Table 2.
Results from clinical trials of next-generation endocrine therapies in hormone receptor-positive MBC.
| Endocrine agent | ET class | Trial description | Trial identifier | Median prior lines of therapy | Prior SERD exposure (%) | Prior CDK4/6i exposure (%) | Baseline ESR1 mutation rate (%) | ORR (%) and CBR (%) | Progression-free survival | Most frequent (>5%) treatment-related adverse events |
|---|---|---|---|---|---|---|---|---|---|---|
| Oral SERDs | ||||||||||
| Elacestrant (RAD1901) | SERD | Phase III; n = 477 Elacestrant versus fulvestrant or AI for ER+ MBC progressed on 1–2 prior lines of ET and CDK4/6i |
NCT03778931 (EMERALD) | 1 | Not reported | 100% | 48% | Not reported | 12-month PFS rate of 22.3% versus 9.4%; 30% reduction in PD or death, HR 0.697 | Nausea (25.3% G1–2), vomiting (11% G1–2), fatigue (11% G1–2) |
| Elacestrant (RAD1901) | SERD | Phase I; n = 50 Elacestrant for ER+ MBC progressed on ET |
NCT02338349 | 3 | 52% | 52% | 50% | ORR 19.4% CBR 42.6% |
Median 4.5 months | Nausea (33% G1–2), hypophosphatemia (25% G1–3), hypertriglyceridemia (25% G1–2), arthralgia (17% G1–2), fatigue (21% G1–2), diarrhea (12% G1–2), vomiting (17% G1–2), dyspepsia (21% G1–2), constipation (21% G1–2), anemia (12% G1–2), AST increased (12% G1–2), ALT increased (12% G1–2) |
| Amcenestrant (SAR439859) | SERD | Phase I–II; n = 62 Amcenestrant for ER+ MBC progressed on ET |
NCT03284957 (AMEERA-1) | 2 | 47% | 63% | 48% | ORR 8.5% CBR 33.9% |
Not reported | Hot flush (16.1% G1–2); constipation (9.7% G1–2), arthralgia (9.7% G1–2), vomiting (8.1% G1–2), diarrhea (8.1% G1–2), nausea (8.1% G1–2), fatigue (6.5% G1–2) |
| Camizestrant (AZD9833) | SERD | Phase I; n = 98 Camizestrant for ER+ MBC progressed on ET |
NCT04214288 (SERENA-1) | 5 | 58% | 69% | 46% | ORR 10% CBR 35.3% |
Median 5.4 months | Visual disturbances (51% G1–2, 2% G3), sinus bradycardia (45% G1–2), nausea (18% G1–2), fatigue (13% G1–2), dizziness (10% G1–2), vomiting (10% G1–3) |
| Giredestrant (GDC-9545) | SERD | Phase I; n = 111 Giredestrant for ER+ MBC progressed on ET |
NCT03332797 | 1 | 21% | 64% | Not reported | ORR 15% CBR 50% |
Median 7.2 months | Sinus bradycardia (7% G1–2), fatigue (21% G1–2), arthralgia (17% G1–2), nausea (16% G1–2) |
| Imlunestrant (LY3484356) | SERD | Phase I; n = 35 Imlunestrant for ER+ MBC progressed on ET |
NCT04188548 (EMBER) | 2 | 60% | 83% | 37% | ORR 6% CBR 48% |
Not reported | Nausea (32% G1–2), fatigue (25% G1–2), diarrhea (18% G1–2) |
| Rintodestrant (G1T48) | SERD | Phase I; n = 67 Rintodestrant for ER+ MBC progressed on ET |
NCT03455270 | 2 | 64% | 70% | 41% | ORR 5% CBR 30% |
Median 2.6–3.6 months | Hot flush (24% G1–2), fatigue (21% G1–2), nausea (19% G1–2), diarrhea (18% G1–2), vomiting (10% G1–2) |
| Other novel ET | ||||||||||
| H3B-6545 | SERCA | Phase I–II; n = 94 H3B-6545 for ER+ MBC progressed on ET |
NCT03250676 | 3 | 72% | 85% | 61% | ORR 17% CBR 40% |
Median 5.1 months | Sinus bradycardia (34% G1, 5% G2), QTcF prolongation (5% G2–3), anemia (19% G2+), fatigue (16% G2+), nausea (17% G2+), diarrhea (12% G2+), creatinine clearance decrease (38% G2+), hemoglobin decrease (37% G2+), bilirubin increase (12% G2+), ALT increase (14% G2+), AST increase (13% G2+) |
| P-1250 | CERAN | Phase I; n = 41 OP-1250 for ER+ MBC progressed on ET |
NCT04505826 | 3 | 68% | 95% | 49% | ORR 17% CBR 46% |
Not reported | Nausea (49% G1–2), fatigue (34% G1–2), vomiting (22% G1–2), headache (17% G1–2) |
| ARV-471 | PROTAC | Phase I; n = 50 ARV-471 for ER+ MBC progressed on ET |
NCT04072952 | Not reported | 83% | 100% | Not reported | ORR 5.2% CBR 40% |
Not reported | Nausea (24% G1–2), fatigue (12% G1–2), vomiting (10% G1–2) |
AI, aromatase inhibitors; ALT, alanine aminotransferase; AST, aspartate transaminase; CBR, clinical benefit rate; CDK4/6i, CDK4/6 inhibitor; CERAN, complete estrogen receptor antagonist; ER+, estrogen receptor positive; ET, endocrine therapy; G, grade; HR, hazard ratio; MBC, metastatic breast cancer; ORR, overall response rate; PD, progression of disease; PFS, progression-free survival; PROTAC, proteolysis targeting chimer; SERCA, selective estrogen receptor covalent antagonist; SERD, selective estrogen receptor degrader; SERM, selective estrogen receptor modulators; TRAE, treatment-related adverse event.