Abstract
Apalutamide, an androgen receptor signaling inhibitor, in combination with androgen-deprivation therapy (ADT), is approved for treatment of patients with nonmetastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer, based on the data from the phase 3 SPARTAN and TITAN studies respectively. Apalutamide is an inducer of cytochrome P450 enzymes and P-glycoprotein, which are involved in the metabolism of oral anticoagulants (OACs) and may thus have potential drug-drug interactions when co-administered with OACs. Concomitant use of certain OACs such as apixaban, rivaroxaban, edoxaban, dabigatran, and warfarin was allowed in the SPARTAN and TITAN studies. A post-hoc analysis was conducted to evaluate the incidence of treatment-emergent thrombotic and embolic adverse events (AEs) in patients receiving concomitant OACs with apalutamide + ADT or placebo + ADT in both the studies. Anticoagulants were identified by WHO Drug Anatomical Therapeutic Chemical level 4 classifications. Thrombotic and embolic AEs were coded using the Medical Dictionary for Regulatory Activities Version 22.1. Data were analyzed from patients receiving concurrent OACs among all treated patients in SPARTAN (apalutamide + ADT: 95/803 [11.8%]; placebo + ADT: 48/398 [12.1%]) and TITAN (apalutamide + ADT: 31/524 [5.9%]; placebo + ADT: 28/527 [5.3%]). No consequential differences were observed in the occurrence of thrombotic and embolic events between apalutamide + ADT and placebo + ADT groups receiving concomitant OACs in SPARTAN (11.6% vs 12.5%) or TITAN (19.4% vs 21.4%). Grade 3/4 thrombotic and embolic AEs observed in patients receiving concomitant OACs with apalutamide + ADT or placebo + ADT were 6 (6.3%) vs 5 (10.4%) in SPARTAN and 3 (9.7%) vs 1 (3.6%) in TITAN. This analysis suggests that when necessary, concomitant OACs can be used with apalutamide with appropriate monitoring.
Keywords: Apalutamide, anti-coagulants, comedication, drug-drug interaction, thromboembolic adverse events
Introduction
Apalutamide, a next-generation, androgen receptor signaling inhibitor, is indicated in combination with androgen-deprivation therapy (ADT) for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) and metastatic castration-sensitive prostate cancer (mCSPC), based on data from two pivotal phase 3 trials, SPARTAN (NCT01946204) and TITAN (NCT02489318) [1]. The final analyses of these studies demonstrated that the long-term use of apalutamide plus ADT provided significant improvements in overall survival (SPARTAN and TITAN), radiographic progression-free survival (TITAN) and metastasis-free survival (SPARTAN) compared with ADT alone in the target population [2,3].
Incidence of prostate cancer increases with age, and an elderly population is more likely to have pre-existing comorbidities requiring anticoagulant treatment. Furthermore, men with prostate cancer have an increased risk for developing thromboembolic diseases, especially in patients receiving ADT [4].
Apalutamide and its pharmacologically active metabolite, N-desmethyl-apalutamide are predominantly eliminated by metabolic clearance, with formation of N-desmethyl-apalutamide, mediated by cytochrome P450 (CYP) 2C8 and CYP3A4 [1,5]. Apalutamide is a strong CYP3A4 and CYP2C19 inducer and a weak CYP2C9 and P-glycoprotein (P-gp) inducer. Co-administration of apalutamide with medications that are substrates of CYP3A4, CYP2C19, CYP2C9, or P-gp may result in lower exposure to these medications. Select CYP450 isoenzymes and transporters are involved in the metabolism of commonly used oral anticoagulants (OACs) such as apixaban, rivaroxaban, edoxaban, dabigatran, and warfarin (Table S1) [6-12]. Concomitant use of certain OACs was allowed in SPARTAN and TITAN studies. A post-hoc analysis of data from SPARTAN and TITAN studies was conducted to evaluate the incidence of treatment-emergent thrombotic and embolic adverse events (AEs) in patients who received concomitant OACs with apalutamide + ADT vs placebo + ADT.
