Enzalutamide for the treatment of metastatic castration-resistant prostate cancer

Figures & data

Figure 1 Mechanism of action of enzalutamide in the androgen receptor signaling pathway.

Abbreviations: AR, androgen receptor; T, testosterone; C, coactivators.

Table 1 Selected published clinical trials with enzalutamide in metastatic CRPC

Author (year)	Description	Patients (n)	Median age (range)	PSA decrease rates	Median time to PSA progression (months, 95% CI)	Measurable disease response	Median PFS (months, 95% CI)	Median OS (months, 95% CI)
Scher et al^Citation16 (2010)	Phase I/II dose-escalation trial in nonmetastatic and metastatic CRPC patients	140	68 (44–93)	<30%: 34.3% 30%–50%: 10% ≥50%: 55.7%	7.3 (4.8–10.3)	PR: 22% SD: 49% (n=59)	10.8 (7.8–NR)a	Not assessed
Scher et al^Citation5 (2012)	Phase III double-blind placebo-controlled trial in metastatic CRPC patients after chemotherapy (AFFIRM trial)	1,199	69 (41–92)	≥50%: 54% with E vs 2% with P (P<0.001) ≥90%: 25% with E vs 1% with P (P<0.001)	8.3 with E (5.8–8.3) vs 3.0 with P (2.9–3.7, HR 0.25, P<0.001)	PR + CR: 29% with E vs 4% with P (n=654, P<0.001)	8.3 with E (8.2–9.4) vs 2.9 with P (2.8–3.4, HR 0.40, 95% CI: 0.35–0.47, P<0.001)b	18.4 with E (17.3–NR) vs 13.6 with P (11.3–15.8, HR 0.63, 95% CI: 0.53–0.75, P<0.001)
Beer et al^Citation6 (2014)	Phase III double-blind placebo-controlled trial in metastatic chemotherapy-naïve CRPC patients (PREVAIL trial)	1,717	72 (43–93)	≥50%: 78% with E vs 3% with P (P<0.001) ≥90%: 47% with E vs 1% with P (P<0.001)	11.2 with E vs 2.8 with P (HR 0.17, 95% CI: 0.15–0.2, P<0.001)	CR: 20% with E vs 1% with P PR: 39% with E vs 4% with P (n=777, P<0.001)	NR with E vs 3.9 with P (HR 0.19, 95% CI: 0.15–0.23, P<0.001)b	NR with E vs 31.0 with P (HR 0.73, 95% CI: 0.63–0.85, P<0.001)

Notes:

a Time to radiological progression.

b Radiographic progression-free survival.

Abbreviations: CRPC, castration-resistant prostate cancer; n, number of patients; PSA, prostate-specific antigen; CI, confidence interval; PFS, progression-free survival; OS, overall survival; PR, partial response; NR, not reached; SD, stable disease; E, enzalutamide; P, placebo; HR, hazard ratio; CR, complete response.

Table 2 Selected retrospective case series of sequential therapy with enzalutamide in metastatic CRPC

