Table 2 Results from completed and ongoing clinical trials investigating the use of androgen receptor inhibition in women with breast cancer.

NCT00186121

Estradiol suppression for the treatment of metastatic breast cancer in premenopausal women

Phase II

single arm

Anastrazole + Goserelin

35 pts

ORR: 37.5% (95% CI: 21–56%)

CBR: 71.9% (95% CI: 53–86%)

Response rate: CR: 1 pt (3%), PR: 11 pts (34%), SD: 11 pts (34%)

TTP: 8.3 (2.1 to NA)^c

OS: NA (11.1 to NA)^d

SAE: 0

Estradiol suppression at baseline: 7.47 pg/mL; 1 month: 20.8 pg/mL; 3 months: 18.7 pg/mL; 6 months: 14.8 pg/mL

Hot flush (60%)

Arthralgia (53%)

Fatigue (50%)

NCT02067741

CR1447 in endocrine responsive-HER2neg and AR+ TNBC

Phase I/II

CR1447

29 pts

MTD: 400 mg/day

DC at 24 weeks: 0 pts (0%)

SD at 12 weeks: 2 pts (14%)

PD at 12 weeks: 11 pts (79%)

4-OHT T_max: 16 h (range: 1.0–72.0)

4-OHT C_max: 0.63 ng/mL (range: 0.0–1.88)

median AUC0-72: 27.2 h ng/mL (range: 0.0–69.8)

Elevated triglycerides (57%)

Anemia (50%)

Elevated AST (29%)

Elevated AP (29%)

High creatinine (29%)

NCT00468715

Bicalutamide in treating patients with metastatic breast cancer

Phase II

Bicalutamide

28 pts

CBR (6 months): 19% (95% CI: 7–39%)

CBR (6 months, ITT): 18% (95% CI: 6–37%)

Median PFS: 12 weeks (95% CI: 11–22 weeks)

Elevated AST (25%)

Fatigue (21%)

Hot flashes (21%)

Limb edema (21%)

NCT02910050

Bicalutamide plus aromatase inhibitors in ER(+)/AR(+)/HER2(−) metastatic breast cancer

Phase II

single arm

Bicalutamide + Aromatase inhibitors

58 pts

CBR (6 months): 16.7%

CR: 0 pts (0%)

PR: 0 pts (0%)

SD: 3 pts (17%)

PD: 15 pts (83%)

PFS: 2.7 months (95% CI: 2.2–3.8 months)

Tumor pain (17%)

Alopecia (6%)

Hot flashes (6%)

Peripheral sensory neuropathy (6%)

Insomnia (6%)

Hypertension (6%)

NCT02605486

Palbociclib in combination with bicalutamide for the treatment of AR(+) metastatic breast cancer (MBC)

Phase I/II

Bicalutamide + Palbociclib

51 pts

The MTD was 150 mg bicalutamide daily and 125 mg palbociclib daily for 21 days in a 28 day cycle.

Neutropenia (33%)

Leukopenia (27%)

Lymphocytopenia (20%)

NCT02457910

Taselisib and enzalutamide in treating patients with androgen receptor positive triple-negative metastatic breast cancer

Phase I/II

Enzalutamide + Taselisib

73 pts

MTD was not reached:

160 mg enzalutamide with 4 mg taselisib had manageable toxicities.

CBR (16 weeks, evaluable population): 35.7%

PFS (evaluable population): 3.4 months

Phase I: metabolism and nutrition (25%), rash maculopapular (25%), rash acneiform (8%), elevated alkaline phosphatase (8%)

Phase II: rash maculopapular (29%), rash acneiform (12%), fatigue (12%)

NCT01597193

Safety study of enzalutamide (MDV3100) in patients with incurable breast cancer

Phase I

Enzalutamide ± Aromatase inhibitors/SERD

101 pts

MTD not yet reported.

160 mg enzalutamide: 22 patients, 3 AE

160 mg enzalutamide + 1 mg anastrozole: 20 patients, 1 AE

160 mg enzalutamide + 50 mg exemestane: 23 patients, 3 AEs

160 mg enzalutamide + 500 mg fulvestrant: 11 patients, 2 AEs

Enzalutamide: 4 pts with ≥ Grade 3 AE; 1 pt discontinued treatment due to AEs

Enzlautamide + Anastrozole: 6 pts with ≥ Grade 3 AE; 1 pt discontinued treatment due to AEs

Enzalutamide + Exemestane: 9 pts with ≥ Grade 3 AE; 3 pts discontinued treatment due to AEs

