New-generation androgen receptor signaling inhibitors (ARSIs) in metastatic hormone-sensitive prostate cancer (mHSPC): pharmacokinetics, drug-drug interactions (DDIs), and clinical impact

Figures & data

Figure 1. Abiraterone acetate (a) and abiraterone (b).

Figure 2. Apalutamide (a) and N-desmethyl apalutamide(b).

Figure 3. Enzalutamide (a) and N-desmethyl enzalutamide(b).

Figure 4. Darolutamide (a) and Ketodarolutamide (b).

Table 1. Main drug-drug interactions (DDI) of ARSI administered in mHSPC patients.

Drug	Enzyme(s)	Known interaction(s)	Recommendations
AA	CYP3A4	Drugs that are strong inducers of CYP3A4 enzyme decrease the exposure to AA	Avoid concomitant use of AA and strong CYP3A4 inducers
	CYP2C8	AA inhibits CYP2C8 enzyme	Caution for concomitant use of AA and drugs substrates of CYP2C8
Apalutamide	CYP3A4, CYP2C19	Apalutamide is a strong inducer of CYP3A4 and CYP2C19 enzymes	Substitute concomitant medications if substrates of these enzymes or monitor their activity if continued
	UGT, BCRP, P-gp and OATP1B1	Apalutamide is a potential inducer of UGT and a weak inducer of BCRP, P-gp and OATP1B1	Caution for concomitant use of apalutamide and substrates of these enzymes
	CYP2C8	Apalutamide inhibits CYP2C8 enzyme	Caution for concomitant use of apalutamide and substrates of CYP2C8
Enzalutamide	CYP2C8	Drugs that are strong inhibitors of CYP2C8 increase the exposure to enzalutamide and its metabolites	Reduce the dose of enzalutamide to 80 mg QD during concomitant use with a strong CYP2C8 inhibitor
	CYP2C9, CYP2C19, CYP3A4	Enzalutamide is a moderate inducer of CYP2C9/19 and a strong inducer of CYP3A4	Avoid concomitant use of enzalutamide and drugs substrates of CYP2C9/19 or CYP3A4
Darolutamide	CYP3A4	Darolutamide is mainly metabolized by CYP3A4	Avoid concomitant use of darolutamide and CYP3A4 inducers
			Monitor more closely for the development of AEs when darolutamide is used with CYP3A4 inhibitors
	P-gp	Darolutamide is a substrate for P-gp	Avoid concomitant use of darolutamide and P-gp inducers
			Monitor more closely for the development of AEs when darolutamide is used with P-gp inhibitors
	BCRP	Darolutamide inhibits BCRP	Avoid concomitant use of darolutamide and BCRP substrates

Abbreviations: AA, abiraterone acetate; AEs, adverse events; P-gp, P-glycoprotein; QD, once daily.

Table 2. Clinical trials with ARSI in mHSPC patients.

Drug	Trial	Arms	Primary endpoints
AAP	LATITUDE	- ADT + AAP - ADT + placebo	rPFS (HR: 0.47, p < 0.001) OS (HR: 0.62, p < 0.001)
	STAMPEDE	- ADT + AAP – ADT	OS (HR: 0.63, p < 0.001)
Apalutamide	TITAN	- ADT + apalutamide - ADT + placebo	PFS at 24 months (HR: 0.48; p < 0.001) OS at 24 months (HR: 0.67; p = 0.005)
Enzalutamide	ENZAMET	- ADT + enzalutamide - ADT + standard NSAA	OS (HR: 0.67, p = 0.002)
	ARCHES	- ADT + enzalutamide - ADT + placebo	rPFS (HR: 0.39; p < 0.001)
Darolutamide	ARASENS	- ADT + docetaxel + darolutamide - ADT + docetaxel + placebo	OS (HR: 0.68, p < 0.001).

Abbreviations: AAP, abiraterone acetate + prednisone; ADT, androgen deprivation therapy; mo., months; HR, hazard ratio; NSAA, nonsteroidal antiandrogen therapy; OS, overall survival; PFS, progression-free survival; rPFS, radiographic progression-free survival.