Author (year)	Sequential therapies	n	Median treatment durationa (months, 95% CI)	PSA decrease ratesa	PSA decrease ≥50%a among abiraterone-refractory patients	Median time to PSA progressiona (months, 95% CI)	Measurable disease responsea	Median PFSa (months, 95% CI)	Median OSa (months, 95% CI)
Schrader et al^Citation23 (2014)	D→A→E	35	4.9 (2.4–7.4)	≥50%: 28.6%	15.8% (n=19)	4.0 (2.0–6.0)	PR: 2.9% SD: 54.3% (n=17)	Not assessed	7.1 (6.2–8.1)
Bianchini et al^Citation24 (2014)	D→A→E	39	2.9 (1.7–4.0)	≥30%: 41% ≥50%: 12.8% ≥90%: 2.5%	9% (n=22)	2.7 (2.5–3.0)	PR: 4.3% SD: 17.4% (n=23)	2.8 (2.0–3.6)	NR
Schmid et al^Citation25 (2014)	D→A→E	35	2.8 (range 0.1–9.5)	30–50%: 3% ≥50%: 10% Rise: 55%	Not assessed	Not assessed	PR: 4% (n=24)	3.1 (1.4–4.8)	7.5 (4.7–10.3)
Thomson et al^Citation26 (2014)	D→A→E	23	Not assessed	≥50%: 39.1% ≥90%: 4.3%	23.1% (n=13)	2.8	Not assessed	Not assessed	8.5
Badrising et al^Citation27 (2014)	D→A→E	61	3.4	≥30%: 46% ≥50%: 21% ≥90%: 3%	Not assessed	4.0	Not assessed	2.7 (2.5–3.6)	7.2
Thomsen et al^Citation28 (2014)	D→A→E	24	4.0 (1.0–8.5)	≥30%: 46% ≥50%: 16.6%	0% (n=10)	Not assessed	Not assessed	Not assessed	4.8 (3.0–8.4)
Brasso et al^Citation29 (2014)	D→A→E	137	3.2 (range 0.03–21.9)	≥30%: 36.9% ≥50%: 18% Rise: 36%	Not assessed	Not assessed	PR: 11.8% (n=59)	3.1 (2.3–3.9)b	8.3 (6.8–9.8)
Vera-Badillo et al^Citation30 (2014)	D→A→E	26	4.4 (range 1.3–9.3)	≥30%: 35% ≥50%: 27%	Not assessed	Not assessed	Not assessed	4.9 (3.8–6.2)	Not assessed
Azad et al^Citation32 (2015)	D→A→E	68	4.1	≥50%: 22% Rise: 35.3%	Not assessed	Not assessed	Not assessed	4.6c	10.6
	A→E	47	4.6	≥50%: 25.5% Rise: 38.3%				6.6c	8.6
Suzman et al^Citation33 (2014)	A→E	30	Not assessed	≥30%: 41% ≥50%: 34%	Not assessed	4.1 (2.8–7.4)	Not assessed	4.7 (3.4–NR)	Not assessed
	A→D	31		≥30%: 53% ≥50%: 40%		4.1 (2.5–5.7)		4.4 (2.9–6.7)
Nadal et al^Citation34 (2014)	D→E E	60 47	3.2 (range 0.4–19.4) 4.9 (range 0.8–14.6)	≥50%: 25.4% ≥50%: 43.2%	Not applicable	2.6 (1.9–3.5) 7.2 (4.5–17.2)	Not assessed	3.3 (2.5–4.8) NR	11.6 (8.7–15.2) 16.2 (11.5–NR)
Cheng et al^Citation35 (2015)	E	36	9.1 (7.3–NR)	≥30%: 67% ≥50%: 58% ≥90%: 22%	Not applicable	5.5 (4.2–9.1)d	Not assessed	Not assessed	78% (range 59–100)e
	D→E	30	5.4 (3.8–8.4)	≥30%: 43% ≥50%: 30% ≥90%: 13%		4.1 (2.9–5.4)d			77% (range 61–97)e
	A→E	79	4.7 (3.7–7.7)	≥30%: 28% ≥50%: 18% ≥90%: 3%	20% (n=30)	4.0 (3.2–4.8)d			64% (range 45–90)e
	A+D→E	165	3.9 (3.0–4.6)	≥30%: 24% ≥50%: 17% ≥90%: 2%		2.8 (2.5–3.2)d			51% (range 41–62)e

Notes:

a With enzalutamide.

b Radiographic progression-free survival.

c Time to progression.

d PSA progression-free survival.

e 12-Month overall survival.

Abbreviations: CRPC, castration-resistant prostate cancer; n, number of patients; CI, confidence interval; PSA, prostate-specific antigen; PFS, progression-free survival; OS, overall survival; D, docetaxel; A, abiraterone acetate; E, enzalutamide; PR, partial response; SD, stable disease; NR, not reached.