Enzalutamide + Fulvestrant: 4 pts with ≥ Grade 3 AE

Maximum plasma concentration (Cmax) of enzalutamide and metabolites after single dosing (enzalutamide 160 mg) [μg/mL]:

enzalutamide: 4.01 (2.09); M1 (carboxylic acid): 0.0707 (0.0379); M2 (N-desmethyl): 0.184 (0.0689)

AUC 24 h after single dosing (enzalutamide 160 mg) [μg h/mL]: enzalutamide: 41.6 (8.19); M1: 1.20 (0.648); M2: 2.76 (1.00)

Terminal elimination half life after single dosing (Enzalutamide 160 mg): 198 h (105)

Enzalutamide:

nausea (50%),

fatigue (45%), back pain (27%), cough (27%)

Enzalutamide + Anastrozole:

fatigue (60%), decreased appetite (50%), nausea

(45%)

Enzalutamide + Exemestane:

fatigue (52%), nausea (52%), vomiting (30%)

Enzalutamide + Fulvestrant:

fatigue (73%), nausea (73%),back pain

(55%)

NCT02091960

A study to assess the efficacy and safety of enzalutamide with trastuzumab in patients with human epidermal growth factor receptor 2 positive (HER2+), androgen receptor positive (AR+) metastatic or locally advanced breast cancer

Phase II

single arm

Enzalutamide + Trastuzumab

103 pts

CBR: 23.6% (95% CI: 15.2–33.8%)

ORR at week 24: 3.4% (95% CI: 0.7–9.5)

Best ORR: 4.5% (95% 1.2–11.1)

PFS: 105 days (95% CI: 61–116)

TTP: 108 days (95% CI: 61–116)

Duration of response: NA^e

Time to response: 57 days (95% CI: 57–222)

Patients with AEs: 94% (related to enzalutamide 73%, related to trastuzumab 38%)

Fatigue (34%)

Nausea (27%)

Hot flush (17%)

NCT02007512

Efficacy and safety study of enzalutamide in combination with exemestane in patients with advanced breast cancer

Phase II

Enzalutamide + Exemestane

vs.

Placebo + Exemestane

247 pts

Enzalutamide + Exemestane: PFS (ITT): 11.8 months (7.3–15.9); PFS (DX+): 16.5 months (11.0-NA^a)

Enzalutamide: PFS (ITT): 5.8 months (3.5–10.9); PFS (DX+): 4.3 months (1.9–10.9)

HT + Enzalutamide + Exemestane: PFS (ITT): 3.6 months (1.9–5.5); PFS (DX+): 6.0 months (2.3–26.7)

HT + Enzalutamide: PFS (ITT): 3.9 months (2.6–5.4); PFS (DX+): 5.3 months (1.8–6.7)

Enzalutamide + Exemestane: CBR 24 weeks: 62% (49–74%); best objective response rate: 31% (17–48%); duration of objective response: 14.0 months (5.6-NA^a); time to response: 12.9 months (7.3-NA^a); time to progression: 11.8 months (7.3–15.9); PFS at 6 months: 67% (53–77%)

Enzalutamide: CBR 24 weeks: 45% (33–58%); best objective response rate: 19% (9–34%); duration of objective response: 9.1 months (3.2–10.2^a); time to response: 14.0 months (7.4-NA^a); time to progression: 7.4 months (3.5–13.5); PFS at 6 months: 50% (37–62%)

HT + Enzalutamide + Exemestane: CBR 24 weeks: 20% (11–32%); best objective response rate: 10% (3–23%); duration of objective response: 18.3 months (3.3–23.1); time to response: NA (3.9-NA^a); time to progression: 3.6 months (1.9–5.6); PFS at 6 months: 32% (20–44%)

HT + Enzalutamide: CBR 24 weeks: 32% (20–45%); best objective response rate: 5% (0.6–16%); duration of objective response: 4.6 months (1.9–7.4); time to response: NA (NA-NA^a); time to progression: 3.9 months (2.6–5.4); PFS at 6 months: 33% (22–46%)

Combined from all arms:

fatigue (32%), nausea (26%), hot flush

(23%)

NCT01889238

Safety and efficacy study of enzalutamide in patients with advanced, androgen receptor-positive, triple-negative breast cancer

Phase II

single arm

Enzalutamide

118 pts

CBR (16 weeks, evaluable population):

33% (95% CI: 26–42%)

CBR (16 weeks, ITT):

25% (95% CI: 19–31%)

CBR (24 weeks, evaluable population): 28% (95% CI: 21–36%)

CBR (24 weeks, ITT): 20% (95% CI: 15–26%)

Best objective response (evaluable population): 8.5% (95% CI: 3–12%)

Best objective response (ITT): 6% (95% CI: 3–9%)

PFS (evaluable population): 14.3 weeks (95% CI: 8.3–16.1)

PFS (ITT): 12.6 weeks (95% CI: 8.1–15.1)

Fatigue (42%)

Nausea (34%)

Decreased appetite (19%)

NCT02750358

Feasibility study of adjuvant enzalutamide for the treatment of early stage AR (+) triple-negative breast cancer

Phase III

Enzalutamide

50 pts

As of 6/27/19, 34 pts (68%) completed 1 year of treatment,

and 15 pts (30%) were off treatment.

