releasing hormone (LHRH) analogues or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumour. Treatment with abiraterone decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRH analogues (or orchiectomy).
Abiraterone decreases serum testosterone and other androgens to levels lower than those achieved by the use of LHRH analogues alone or by orchiectomy. This results from the selective inhibition of the CYP17 enzyme required for androgen biosynthesis.
The efficacy of Akeega was established in a randomised placebo-controlled multicentre Phase 3 clinical study of patients with mCRPC, MAGNITUDE (Study 64091742PCR3001).
MAGNITUDE was a Phase 3, randomised, double-blind, placebo-controlled, multicentre study that evaluated treatment with the combination of niraparib (200 mg) and abiraterone acetate (1 000 mg) plus prednisone (10 mg) daily versus AAP standard of care. Efficacy data are based on Cohort 1 that consisted of 423 patients with mCRPC and select HRR gene mutations, who were randomised (1:1) to receive either niraparib plus AAP (N=212) or placebo plus AAP (N=211) orally daily. Treatment was continued until disease progression, unacceptable toxicity, or death.
Patients with mCRPC who had not received prior systemic therapy in the mCRPC setting except for a short duration of prior AAP (up to 4 months) and ongoing ADT, were eligible. Plasma, blood, and/or tumour tissue samples for all patients were tested by validated next generation sequencing tests to determine germline and/or somatic HRR gene mutation status. There were 225 subjects with a BRCA1/2 mutation enrolled in the study (113 received Akeega). There were an additional 198 patients with a non-BRCA1/2 mutation (ATM, CHEK2, CDK12, PALB2, FANCA, BRIP1, HDAC2) enrolled in the study (99 received Akeega).
The primary endpoint was radiographic progression free survival (rPFS) as determined by blinded independent central radiology (BICR) review based on Response Evaluation Criteria In Solid Tumours (RECIST) 1.1 (soft and tissue lesions) and Prostate Cancer Working Group-3 (PCWG-3) criteria (bone lesions). Time to symptomatic progression (TSP), time to cytotoxic chemotherapy (TCC), and overall survival (OS) were included as secondary efficacy endpoints.
In the All HRR Population, the primary efficacy results with a median follow-up of 18.6 months showed statistically significant improvement in BICR-assessed rPFS with a HR =0.729 (95% CI: 0.556, 0.956; p=0.0217).
Table 4 summarises the demographics and baseline characteristics of BRCA patients enrolled in Cohort 1 of the MAGNITUDE study. The median PSA at diagnosis was 41.07 ug/L (range 01-12080). All patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry. All patients who had not received prior orchiectomy continued background androgen deprivation therapy with a GnRH analogue.
Table 4. Summary of demographics and baseline characteristics in the MAGNITUDE study Cohort 1 (BRCA):
| Total N=225 n (%) | |
|---|---|
| Age (years) | |
| <65 | 76 (33.8) |
| ≥65-74 | 96 (42.7) |
| ≥75 | 53 (23.6) |
| Median | 68.0 |
| Range | 43-100 |
| Race | |
| Caucasian | 162 (72.0) |
| Asian | 38 (16.9) |
| Black | 3 (1.3) |
| Unknown | 22 (9.8) |
| Stratification factors | |
| Past taxane-based chemotherapy exposure | 55 (24.4) |
| Past AR-targeted therapy exposure | 11 (4.9) |
| Prior AAP use | 59 (26.2) |
| Baseline disease characteristics | |
| Gleason score ≥ 8 | 155 (69.2) |
| Bone involvement | 192 (85.3) |
| Visceral disease (liver, lung, adrenal gland, other) | 48 (21.3) |
| Metastasis stage at initial diagnosis (M1) | 120 (53.3) |
| Median time from initial diagnosis to randomization (years) | 2.26 |
| Median time from mCRPC to first dose (years) | 0.27 |
| BPI-SF pain score at baseline (last score before first dose) 0 1 to 3 >3 | 114 (50.7) 91 (40.4) 20 (8.9) |
A statistically significant improvement in BICR-assessed rPFS was observed in the primary analysis for BRCA subjects treated with niraparib plus AAP, compared with BRCA subjects treated with placebo plus AAP. Key efficacy results in the BRCA population are presented in Table 5. The KaplanMeier curves for BICR assessed rPFS in the BRCA population are shown in Figure 1.
