Akeega

Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, ATC code: L01XK52 Mechanism of action 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 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 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). Pharmacodynamic effects Abiraterone acetate 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. Clinical efficacy and safety First-line treatment of mCRPC patients with BRCA 1/2 mutations 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) Akeega+P 1 N=113 n (%) Placebo+AAP 1 N=112 n (%) Total N=225 n (%) Age (years) < 65 39 (34.5) 37 (33.0) 76 (33.8) ≥ 65-74 44 (38.9) 52 (46.4) 96 (42.7) ≥ 75 30 (26.5) 23 (20.5) 53 (23.6) Median 67.0 68.0 68.0 Range 45-100 43-88 43-100 Race Caucasian 78 (69.0) 84 (75.0) 162 (72.0) Asian 18 (15.9) 20 (17.9) 38 (16.9) Black 3 (2.7) 0 3 (1.3) Unknown 14 (12.4) 8 (7.1) 22 (9.8) Stratification factors Past taxane-based chemotherapy exposure 26 (23.0) 29 (25.9) 55 (24.4) Past AR-targeted therapy exposure 6 (5.3) 5 (4.5) 11 (4.9) Prior AAP use 30 (26.5) 29 (25.9) 59 (26.2) Baseline disease characteristics Gleason score ≥ 8 83 (74.1) 72 (64.3) 155 (69.2) Bone involvement 99 (87.6) 93 (83.0) 192 (85.3) Visceral disease (liver, lung, adrenal gland, other) 26 (23.0) 22 (19.6) 48 (21.3) Metastasis stage at initial diagnosis (M1) 70 (61.9) 50 (44.6) 120 (53.3) Median time from initial diagnosis to randomisation (years) 2.00 2.31 2.26 Median time from mCRPC to first dose (years) 0.27 0.28 0.27 BPI-SF pain score last score before first dose) 0 1 to 3 > 3 57 (50.4) 51 (45.1) 5 (4.4) 57 (50.9) 40 (35.7) 15 (13.4) 114 (50.7) 91 (40.4) 20 (8.9) ECOG Performance Status Score 0 1 69 (61.1) 44 (38.9) 80 (71.4) 32 (28.6) 149 (66.2) 76 (33.8) 1 P=prednisone or prednisolone 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 Kaplan-Meier 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+P 1 (N=113) Placebo+AAP 1 (N=112) Radiographic Progression-free Survival 2 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 Survival 3 Hazard Ratio (95% CI) 0.788 (0.554, 1.120) 1 P=prednisone or prednisolone 2 Primary analysis/Interim analysis (data cut-off: 08OCT2021), with 18.6 months median follow-up 3 Final Analysis (data cut-off: 15May2023), with 35.9 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) Figure 2: Kaplan-Meier Plot of Overall Survival (MAGNITUDE Cohort 1, BRCA, final analysis) Paediatric population 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.