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Table 2 Novel SERM, SERCA, and SERD drugs targeting ER

From: ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer

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
  1. Shown are preclinical data reporting efficacy against ESR1-MUT cells or PDX models, published trial results, and ongoing trials. References and details are in the main text