Introduction

Apalutamide and darolutamide are androgen receptor inhibitors approved for treating non-metastatic castration-resistant prostate cancer (nmCRPC). In phase 3 trials (SPARTAN for apalutamide, ARAMIS for darolutamide), both combined with androgen deprivation therapy (ADT) significantly improved metastasis-free and overall survival vs placebo.

Aim 

The study compared the efficacy and tolerability of apalutamide + ADT versus darolutamide + ADT for treating non-metastatic castration-resistant prostate cancer (nmCRPC) using a matching-adjusted indirect comparison (MAIC). 

Patient Profile 

Methods 

• Matching-adjusted indirect comparison (MAIC)  
• Individual patient data from the SPARTAN study (apalutamide + ADT vs. placebo + ADT) and ARAMIS study (darolutamide + ADT vs. placebo + ADT) was analysed
• Patients from SPARTAN were weighted to match baseline characteristics reported in ARAMIS, such as age, PSA levels, PSA doubling time, ECOG performance status, and other clinically relevant factors. 

Study Endpoints

• Primary endpoint: Metastasis-free survival (MFS). 
• Secondary endpoints: PSA progression, progression-free survival (PFS), overall survival (OS), and tolerability (adverse events and serious adverse events). 
• Hazard ratios (HRs) and odds ratios (ORs) were calculated using Bayesian network meta-analysis. 
• Fixed-effects models were used due to limited data variability. 

Results 

Efficacy

• Metastasis-Free Survival (MFS): Apalutamide + ADT showed a higher probability of being more effective than darolutamide + ADT ( HR: 0.70; Bayesian probability: 98.3%). 
• Prostate-Specific Antigen (PSA) Progression: Apalutamide + ADT was more effective (HR: 0.46; Bayesian probability: ~100%). 
• Progression-Free Survival (PFS): Apalutamide + ADT had a higher probability of effectiveness (HR: 0.79; Bayesian probability: 93.2%). 
• Overall Survival (OS): Both treatments showed similar results (HR: 1.02; Bayesian probability: 45.8%).

Table 1 : Efficacy of apalutamide + ADT versus darolutamide + ADT

Efficacy Endpoint	Apalutamide + ADT vs. Placebo + ADT (SPARTAN, Original)	Darolutamide + ADT vs. Placebo + ADT (ARAMIS)	Apalutamide + ADT vs. Placebo + ADT (SPARTAN, Reweighted)	Apalutamide + ADT vs. Darolutamide + ADT (MAIC)	Probability of HR < 1
Primary: Metastasis-Free Survival (MFS)	HR: 0.28	HR: 0.41	HR: 0.29	HR: 0.70	98.3%
Secondary: PSA Progression	HR: 0.06	HR: 0.13	HR: 0.06	HR: 0.46	~100%
Secondary: Progression-Free Survival (PFS)	HR: 0.29	HR: 0.38	HR: 0.30	HR: 0.79	93.2%
Secondary: Overall Survival (OS, IA1)	HR: 0.70	HR: 0.71	HR: 0.75	HR: 1.05	43.5%
Secondary: Overall Survival (OS, IA2 Updated)	HR: 0.75	HR: 0.69	HR: 0.71	HR: 1.02	45.8%

HR: Hazard Ratio; ADT: Androgen Deprivation Therapy ;MAIC: Matching-Adjusted Indirect Comparison ;IA: Interim Analysis ;CrI: Credible Interval 

Tolerability

Table 2: Tolerability of apalutamide + ADT or darolutamide + ADT in each study and in the matching-adjusted indirect

	Tolerability endpoint
	Any adverse event	Any serious adverse event
Apalutamide + ADT versus placebo + ADT (SPARTAN, Original	2.01	1.10
Darolutamide+ ADT versus placebo + ADT (ARAMIS)	1.49	1.32
Apalutamide+ ADT versus placebo ADT (SPARTAN)	1.52	1.20
Apalutamide +  ADT versus darolutamide + ADT (matching-adjusted, indirect comparison) OR (95% CrI)	1.02	0.91
Probability of OR < 1	48	64

ADT androgen deprivation therapy, CrI credible interval, OR odds ratio

Conclusion

Apalutamide + ADT is more effective for MFS, PSA progression, and PFS, while both treatments have similar OS and tolerability profiles. 

Reference

Adv Ther.2022;39:518–531