Galeterone for the treatment of advanced prostate cancer: the evidence to date

Figures & data

Table 1 Phase III clinical trials of FDA-approved drugs for metastatic castration-resistant prostate cancer

Study	Year	Indication	N	PSA50 declinea	SRE benefit	Quality of life	mPFS (months)	Overall survival
								Median (months)	HR	P-value
Docetaxel vs mitoxantroneb,^Citation23	2004	1st line chemo	1,006	45% vs 32%	NA	Yes	NS	18.9 vs 16.5	0.76	0.009
Cabazitaxel vs mitoxantroneb,^Citation22	2010	Post-docetaxel	755	39% vs 18%	NA	NA	2.8 vs 1.4	15.1 vs 12.7	0.70	<0.001
Sipuleucel-T vs placebo^Citation26	2010	Pre- and post-docetaxel	512	2.6% vs 1.3%	NA	NA	3.7 vs 3.6	25.8 vs 21.7	0.78	0.03
Abiraterone vs placebo^Citation8,Citation24	2011	Post-docetaxel	1,195	29% vs 6%	Yes	Yes	5.6 vs 3.6	14.8 vs 10.9	0.65	<0.001
Abiraterone vs placebo^Citation9,Citation25	2012	Pre-docetaxel	1,088	62% vs 24%	NA	Yes	16.5 vs 8.3	34.7 vs 30.3	0.81	0.0033
Enzalutamide vs placebo^Citation10	2012	Post-docetaxel	1,199	54% vs 2%	Yes	Yes	8.3 vs 2.9c	18.4 vs 13.6	0.63	<0.001
Radium-223 vs placebod,^Citation27	2013	Pre- and post-docetaxele	921	16% vs 6%f	Yes	Yes	3.6 vs 3.4g	14.9 vs 11.3	0.70	<0.001
Enzalutamide vs placebo^Citation11	2014	Pre-docetaxel	1,717	78% vs 3%	Yes	Yes	NR vs 3.9c	NR vs 31.0	0.73	<0.001

Notes:

a Defined as PSA reduction ≥50%;

b prednisone was included in both experimental and control arms;

c radiographic progression-free survival;

d both arms received best standard of care;

e post-docetaxel or not candidates for docetaxel;

f PSA reduction ≥30%;

g time to PSA progression.

Abbreviations: N, number of patients; SRE, skeletal related events; mPFS, median progression-free survival; chemo, chemotherapy; NS, non-significant; NA, not assessed; NR, not reached; PSA, prostate specific antigen; FDA, US Food and Drug Administration; HR, hazard ratio.

Figure 1 Three mechanisms of action of galeterone.

Notes: This figure highlights the androgen receptor (AR) activation axis, with conversion of testosterone to dihydrotestosterone (DHT) by the 5α-reductase enzyme, and subsequent AR activation, dimerization, nuclear translocation and activation of transcriptional activation of target genes. The figure also demonstrates potential mechanisms of resistance to AR therapies, including the development of AR splice variants (AR-V) and AR mutations. Finally, it highlights galeterone’s mechanisms of action in each of these AR signaling pathways implicated in resistance to novel androgen/AR-directed therapies: 1) CYP lyase inhibition; 2) AR antagonism to both full-length and mutant AR; and 3) degradation of the AR, including AR splice variants.
Abbreviation: Enz, enzalutamide.

Table 2 Main characteristics and outcomes of the ARMOR1 and ARMOR2 clinical trials

	ARMOR1^Citation69	ARMOR2, part 1^Citation69	ARMOR2, parts 1 and 2 (combined study)^Citation70
Number of patients	49	28	107
Metastatic disease (M)	51%	86%	77%
Abi-R or Enz-R patients	No	Abi-R: three patients	Abi-R: 37 patients Enz-R: nine patients
Drug formulation	Capsules	SDD tablets	SDD tablets
Food effect	Yes	No	No
Dose range	650 mg	1,700 mg	2,550 mg
	975 mg	2,550 mg
	1,300 mg	3,400 mg
	1,950 mg
	2,600 mg
PSA decline ≥30%	49%	64%	83%a
PSA50	22.4%	48%	70%a

Note:

a PSA decline results in the M₀ and M₁ treatment-naïve cohorts.

Abbreviations: Abi-R, abiraterone refractory; Enz-R, enzalutamide refractory; SDD, spray dry dispersion; PSA₅₀, PSA decline ≥50%.

Table 3 Main adverse events in the ARMOR1 and ARMOR2 clinical trials

	ARMOR1^Citation69	ARMOR2, part 1^Citation69	ARMOR2, parts 1 and 2 (combined study)^Citation70
Main grade 1 or 2 AEsa
Fatigue	16 (32.7%)	9 (32.1%)	35 (32.7%)
Nausea	12 (24.5%)	13 (46.4%)	36 (33.6%)
Vomiting	6 (12.2%)	8 (28.6%)	13 (12.1%)
Diarrhea	11 (22.4%)	4 (14.3%)	17 (15.9%)
Decreased appetite	6 (12.2%)	6 (21.4%)	22 (20.6%)
Pruritus	11 (22.4%)	9 (32.1%)	28 (26.2%)
Increased AST level	13 (26.5%)	1 (3.6%)	9 (8.4%)
All grade ≥3 AEsb
Increased ALT level	8 (16.3%)	3 (10.7%)	5 (4.7%)
Increased AST level	3 (6.1%)	1 (3.6%)	2 (1.9%)
Increased bilirubin	1 (2%)	0	1 (<1%)
Constipation	0	1 (3.6%)	0
Diarrhea	0	1 (3.6%)	1 (<1%)
Fatigue	1 (2%)	0	3 (2.8%)
Rash	0	1 (3.6%)	1 (<1%)
Pruritus	0	0	4 (3.7%)
Hypokalemia	NR	NR	3 (2.8%)
Hypertension	NR	NR	2 (1.9%)

Notes:

a Adverse events that occurred in at least 20% of patients in any cohort;

b grade ≥3 adverse events that occurred in >1% of patients in any cohort.

Abbreviations: AEs, adverse events; NR, not reported; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Table 4 ARMOR2: galeterone efficacy summary

Cohort	Number of patients	Any PSA decline	Best response by PCWG2
Non-metastatic (M0-TN) mCRPC	21	21 (100%)	No evidence of metastasis at 12 weeks
Metastatic (M1-TN) mCRPC	39	35 (90%)	Stable disease: 75%
Abi-R mCRPC	30	11 (37%)	Stable disease: 47%
Enz-R mCRPC	9	4 (44%)	Stable disease: 57%

Note: Data from Taplin et al.⁷⁰

Abbreviations: mCRPC, metastatic castration-resistant prostate cancer; TN, treatment-naïve; Abi-R, abiraterone refractory; Enz-R, enzalutamide refractory; PCWG2, Prostate Cancer Working Group 2; PSA, prostate specific antigen.

Figure 2 ARMOR3-SV: Phase III randomized trial design and study endpoints.

Note: Data from Taplin et al.⁷³
Abbreviations: CRPC, castration-resistant prostate cancer; AR-V7, androgen receptor splice variant 7.

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