Table 5. Efficacy results from the BRCA population of the MAGNITUDE study:
| Endpoints | Akeega (N=113) | Placebo (N=112) |
|---|---|---|
| Radiographic Progression-free Survival1 | ||
| Event of disease progression or death (%) | 45 (39.8%) | 64 (57.1%) |
| Median, months (95% CI) | 16.6 (13.9, NE) | 10.9 (8.3, 13.8) |
| Hazard Ratio (95% CI) | 0.533 (0.361, 0.789) | |
| p-value | 0.0014 | |
| Overall Survival2 | ||
| Hazard Ratio (95% CI) | 0.881 (0.582, 1.335) | |
1 Primary analysis/Interim analysis (data cut-off: 08OCT2021), with 18.6 months median follow-up
2 Interim analysis 2 (data cut-off: 17JUN2022), with 26.8 months median follow-up
NE = Not estimable
Figure 1. Kaplan-Meier Plot of BICR assessed radiologic progression-free survival in the BRCA population (MAGNITUDE, primary analysis):
The European Medicines Agency has waived the obligation to submit the results of studies with Akeega in all subsets of the paediatric population in prostate malignant neoplasms. See section 4.2 for information on paediatric use.
Co-administration of niraparib and abiraterone has no impact on the exposures of the individual moeities. The AUC and Cmax are comparable for niraparib and abiraterone when administered as Akeega regular strength (100 mg/500 mg) film-coated tablet or as combination of individual components when compared to respective monotherapy exposures.
In mCRPC patients, under fasted and modified fasted conditions, upon administration of multiple doses of Akeega tablets, the maximum plasma concentration was achieved within a median of 3 hours for niraparib, and a median of 1.5 hours for abiraterone.
In a relative bioavailability study, the maximum (Cmax) and total (AUC0-72h) exposure of abiraterone in mCRPC patients (n=67) treated with Akeega lower strength film-coated tablets (2 × 50 mg/500 mg) was 33% and 22% higher, respectively, when compared to exposures in patients (n=67) taking individual single agents (100 mg niraparib capsule and 4 × 250 mg abiraterone acetate tablets) (see section 4.2). The inter-subject variability (CV) in exposures were 80.4 and 72.9%, respectively. Niraparib exposure was comparable between Akeega lower strength film-coated tablets and single agents.
The absolute bioavailability of niraparib is approximately 73%. Niraparib is a substrate of Pglycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). However, due to its high permeability and bioavailability, the risk of clinically relevant interactions with medicinal products that inhibit these transporters is unlikely.
Abiraterone acetate is rapidly converted in vivo to abiraterone (see section 5.1). 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 (Cmax) 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 highly variable exposures. Therefore, abiraterone acetate must not be taken with food.
Based on population pharmacokinetic analysis, the apparent volume of distribution of niraparib and abiraterone were 1,117 L and 25,774 L, respectively, indicative of extensive extravascular distribution.
Niraparib was moderately protein-bound in human plasma (83.0%), mainly with serum albumin.
The plasma protein binding of 14C-abiraterone in human plasma is 99.8%.
Niraparib is metabolised primarily by carboxylesterases (CEs) to form a major inactive metabolite, M1. In a mass balance study, M1 and M10 (the subsequently formed M1 glucuronides) were the major circulating metabolites. The potential to inhibit CYP3A4 at the intestinal level has not been established at relevant niraparib concentrations. Niraparib weakly induces CYP1A2 at high concentrations in vitro.
Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolysed by CEs to abiraterone, which then undergoes metabolism including sulphation, hydroxylation and oxidation primarily in the liver. Abiraterone is a substrate of CYP3A4 and sulfotransferase 2A1 (SULT2A1). The majority of circulating radioactivity (approximately 92%) is found in the form of metabolites of abiraterone. Of 15 detectable metabolites, two main metabolites, abiraterone sulphate and N-oxide abiraterone sulphate, each represents approximately 43% of total radioactivity. Abiraterone is an inhibitor of the hepatic drug metabolising enzymes CYP2D6 and CYP2C8 (see section 4.5).
The mean t½ of niraparib and abiraterone when given in combination were approximately 62 hours and 20 hours, respectively, and apparent CL/F of niraparib and abiraterone were 16.7 L/h and 1673 L/h, respectively based on the population pharmacokinetic analysis in subjects with mCRPC.
Niraparib is eliminated primarily through the hepatobiliary and renal routes. Following an oral administration of a single 300 mg dose of [14C]-niraparib, on average 86.2% (range 71% to 91%) of the dose was recovered in urine and faeces over 21 days. Radioactive recovery in the urine accounted for 47.5% (range 33.4% to 60.2%) and in the faeces for 38.8% (range 28.3% to 47.0%) of the dose. In pooled samples collected over six days, 40.0% of the dose was recovered in the urine primarily as metabolites and 31.6% of the dose was recovered in the faeces primarily as unchanged niraparib. The metabolite M1 is a substrate of Multidrug And Toxin Extrusion (MATE) 1 and 2.
Following oral administration of 14C-abiraterone acetate 1 000 mg, approximately 88% of the radioactive dose is recovered in faeces and approximately 5% in urine. The major compounds present in faeces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).