Fatigue (48%)

Hot flashes (22%)

Headache (18%)

Hyperglycemia (18%)

Nausea (18%)

NCT03004534

A study to evaluate changes in human breast cancer tissue following short-term use of darolutamide

Early Phase I

single arm

Darolutamide

36 pts

Presurgical molecular assessment:

AR up (7 pts, 20.6%)

AR unchanged (12 pts, 35.3%)

AR down (15 pts, 44.1%)

26 pts with TEAE (72%)

10 pts with no TEAE (28%)

Fatigue (22%)

Constipation (8%)

Diarrhea (8%)

Nausea (8%)

NCT02580448

CYP17-lyase and androgen receptor inhibitor treatment with seviteronel trial (CLARITY-01)

Phase I/II

Seviteronel

175 pts

CBR (16 weeks, TNBC): 2 pts (33%)^b

CBR (24 weeks, ER + BC): 2 pts (18%)^b

Change in CTC at C2D1: −94.3% (range: −27.5,−100)^b

Fatigue (50%)

Nausea (43%)

Decreased appetite (33%)

NCT01842321

Abiraterone acetate in molecular apocrine breast cancer

Phase II

single arm

Abiraterone acetate + Prednisone

31 pts

CBR (6 months): 20.0% (95% CI: 8–39%).

CR (6 months): 1 pt (3%)

PR (6 months): 0 pt (0%)

SD (6 months): 5 pts (17%)

Progression at 6 months: (23 pts (77%)

Treatment stopped for toxicity before 6 months evaluation: 1 pt (3%)

ORR: 6.7% (95% CI 0.8–22%)

DoR: CR: 23.4 months; PR: 5.6 months

PFS: 2.8 months (95% CI: 1.7–5.4)

Fatigue (18%)

Hypertension (12%)

Hypokalemia (9%)

NCT00212095

Docetaxel combined with ketoconazole in treatment of breast cancer

Phase II

Ketaconazole + Docetaxel

30 pts

Cycles of docetaxel: 4 (ketoconazole); 6 (conventional)

Ketoconazole-dosed Docetaxel: 52% of pts had reduction in tumor dimension; CR: 9.7%; PR: 54.8%; ORR: 64.5; SD: 4.1%; PD: 77.6%

Conventional-dosed docetaxel (doxirubicin): 55% of pts had reduction in tumor dimension; CR: 4.1%; PR: 776%; ORR: 81.7%; SD: 16.3%; PD: 2.0%

AUC (mg/L h): ketaconazole-modulated docetaxel: 3.93 ± 2.77; conventional-dosed docetaxel: 3.77 ± 2.70 [p-value = 0.794]

Clearance (L/h): ketaconazole-modulated docetaxel: 22.05 ± 8.29; conventional-dosed docetaxel: 36.52 ± 13.39 [p-value < 0.001]

Half-life (h): ketaconazole-modulated docetaxel: 13.46 ± 5.05; conventional-based docetaxel: 12.25 ± 3.47 [p-value = 0.206]

C_max (mg/L): ketaconazole-modulated docetaxel: 2.53 ± 1.14; conventional-based docetaxel: 2.68 ± 1.09 [p-value = 0.568]

Fatigue (81%)

Diarrhea (58%)

Myalgia (36%)

NCT01808040

A Phase 1b study of TAK-700 in postmenopausal women with hormone-receptor positive metastatic breast cancer

Phase Ib

Orteronel

8 pts

MTD not yet reported.

Dose level 1: 300 mg (4 pts, 1 not evaluated)

Dose level 2: 400 mg (3 pts)

1 patient with SD > 6 months

1 patient with SD for 3 months

Hot flashes (28%)

Nausea (28%)

Hypokalemia (28%)

Elevated AST (28%)

NCT02971761

Pembrolizumab and enobosarm in treating patients with androgen receptor positive metastatic triple-negative breast cancer

Phase II

Enobosarm + Pembrolizumab

29 pts

PR: 2 pts (13%)

SD at 18 and 19 weeks: 2 pts (13%)

PD: 11 pts (69%)

Elevated liver function (19%)

Diarrhea (13%)

6% of the following: adrenal insufficiency, dry skin, headache, hot flashes, hyperhidrosis, hyperthyroidism, or palpitation