Methods
In SPARTAN, 1207 patients with nmCRPC, receiving ongoing ADT, were randomized (2:1) to apalutamide (n=806) or matched placebo (n=401) [13]. In TITAN, 1052 patients with mCSPC were randomized (1:1) to receive apalutamide + ADT (n=525) or placebo + ADT (n=527) [14]. Full details of study design and eligibility criteria have been published elsewhere [13,14]. Investigators were informed of the potential drug-drug interactions of apalutamide with concomitant medications, particularly strong CYP3A4 inducers or drugs with a narrow therapeutic index and directed to monitor loss of efficacy for these medications.
The safety population in both studies was defined as all patients who received at least one dose of study drug. In the present post-hoc analysis, data from patients who did or did not receive concurrent OACs in SPARTAN and TITAN safety populations were analyzed. Descriptive post-hoc analyses were conducted to assess the occurrence of thrombotic and embolic AEs in the overall safety population and in the subgroups that did or did not receive OACs as concomitant medications in the SPARTAN and TITAN studies. Thrombotic and embolic AEs were identified using the Medical Dictionary for Regulatory Activities (MedDRA, Version 22.1) Embolic and Thrombotic Events Standardized MedDRA Query (SMQ). Anticoagulant medications were identified using the Anatomical Therapeutic Chemical (ATC) level 4 classifications (Direct factor Xa inhibitors, direct thrombin inhibitors, vitamin K antagonists) from the ATC level 2 classification of Antithrombotic agents: version 4.0 for SPARTAN and version 4.03 for TITAN.
Results
Data from patients who received concurrent OACs in SPARTAN (apalutamide + ADT: n=95/803 [11.8%]; placebo + ADT: n=48/398 [12.1%]) and TITAN (apalutamide + ADT: n=31/524 [5.9%]; placebo + ADT: n=28/527 [5.3%]) safety populations were analyzed (Figure 1). Further details on specific OACs received in SPARTAN and TITAN studies are provided in Tables S2 and S3, respectively.
Figure 1.
Patient disposition. All patients received a concomitant gonadotropin-releasing hormone analog or had a bilateral orchiectomy. Patients were excluded if they had evidence of severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events, or clinically significant ventricular arrhythmias within 6 months before randomization.
The post-hoc analysis of SPARTAN data showed that the incidence of treatment-emergent thrombotic and embolic AEs was comparable between apalutamide + ADT (38 [4.7%]) and placebo + ADT (14 [3.5%]) groups in the overall safety population. The incidence of thrombotic and embolic AEs (any grade) was also similar in the subgroup receiving concomitant OACs with apalutamide + ADT (11 [11.6%]) and placebo + ADT (6 [12.5%]; Table 1). In SPARTAN, thrombotic and embolic AEs of grade 3/4 were reported in 6 (6.3%) patients in apalutamide + ADT group vs 5 (10.4%) in placebo + ADT group in the subgroup receiving concomitant OACs. With the very small number of grade 3/4 events observed on either of the two arms, essentially there was no difference in the rate of occurrence. Grade 3/4 events reported in apalutamide group were acute myocardial infarction, ischemic stroke, myocardial infarction, intracardiac thrombus, device occlusion and pulmonary embolism (n=1 each), and those reported in placebo group were acute myocardial infarction, stress cardiomyopathy, peripheral arterial occlusive disease (n=1 each), and pulmonary embolism (n=2). No grade 5 AEs were observed in either group. All events as reported in each arm of the SPARTAN study are listed in Table 2. Actual types of grade 3/4 AEs were slightly different on each of the arm; however, no further conclusion can be drawn due to relatively small number of events.
Table 1.