Niraparib inhibits P-gp weakly with an IC50=161 μM. Niraparib is an inhibitor of BCRP, Organic Cation Transporter 1 (OCT1), MATE-1 and 2 with IC50 values of 5.8 μM, 34.4 μM, 0.18 μM and ≤0.14 μM, respectively. The major metabolites of abiraterone, abiraterone sulphate and N-oxide abiraterone sulphate, were shown to inhibit the hepatic uptake transporter Organic Anion Transport Polypeptide 1B1 (OATP1B1) and as a consequence, the plasma exposures of medicinal products eliminated by OATP1B1 may increase. There are no clinical data available to confirm transporter OATP1B1 based interaction.
Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancer patients received niraparib alone or niraparib/AA in combination, mild hepatic impairment (NCIODWG criteria, n=231) did not affect the exposure of niraparib.
In a clinical study of cancer patients using NCI-ODWG criteria to classify the degree of hepatic impairment, niraparib AUCinf in patients with moderate hepatic impairment (n=8) was 1.56 (90% CI: 1.06 to 2.30) times the niraparib AUCinf in patients with normal hepatic function (n=9) following administration of a single 300 mg dose.
The pharmacokinetics of abiraterone was examined in subjects with pre-existing mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects. Systemic exposure to abiraterone after a single oral 1,000 mg dose increased by approximately 1.11-fold and 3.6-fold in subjects with mild and moderate pre-existing hepatic impairment, respectively.
In another study, the pharmacokinetics of abiraterone were examined in subjects with pre-existing severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The AUC of abiraterone increased by approximately 7-fold and the fraction of free drug increased by 1.8-fold in subjects with severe hepatic impairment compared to subjects with normal hepatic function. There is no clinical experience using Akeega in patients with moderate and severe hepatic impairment (see section 4.2).
Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancer patients received niraparib alone or niraparib/AA in combination, patients with mild (creatinine clearance 60-90 mL/min, n=337) and moderate (creatinine clearance 30-60 mL/min, n=114) renal impairment had mildly reduced niraparib clearance compared to individuals with normal renal function (up to 13% higher exposure in mild and 13-40% higher exposure in moderate renal impairment).
The pharmacokinetics of abiraterone was compared in patients with end-stage renal disease on a stable haemodialysis schedule (n=8) versus matched control subjects with normal renal function (n=8). Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in subjects with end-stage renal disease on dialysis. There is no clinical experience using Akeega in patients with severe renal impairment (see section 4.2).
Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancer patients received niraparib or abiraterone acetate alone or in combination:
No studies have been conducted to investigate the pharmacokinetics of Akeega in paediatric patients.
Non-clinical studies with Akeega have not been performed. The nonclinical toxicology data are based on findings in studies with niraparib and abiraterone acetate individually.
In vitro, niraparib inhibited the dopamine transporter at concentration levels below human exposure levels. In mice, single doses of niraparib increased intracellular levels of dopamine and metabolites in cortex. Reduced locomotor activity was seen in one of two single dose studies in mice. The clinical relevance of these findings is not known. No effect on behavioural and/or neurological parameters have been observed in repeat-dose toxicity studies in rats and dogs at estimated CNS exposure levels similar to or below expected therapeutic exposure levels.
Decreased spermatogenesis was observed in both rats and dogs at exposure levels below therapeutic exposure levels and were largely reversible within four weeks of cessation of dosing.
Niraparib was not mutagenic in a bacterial reverse mutation assay (Ames) test but 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.
Reproductive and developmental toxicity studies have not been conducted with niraparib.
Carcinogenicity studies have not been conducted with niraparib.
In animal toxicity studies, circulating testosterone levels were significantly reduced. As a result, reduction in organ weights and morphological and/or histopathological changes in the reproductive organs, and the adrenal, pituitary and mammary glands were observed. All changes showed complete or partial reversibility. The changes in the reproductive organs and androgen-sensitive organs are consistent with the pharmacology of abiraterone. All treatment-related hormonal changes reversed or were shown to be resolving after a 4-week recovery period.
In fertility studies in both male and female rats, abiraterone acetate reduced fertility, which was completely reversible in four to 16 weeks after abiraterone acetate was stopped.
In a developmental toxicity study in the rat, abiraterone acetate affected pregnancy including reduced foetal weight and survival. Effects on the external genitalia were observed though abiraterone acetate was not teratogenic.
In these fertility and developmental toxicity studies performed in the rat, all effects were related to the pharmacological activity of abiraterone.
Aside from reproductive organ changes seen in all animal toxicology studies, non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse. In a 24-month carcinogenicity study in the rat, abiraterone acetate increased the incidence of interstitial cell neoplasms in the testes. This finding is considered related to the pharmacological action of abiraterone and rat-specific. Abiraterone acetate was not carcinogenic in female rats.
The active substance, abiraterone, shows an environmental risk for the aquatic environment, especially to fish (see section 6.6).
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