Table 3.

Potential therapeutic combinations of AR antagonists with other agents.

Combined strategy	Examples	Preclinical or clinical evidence
AR antagonist+ Immunotherapy	Enza & CART cell (EPhA2)	Enza-induced EPhA2R expression in prostate cancer cells, as well as the ability of agonistic dimeric synthetic (135H12) and natural EPhA2R ligands to degrade EPhA2R and delay tumor migration and growth in mouse model [166].
AR antagonist+ AR cofactor inhibitor	Enza/Daro & GATA2/HSP90 inhibitor etc.	Enza/Daro combination with GATA2 inhibitor (K7174) inhibits PCa cell growth more effectively than Enza alone [104]. Co-targeting AR and HSP90 suppresses both PCa cell growth and Enza resistance. Bruceantin targeting of HSP90 overcomes resistance to hormone therapy in CRPC [167, 168].
AR pathway inhibitor (sequencing)	Abiraterone acetate followed by Enza	A multicenter, randomized, open-label, phase II, crossover trial has shown that a sequencing strategy of abiraterone acetate treatment followed by Enza provides a greater clinical benefit than the opposite treatment sequence [157].
AR antagonist+ AR independent target inhibitor	Enza & AU-15330 (PROTAC targets SWI/SNF)	AU-15330 induces potent inhibition of tumor growth in xenograft models and synergizes with Enza, even inducing disease remission in CRPC models without toxicity [169].
	Enza & Olaparib/Rucaparib (PARP inhibitor)	A RAMP phase Ib trial of rucaparib and Enza has shown safety and early efficacy [170]. Several clinical trials are underway to evaluate the potential of combinatorial therapy for mCRPC patients (NCT04455750/NCT03395197).
	AR antagonists & CDK4/6 inhibitor (e.g. palbociclib, abemaciclib)	The Cyclin-CDK-RB axis is critical to resistance to AR antagonists, and CDK inhibitors effectively inhibit cancer growth in vitro and in vivo [120, 171]. Clinical trials are underway to evaluate the combination of CDK-inhibitors with enzalutamide in CRPC patients (NCT03685591/NCT02555189).
AR antagonist+ radiotherapy	Enza & Stereotactic body radiotherapy/radium-223?	A study by Maughan et al. has shown the combination of Enza and radium-223 to be safe and associated with promising efficacy in men with mCRPC [172], while another group found limited benefit [173–175]. Metastasis-directed therapy (MDT) in mCRPC oligo-progressive lesions extends the efficacy of treatment with AR-targeted agents [176].