Occurrence of treatment-emergent thrombotic and embolic adverse events in the SPARTAN and TITAN studies (safety population)
| SPARTAN | TITAN | |||
|---|---|---|---|---|
|
|
|
|||
| Apalutamide + ADT | Placebo + ADT | Apalutamide + ADT | Placebo + ADT | |
| Safety population, n | 803 | 398 | 524 | 527 |
| Thrombotic and embolic TEAEs, n (%) | 38 (4.7) | 14 (3.5) | 22 (4.2) | 20 (3.8) |
| Number of patients who received concomitant OACs, n | 95 | 48 | 31 | 28 |
| Thrombotic and embolic TEAEs, n (%) | 11 (11.6) | 6 (12.5) | 6 (19.4) | 6 (21.4) |
| Number of patients who did not receive concomitant OACs, n | 708 | 350 | 493 | 499 |
| Thrombotic and embolic TEAEs, n (%) | 27 (3.8) | 8 (2.3) | 16 (3.2) | 14 (2.8) |
Percent is based on the safety population. Abbreviations: ADT, androgen-deprivation therapy; TEAEs, treatment emergent adverse events; OACs, oral anticoagulants.
Table 2.
Summary of treatment-emergent thrombotic and embolic adverse events for patients who received anticoagulant concomitant medications in SPARTAN study (safety population)
| Apalutamide + ADT (n=95) | Placebo + ADT (n=48) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
|
|
|
|||||||||
| Toxicity Grade | Toxicity Grade | |||||||||
|
|
|
|||||||||
| Any grade | 1 | 2 | 3 | 4 | Any grade | 1 | 2 | 3 | 4 | |
| Patients with ≥1 TEAEs, n (%) | 11 (11.6) | 1 (1.1) | 4 (4.2) | 4 (4.2) | 2 (2.1) | 6 (12.5) | 0 | 1 (2.1) | 5 (10.4) | 0 |
| System Organ Class, n (%) | ||||||||||
| Cardiac disorders | 3 (3.2) | 0 | 0 | 2 (2.1) | 1 (1.1) | 2 (4.2) | 0 | 0 | 2 (4.2) | 0 |
| Acute myocardial infarction | 1 (1.1) | 0 | 0 | 1 (1.1) | 0 | 1 (2.1) | 0 | 0 | 1 (2.1) | 0 |
| Coronary artery occlusion | 1 (1.1) | 0 | 1 (1.1) | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Intracardiac thrombus | 1 (1.1) | 0 | 0 | 1 (1.1) | 0 | 0 | 0 | 0 | 0 | 0 |
| Myocardial infarction | 1 (1.1) | 0 | 0 | 0 | 1 (1.1) | 0 | 0 | 0 | 0 | 0 |
| Stress cardiomyopathy | 0 | 0 | 0 | 0 | 0 | 1 (2.1) | 0 | 0 | 1 (2.1) | 0 |
| Nervous system disorders | 3 (3.2) | 1 (1.1) | 1 (1.1) | 0 | 1 (1.1) | 1 (2.1) | 0 | 1 (2.1) | 0 | 0 |
| Transient ischemic attack | 2 (2.1) | 1 (1.1) | 1 (1.1) | 0 | 0 | 1 (2.1) | 0 | 1 (2.1) | 0 | 0 |
| Ischemic stroke | 1 (1.1) | 0 | 0 | 0 | 1 (1.1) | 0 | 0 | 0 | 0 | 0 |
| Vascular disorders | 3 (3.2) | 0 | 3 (3.2) | 0 | 0 | 1 (2.1) | 0 | 0 | 1 (2.1) | 0 |
| Deep vein thrombosis | 3 (3.2) | 0 | 3 (3.2) | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Peripheral arterial occlusive disease | 0 | 0 | 0 | 0 | 0 | 1 (2.1) | 0 | 0 | 1 (2.1) | 0 |
| Respiratory, thoracic, and mediastinal disorders | 1 (1.1) | 0 | 0 | 1 (1.1) | 0 | 2 (4.2) | 0 | 0 | 2 (4.2) | 0 |
| Pulmonary embolism | 1 (1.1) | 0 | 0 | 1 (1.1) | 0 | 2 (4.2) | 0 | 0 | 2 (4.2) | 0 |
| Product issues | 1 (1.1) | 0 | 0 | 1 (1.1) | 0 | 0 | 0 | 0 | 0 | 0 |
| Device occlusion | 1 (1.1) | 0 | 0 | 1 (1.1) | 0 | 0 | 0 | 0 | 0 | 0 |
Percent is based on the safety population. Abbreviations: ADT, androgen-deprivation therapy; TEAEs, treatment emergent adverse events.