Table 3 Selected ongoing clinical trials with enzalutamide in metastatic CRPC

Identifier (status)	Description and type of study	Population	Treatment	Primary endpoint
NCT01288911 (completed recruitment)	Randomized, double-blind, Phase II study of enzalutamide vs bicalutamide in men with CRPC (TERRAIN)	Metastatic chemotherapy-naïve CRPC progressing to ADT	Enzalutamide vs bicalutamide	PFS
NCT01664923 (completed recruitment)	Multicenter Phase II, randomized, double-blind, study of enzalutamide vs bicalutamide in men with prostate cancer who have failed primary ADT (STRIVE)	Nonmetastatic and metastatic chemotherapy-naïve CRPC progressing to ADT	Enzalutamide vs bicalutamide	PFS
NCT01650194 (completed recruitment)	Single-arm Phase II study determining safety and tolerability of enzalutamide in combination with abiraterone acetate in bone metastatic CRPC	Bone metastatic CRPC (pre- or post-chemotherapy setting)	Enzalutamide plus abiraterone	Safety
NCT01949337 (completed recruitment)	Open-label, randomized Phase III trial of enzalutamide alone vs enzalutamide plus abiraterone in metastatic CRPC patients (ALLIANCE A031201)	Metastatic chemotherapy-naïve CRPC progressing to ADT	Enzalutamide alone vs enzalutamide plus abiraterone	OS
NCT02194842 (not yet open for recruitment)	Randomized, multicenter, Phase III trial comparing enzalutamide vs radium-223 plus enzalutamide in asymptomatic or mildly symptomatic CRPC patients metastatic to bone	Bone metastatic CRPC (pre- and post-chemotherapy setting)	Enzalutamide alone vs enzalutamide plus radium-223	rPFS
NCT01981122 (completed recruitment)	Randomized, Phase II, open-label study of sipuleucel-T with concurrent vs sequential enzalutamide in metastatic CRPC (STRIDE)	Metastatic chemotherapy-naïve CRPC, no visceral metastases, asymptomatic or minimally symptomatic	Sipuleucel-T with concurrent vs sequential enzalutamide	Peripheral T-cell immune response
NCT02288247 (recruiting)	Randomized, double-blind, placebo-controlled, Phase IIIb study of continuing enzalutamide in chemotherapy-naïve metastatic CRPC patients treated with docetaxel who have progressed on enzalutamide alone (PRESIDE)	Metastatic chemotherapy-naïve CRPC, asymptomatic or minimally symptomatic	Maintenance enzalutamide plus docetaxel vs placebo plus docetaxel	PFS
NCT01995513 (completed recruitment)	Randomized, double-blind, placebo-controlled, Phase IV study of continued enzalutamide treatment beyond progression in patients with chemotherapy-naïve metastatic CRPC treated with abiraterone (PLATO)	Metastatic chemotherapy-naïve CRPC, asymptomatic or minimally symptomatic	Maintenance enzalutamide plus abiraterone vs placebo plus abiraterone	PFS
NCT02116582 (recruiting)	Multicenter, single-arm Phase IV study of enzalutamide in patients with progressive metastatic CRPC previously treated with abiraterone acetate	Metastatic CRPC previously treated with abiraterone (pre- or post-chemotherapy setting)	Enzalutamide	rPFS
NCT02003924 (recruiting)	Randomized, double-blind, Phase III study of enzalutamide in nonmetastatic CRPC (PROSPER)	Nonmetastatic CRPC patients with PSA recurrence only	Enzalutamide vs placebo	Metastasis-free survival

Abbreviations: CRPC, castration-resistant prostate cancer; ADT, androgen deprivation therapy; PFS, progression-free survival; OS, overall survival; rPFS, radiographic progression-free survival; PSA, prostate-specific antigen.

Table 4 Most common adverse events with enzalutamide

Adverse event	AFFIRM trial^Citation5		PREVAIL trial^Citation6
	Any grade	Grade ≥3	Any grade	Grade ≥3
Fatigue	34%	6%	36%	2%
Back pain	Not reported	Not reported	27%	3%
Constipation	Not reported	Not reported	22%	<1%
Diarrhea	21%	1%	16%	<1%
Arthralgia	Not reported	Not reported	20%	1%
Hot flash	20%	0%	18%	<1%
Decreased appetite	Not reported	Not reported	18%	<1%
Musculoskeletal pain	14%	1%	Not reported	Not reported
Hypertension	6.6%	Not reported	13%	7%
Headache	12%	<1%	10%	<1%
Peripheral edema	Not reported	Not reported	11%	<1%
Any cardiac disorder	6%	1%	10%	3%
Myocardial infarction	<1%	<1%	1%	1%
Abnormality on liver-function testing	1%	<1%	1%	<1%
Seizure	<1%	<1%	<1%	<1%
Any serious adverse event	34%	28%	32%	Not reported
Adverse event leading to treatment discontinuation	8%	5%	6%	6%
Adverse event leading to death	3%	3%	4%	4%

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