Table 2.
Results from completed and ongoing clinical trials investigating the use of androgen receptor inhibition in women with breast cancer.
| NCT number | Title | Phase | Treatments tested | Actual or planned patients | Primary endpoint | Secondary endpoints | Three most common adverse events |
|---|---|---|---|---|---|---|---|
| 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 Tmax: 16 h (range: 1.0–72.0) 4-OHT Cmax: 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: NAe 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-NAa) 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-NAa); time to response: 12.9 months (7.3-NAa); 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 (3.2–10.2a); time to response: 14.0 months (7.4-NAa); 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-NAa); 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-NAa); 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] Cmax (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 |
AE adverse events, CBR clinical benefit rate, CI confidence interval, CR complete response, CTC circulating tumor cells, DC disease control, DLT dose-limiting toxicities, DoR duration of overall response, DX+ diagnostic positive, HT prior hormone therapy treatment, ITT intent to treat, MTD maximum tolerated dose, ORR objective response rate, PD progressive disease, PFS progression-free survival, PR partial response, SAE serious adverse events, SD stable disease, TEAE treatment-related adverse events, TTP time to progression.
aUpper limit of 95% confidence interval or median was not reached due to insufficient number of events at the time of data cut-off.
bOnly Phase 2 Stage 1 results have been reported.
cUpper limit of TTP range was not determined/reached.
dThe median and upper limit of the range for OS were not reached/not determined. The upper limit exceeded 63 months.
eCould not be estimated due to low number of events.