Similarly, the post-hoc analysis of TITAN data showed that the incidence of thrombotic and embolic AEs was comparable between apalutamide + ADT (22 [4.2%]) and placebo + ADT (20 [3.8%]) groups in the overall safety population. The incidence of thrombotic and embolic AEs (any grade) was also similar in the subgroup receiving concomitant OACs with apalutamide + ADT (6 [19.4%]) and placebo + ADT (6 [21.4%]; Table 1). All events as reported in each arm of the TITAN study are listed in Table 3. Grade 3/4 thrombotic and embolic AEs were observed in 3 (9.7%) patients in apalutamide + ADT group, including pulmonary embolism (n=2) and cerebrovascular accident (n=1). One (3.6%) grade 3 AE of pulmonary embolism was reported in placebo + ADT group. One patient in apalutamide + ADT group reported grade 5 AE of myocardial infarction vs none in placebo + ADT group.
Table 3.
Summary of treatment-emergent thrombotic and embolic adverse events for patients who received anticoagulant concomitant medications in TITAN study (safety population)
| Apalutamide + ADT (n=31) | Placebo + ADT (n=28) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
|
|
|||||||||||
| Toxicity Grade | Toxicity Grade | |||||||||||
|
|
|
|||||||||||
| Any grade | 1 | 2 | 3 | 4 | 5 | Any grade | 1 | 2 | 3 | 4 | 5 | |
| Patients with ≥1 TEAEs, n (%) | 6 (19.4) | 0 | 2 (6.5) | 2 (6.5) | 1 (3.2) | 1 (3.2) | 6 (21.4) | 1 (3.6) | 4 (14.3) | 1 (3.6) | 0 | 0 |
| System Organ Class, n (%) | ||||||||||||
| Respiratory, thoracic, and mediastinal disorders | 2 (6.5) | 0 | 0 | 1 (3.2) | 1 (3.2) | 0 | 2 (7.1) | 0 | 1 (3.6) | 1 (3.6) | 0 | 0 |
| Pulmonary embolism | 2 (6.5) | 0 | 0 | 1 (3.2) | 1 (3.2) | 0 | 2 (7.1) | 0 | 1 (3.6) | 1 (3.6) | 0 | 0 |
| Cardiac disorders | 2 (6.5) | 0 | 1 (3.2) | 0 | 0 | 1 (3.2) | 0 | 0 | 0 | 0 | 0 | 0 |
| Myocardial infarction | 2 (6.5) | 0 | 1 (3.2) | 0 | 0 | 1 (3.2) | 0 | 0 | 0 | 0 | 0 | 0 |
| Vascular disorders | 1 (3.2) | 0 | 1 (3.2) | 0 | 0 | 0 | 3 (10.7) | 0 | 3 (10.7) | 0 | 0 | 0 |
| Deep vein thrombosis | 1 (3.2) | 0 | 1 (3.2) | 0 | 0 | 0 | 3 (10.7) | 0 | 3 (10.7) | 0 | 0 | 0 |
| Nervous system disorders | 1 (3.2) | 0 | 0 | 1 (3.2) | 0 | 0 | 1 (3.6) | 1 (3.6) | 0 | 0 | 0 | 0 |
| Cerebrovascular accident | 1 (3.2) | 0 | 0 | 1 (3.2) | 0 | 0 | 1 (3.6) | 1 (3.6) | 0 | 0 | 0 | 0 |
Percent is based on the safety population. Abbreviations: ADT, androgen-deprivation therapy; TEAEs, treatment emergent adverse events.
Discussion and conclusion
Between SPARTAN and TITAN, the two large phase 3, registrational studies of apalutamide, a total of 202 patients received OACs on either experimental or placebo arms. This post-hoc analysis did not find any consequential differences in the occurrence of thrombotic and embolic AEs between apalutamide and placebo groups receiving concomitant OACs. These findings are particularly relevant in advanced prostate cancer, which tends to affect older men who are at a higher risk of thromboembolic events.
