Table 2 Novel SERM, SERCA, and SERD drugs targeting ER
Drug; Class | ESR1-MUT cells/PDX | Completed trials | Current trials |
|---|---|---|---|
lasofoxifene; SERM | Drug effective; no resistance | PEARL Phase 3 trial for osteoporosis showed ↓ breast cancer incidence Toxicities arthralgia (25%), hot flashes (13%), VTE (1.5% over 5Y) | Phase 2 NCT04432454 (ELAINE-2): lasofoxifene + abemaciclib for ESR1-MUT and progressed on ET NCT03781063 (ELAINE): lasofoxifene versus fulvestrant for ESR1-MUT and progressed on AI + CDK4/6i |
bazedoxifene; SERM/SERD | Drug effective; relative resistance | FDA-approved, EMA-approved for postmenopausal osteoporosis/hot flashes Toxicities hot flashes (13%), arthralgia (11%), VTE (0.5% over 3Y) | Phase 2 NCT02448771: bazedoxifene + palbociclib for progressed on ET |
H3B-6545; SERCA | Drug effective; relative resistance | Phase 1 NCT03250676: H3B-6545   progressed on ET + CDK4/6i: 47% stable disease, 9% partial response Toxicities Sinus bradycardia, diarrhea, nausea, fatigue, hot flashes, anemia | Phase 1 NCT04288089: H3B-6545 + palbociclib for progressed on ET Phase 2 NCT03250676: H3B-6545 for progressed on ET + CDK4/6i |
Elacestrant (RAD1901); SERD | Drug effective; relative resistance | Phase 1 NCT02338349: elacestrant   progressed on fulvestrant and CDK4/6i: ORR 0%, 24-wk CBR 22%, PFS 1.9 mo   progressed on ET: ORR 27%, 24-wk CBR 47%, PFS 5.4 mo Toxicities Nausea (33% G1-2), hypophosphatemia (25% G1-2, 8% G3), arthralgia (17%), fatigue (21% G1-2), diarrhea (12% G1-2), anemia (12% G1-2) | Phase 3 NCT03778931 (EMERALD): elacestrant versus AI/fulvestrant for progressed on ET + CDK4/6i |
Amcenestrant (SAR439859); SERD | Drug effective; relative resistance | Phase 1/2 NCT03284957 (AMEERA-1): amcenestrant + palbociclib or alpelisib progressed on ET, ESR1-WT: 24-wk CBR 37% progressed on ET, ESR1-MUT: 24-wk CBR 32% Toxicities Nausea (18% G1-2), fatigue (18% G1-2), hot flashes (10% G1-2) | Phase 2 NCT04059484 (AMEERA-3): amcenestrant versus AI/fulvestrant/tamoxifen for progressed on ET Phase 3 NCT04478266 (AMEERA-5): amcenestrant + palbociclib versus letrozole + palbociclib for treatment-naïve |
camizestrant (AZD9833); SERD | Drug effective; no resistance | Phase 1 NCT03616587 (SERENA-1): camizestrant   progressed on ET (82% fulvestrant, 68% CDK4/6i): ORR 14%, 24-wk CBR 67% Toxicities Visual disturbances (51% G1-2, 2% G3), sinus bradycardia (45% G1-2), nausea (18% G1-2), fatigue (13% G1-2), dizziness (8% G1-2, 2% G3) | Phase 2 NCT04214288 (SERENA-2): camizestrant versus fulvestrant for progressed on ET NCT04588298 (SERENA-3): camizestrant versus fulvestrant for treatment-naïve Phase 3 NCT04711252 (SERENA-4): camizestrant + palbociclib versus anastrozole + palbociclib for treatment-naïve |
giredestrant (GDC-9545); SERD | Drug effective | Phase 1 NCT03332797: giredestrant   progressed on ET: ORR 11%, 24-wk CBR 44% Toxicities Fatigue (21% G1-2), nausea (21% G1-2), hot flashes (17% G1-2), arthralgia (17% G1-2), diarrhea (17% G1-2) | Phase 2 NCT04576455 (acelERA): giredestrant versus fulvestrant/AI for progressed on ET Phase 3 NCT04546009: giredestrant + palbociclib versus letrozole + palbociclib for treatment-naïve |
rintodestrant (G1T48); SERD | Drug effective; no resistance | - | Phase 1 NCT03455270: rintodestrant + palbociclib for progressed on ET |
Zn-c5; SERD | Drug effective | - | Phase 1 NCT04176747: ZN-c5 NCT04514159: ZN-c5 + abemaciclib NCT03560531: ZN-c5 + palbociclib |
LSZ102; SERD | Not reported | - | Phase 1 NCT02734615: LSZ102 + ribociclib or alpelisib for ET-resistant |
ARV-471; SERD (PROTAC) | Drug effective | - | Phase 2 NCT04072952: ARV-471 + palbociclib for progressed on ET |
LY3484356; SERD | Not reported | - | Phase 1 NCT04188548 (EMBER): LY3484356 + abemaciclib, everolimus, alpelisib, trastuzumab, AI in various combinations |
D-0502; SERD | Drug effective | - | Phase 1 NCT03471663: D-0502 + palbociclib for progressed on ET |