Enzalutamide-resistant castration-resistant prostate cancer: challenges and solutions

Figures & data

Table 1 Proposed strategies to overcome enzalutamide mechanism of resistance, approved drugs and ongoing clinical trial

Mechanism of resistance	How to overcome it	Ongoing clinical trials	Status (updated to March 2018)	Approved drug and relative clinical trial
AR overexpression	Enzalutamide+testosterone	NCT2286921: Phase II	Recruiting
		NCT2090114: Phase II	Recruiting
AR mutations	Darolutamide	NCT2200614 – ARAMIS trial: Phase III	Active, not recruiting
		NCT3314324 – ODENZA trial: Phase II	Recruiting
	Darolutamide+docetaxel	NCT2799602 – ARASENS trial: Phase III	Recruiting
	Apalutamide			SPARTAN trial: Phase III → FDA approval in nonmetastatic high-risk CRPC
	Apalutamide+abiraterone	NCT2257736: Phase III	Active, not recruiting
		NCT3360721: Phase II	Recruiting
		NCT3098836: Phase II	Recruiting
		NCT3173859: Phase II	Not yet recruiting
	Apalutamide+docetaxel	NCT3093272: Phase II	Recruiting
	Apalutamide+docetaxel+abiraterone	NCT2913196: Phase I	Recruiting
	Apalutamide+everolimus	NCT2106507: Phase I	Active, not recruiting
ARvs	EPI-506 (NTTD-binding AR antagonist)	NCT2606123: Phase I/II	Accrual terminated
	Enzalutamide+niclosamide (ARV7 proteasomic degradation)	NCT3123978: Phase I	Recruiting
		NCT2532114: Phase I	Active, not recruiting
	Enzalutamide+ZEN003694 (BET inhibitor)	NCT2711956: Phase I/II	Recruiting
	Enzalutamide+GS-5829 (BET inhibitor)	NCT2607228: Phase I/II	Active, not recruiting
	Enzalutamide+GSK525762 (BET inhibitor)	NCT3150056: Phase I	Recruiting
Altered steroidogenesis	Enzalutamide+indomethacin (AKR1c inhibitor)	NCT2935205: Phase I/II	Recruiting
Glucocorticoids receptor	Dexamethasone	NCT2491411: pilot study	Recruiting
	Enzalutamide+CORT125281	NCT3437941: Phase I/II	Recruiting
	Enzalutamide+mifepristone (GR and PgR antagonist)	NCT2012296: Phase I/II	Recruiting
EMT	Enzalutamide+metformin (TGF-β1/STAT3 inhibitor)	NCT2339168: Phase I	Recruiting
		NCT2640534: Phase II	Recruiting
	Enzalutamide+LY2157299 (TGF-β inhibitor)	NCT2452008: Phase II	Recruiting
Neuroendocrine transformation	Alisertib (AUR-KA inhibitor)	NCT1799278: Phase II	Completed
Activation of other pathways	Enzalutamide+AZD5363 (AKT inhibitor)	NCT3310541: Phase I	Recruiting
		NCT2525068: Phase II	Recruiting
	Enzalutamide+GSK2636771 (PI3K-β inhibitor)	NCT2215096: Phase I	Recruiting
	Enzalutamide+BI836845 (IGF1/2 inhibitor)	NCT2204072: Phase Ib/II	Active, not recruiting
	Enzalutamide+everolimus (mTOR inhibitor)	NCT2125084: Phase I	Active, not recruiting
	Enzalutamide+CC-115 (mTOR inhibitor)	NCT2833883: Phase I	Recruiting
	MLN0128 (mTOR inhibitor)	NCT2091531: Phase II	Active, not recruiting
	Enzalutamide+LY3023414 (PI3K/mTOR dual inhibitor)	NCT2407054: Phase II	Recruiting
Immune system activation	Enzalutamide+pembrolizumab (anti-PD-1 checkpoint inhibitor)	NCT2861573 – KEYNOTE 365: Phase I	Recruiting
		NCT2787005 – KEYNOTE 199: Phase II	Recruiting
	Enzalutamide+nivolumab (anti-PD-1 checkpoint inhibitor)	NCT3338790 – Checkmate 9KD: Phase II	Recruiting
	Enzalutamide+atezolizumab (anti-PD-L1 checkpoint inhibitor)	NCT3016312 – IMbassador250: Phase III	Recruiting
	Enzalutamide+AZD5069 (CXCR2 inhibitor)	NCT3177187: Phase I/II	Not yet recruiting
	Sipuleucel-T (autologous cellular immunotherapy)			IMPACT study – FDA approval in mCRPC
Association with chemotherapy	Enzalutamide+docetaxel	NCT3246347: Phase II	Recruiting
		NCT2288247: Phase III	Active, not recruiting
	Enzalutamide+cabazitaxel	NCT2522715: Phase I/II	Recruiting
	Enzalutamide+prednisone+cabazitaxel+abiraterone	NCT3110588	Not yet recruiting
PARP inhibitors	Rucaparib	NCT2975934: Phase III	Recruiting
		NCT2952534 – TRITON2: Phase II	Recruiting
		NCT2975934 – TRITON3: Phase III	Recruiting
	Rucaparib+carboplatin+docetaxel	NCT3442556: Phase II	Active, not recruiting
	Olaparib	NCT3047135: Phase II	Recruiting
		NCT1078662: Phase II	Active, not recruiting
	Olaparib+abiraterone	NCT1972217: Phase II	Active, not recruiting
		NCT3012321: Phase II	Recruiting
	Olaparib+Radium-223	NCT3317392: Phase I/II	Recruiting
	Olaparib±cediranib	NCT2893917: Phase II	Recruiting
	Olaparib+MEDI4736 ± cediranib	NCT2484404: Phase I/II	Recruiting
	Talazoparib+avelumab	NCT3330405: Phase I/II	Recruiting
	Veliparib	NCT892736: Phase I	Active, not recruiting
	Veliparib+abiraterone	NCT1576172: Phase II	Active, not recruiting
	Niraparib	NCT2854436: Phase II	Recruiting

Abbreviations: AR, androgen receptor; ARvs, AR splice variants; CRPC, castration-resistant prostate cancer; EMT, epithelial–mesenchymal transition; FDA, Food and Drug Administration; GR, glucocorticoid receptor; mCRPC, metastatic CRPC; NTTD, N-terminal transactivation domain; PARP, poly(ADP-ribose) polymerase; PgR, progesterone.