Apalutamide is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9. Concomitant use of apalutamide with medications that are primarily metabolized by CYP3A4 (e.g., apixaban, rivaroxaban), CYP2C19, or CYP2C9 (e.g., warfarin) may result in lower exposure to these medications. Substitution for these medications or evaluation for loss of efficacy is recommended [1]. In patients in whom co-administration cannot be avoided, drug-interaction management should be individually tailored, and close monitoring is recommended.
Apalutamide was clinically shown to be a weak inducer of P-gp. Concomitant use of apalutamide with medications that are substrates of P-gp may result in lower exposure of these medications. Medications that are substrates of P-gp (e.g., apixaban, rivaroxaban, edoxaban, dabigatran etexilate) must be co-administered with caution, along with monitoring for loss of efficacy.
While our analysis is limited by the small subgroups and the post-hoc design; our results, nonetheless, underscore the need to consider larger studies in real-world settings to assess the incidence of thromboembolic AEs and clinical implications of drug-drug interactions following concurrent use of next-generation oral anti-androgens with OACs. Findings of the present analysis may help guide treating physicians to make appropriate risk-benefit decisions to administer apalutamide concomitantly with OACs in suitable settings with appropriate monitoring.
Acknowledgements
The authors would like to thank the patients, investigators, and their medical, nursing and laboratory staff who participated in the clinical studies included in the present work. Writing assistance was provided by Akshada Deshpande, PhD (SIRO Clinpharm Pvt. Ltd.) and additional editorial support was provided by Jennifer Han, MS and Harman Kaur, PharmD (Janssen Scientific Affairs, LLC). This analysis was conducted and supported by Janssen Scientific Affairs, LLC. The original trials were conducted and funded by Janssen Research & Development, LLC.
Disclosure of conflict of interest
Benjamin A Gartrell: Personal fees from Exelixis Inc, Pfizer, Janssen, Genomic Health, and EMD Serono, outside the submitted work. Robert Given: Speaker for Janssen, Myovant and Bayer; Investigator for research trials with Janssen, Bayer, Tavanta, Merck, and Pfizer. Lawrence Karsh: Honoraria from Astellas, Bayer, Janssen, Pfizer and Dendreon; Consultancy for 3D Biopsy, Astellas, Astra-Zeneca, Bayer, Dendreon, Ferring, Janssen, Pfizer, and Vaxiion; Speakers’ Bureau: Astellas, Bayer, Janssen, Pfizer, and Clovis; received Travel, Accommodations, Expenses from Astellas, Bayer, Janssen, Pfizer, and Dendreon; received research funding from Astellas, Astra Zeneca, Bayer, BioXcel Therapeutics, Bristol Meyers Squibb, CU Optics, CUSP, Dendreon, Epizyme, Exact Sciences, Ferring, FKD, Genentech/Roche, GenomeDx, Genomic Health, Janssen, Merck, Myovant, Nucleix, OncoCell MDx, Pfizer, Pharmtech/Veru, Precision Med, QED Therapeutics, Siemens, Urogen, and Vaxiion; Stock Owner: Swan Valley Medical. Jeffrey Frankel: Investigator for Urovant Sciences; Investigator and speaker for Astellas Pharma and Pfizer Inc.; Speaker for Tolmar Inc. Karen Nenno: Consulting fees from Karyopharm to participate in an advisory board. Kris O’MalleyLeFebvre: Nothing to disclose. Christopher Pieczonka: Consultancy: Dendreon, Bayer, Astra Zeneca, Merck, LUGPA, UroGPO, Janssen, Astellas, Pfizer, Foundation Medicine, Sun; Compensated Research Studies: Dendreon, Bayer, Astra Zeneca, Merck, Janssen, Astellas, Pfizer, Very, Eli-Lilly, Laekna. Rushikesh Potdar and Tracy McGowan: Employees of Janssen Pharmaceuticals and own stock in Johnson and Johnson, of which Janssen is a wholly owned subsidiary. Amitabha Bhaumik and Sharon McCarthy: Employees of Janssen Research & Development, LLC and own stock in Johnson & Johnson, of which Janssen Research & Development is a wholly owned subsidiary.
Tables S1-S3
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