P1, N=48, Recruiting, Pfizer | Not yet recruiting --> Recruiting

P1/2, N=67, Recruiting, Pfizer | Trial completion date: Aug 2027 --> Jan 2027 | Trial primary completion date: Feb 2027 --> Jul 2026

P1, N=21, Terminated, Accutar Biotechnology Inc | N=30 --> 21 | Trial completion date: Dec 2024 --> Apr 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Apr 2024; Voluntarily terminate the study since the sponsor's development strategy was adjusted.

P1, N=30, Active, not recruiting, Accutar Biotechnology Inc | Trial completion date: Feb 2024 --> Dec 2024 | Trial primary completion date: Jan 2024 --> Dec 2024

P1, N=48, Not yet recruiting, Pfizer

P1, N=16, Recruiting, Pfizer | Not yet recruiting --> Recruiting

P1/2, N=67, Recruiting, Pfizer | Trial completion date: Feb 2027 --> Aug 2027 | Trial primary completion date: Aug 2026 --> Feb 2027

P1, N=12, Recruiting, Pfizer | Not yet recruiting --> Recruiting

P1/2, N=47, Recruiting, Pfizer | Phase classification: P1b/2 --> P1/2 | N=35 --> 47 | Trial completion date: Oct 2027 --> Dec 2026 | Trial primary completion date: Apr 2026 --> Dec 2026

P1/2, N=65, Recruiting, Pfizer | Not yet recruiting --> Recruiting | Trial completion date: Nov 2026 --> Feb 2026 | Trial primary completion date: May 2026 --> Aug 2025

P1/2, N=67, Recruiting, Pfizer | Phase classification: P2 --> P1/2

P1, N=12, Not yet recruiting, Pfizer

P1/2, N=40, Recruiting, Pfizer | Phase classification: P1b/2 --> P1/2 | Trial completion date: Jun 2027 --> Dec 2025

P2, N=67, Recruiting, Pfizer

P1, N=16, Not yet recruiting, Pfizer

P2, N=67, Recruiting, Pfizer | Not yet recruiting --> Recruiting

As of the end of 2022, more than 20 drugs have entered clinical trials, with ARV-471 targeting estrogen receptor (ER) showing remarkable progress by entering phase III clinical studies...In this review, we aimed to update the PROTAC degraders as potential anticancer agents covering articles published in 2022. The design strategies, degradation effects, and anticancer activities were highlighted, which might provide an updated sight to develop novel PROTAC degraders with great potential as anticancer agents as well as favorable drug-like properties.

P1, N=6, Terminated, Accutar Biotechnology Inc | Trial completion date: Dec 2024 --> Sep 2023 | Active, not recruiting --> Terminated; Voluntarily terminate the study since the sponsor's development strategy was adjusted.

P1, N=32, Active, not recruiting, Arvinas Estrogen Receptor, Inc. | Recruiting --> Active, not recruiting | Phase classification: P1b --> P1

P2, N=152, Active, not recruiting, Arvinas Inc. | Recruiting --> Active, not recruiting

P1, N=9, Active, not recruiting, Pfizer | Trial primary completion date: Nov 2023 --> Mar 2024

P1, N=12, Completed, Pfizer | Active, not recruiting --> Completed

P1/2, N=65, Not yet recruiting, Pfizer

P1, N=12, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting

Modulation of estrogen activity with therapeutics such as tamoxifen and aromatase inhibitors have been the mainstay therapeutic strategy for ER-positive breast cancer. Several ER-directed therapies have been developed to antagonize the oncogenic ER function, including Selective ER Degraders (SERDs) such as fulvestrant which is approved to treat patients with advanced or metastatic breast cancer...Enrollment began in December 2022 with five sites in the United States planned. NCT05654532.

Eligible patients (aged ≥18 years) must have histologically or cytologically confirmed ER+/HER2- locoregionally recurrent or metastatic breast cancer, with no prior treatment in the advanced setting, and no prior treatment in any setting with CDK4/6 inhibitors, vepdegestrant, fulvestrant, elacestrant, or other investigational agents (including novel endocrine therapy, selective ER degraders, selective ER covalent antagonists, and complete ER antagonists). The primary efficacy endpoint of the phase 3 portion is progression-free survival based on blinded independent central review. Enrollment began June 2023 and is ongoing.

The cyclin-dependent kinase (CDK)4/6 inhibitors abemaciclib and ribociclib are approved in combination with an aromatase inhibitor or fulvestrant, or as monotherapy (abemaciclib), for ER+/HER2- advanced or metastatic breast cancer...Vepdegestrant is being evaluated in combination with abemaciclib (sub-study A; NCT05548127), ribociclib (sub-study B; NCT05573555), and samuraciclib (sub-study C)...The phase 2 portion of each sub-study will further evaluate the antitumor activity of the combinations; the primary endpoint is objective response and secondary endpoints include antitumor activity (CBR and DOR), PFS, overall survival, safety, plasma concentration of study drugs, and changes in circulating tumor DNA. Future combination sub-studies will be included in TACTIVE-U.

With 12 months of additional follow-up from the first data report, durable clinical activity with vepdegestrant 200 mg QD was seen in heavily pretreated patients with ER+/HER2- advanced breast cancer, in addition to sustained reduction in circulating mutant ESR1 tumor DNA levels. Vepdegestrant 200 mg QD continued to show a favorable safety profile. The ongoing global, randomized phase 3 VERITAC-2 study (NCT05654623) is evaluating vepdegestrant 200 mg QD vs intramuscular fulvestrant in patients with ER+/HER2- advanced breast cancer after prior combination CDK4/6 inhibitor therapy and endocrine therapy.

The primary endpoint, progression-free survival, will be assessed by blinded independent central review in the intention-to-treat population and the ESR1 mutation subpopulation. Secondary outcome measures include overall survival, antitumor activity (objective response rate, duration of response, and clinical benefit rate), safety, and quality of life assessments.

In xenograft models, vepdegestrant plus palbo showed substantially greater tumor growth inhibition vs fulvestrant plus palbo, supporting investigation in patients with breast cancer. The combination of vepdegestrant plus palbo showed promising clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer who had received extensive prior treatment. The safety profile of vepdegestrant plus palbo was generally consistent with the known safety profiles of the 2 agents except for an increased occurrence of grade 3/4 neutropenia, which was readily managed with laboratory monitoring and dose reductions of palbo. There is an ongoing study lead-in to the global VERITAC-3 study (NCT05909397) that is evaluating 2 doses of palbo (100 mg and 75 mg) in combination with vepdegestrant 200 mg QD to determine the recommended phase 3 combination to compare with letrozole plus palbo as first-line treatment for ER+/HER2- advanced breast cancer.

P1, N=6, Active, not recruiting, Accutar Biotechnology Inc | Recruiting --> Active, not recruiting | N=150 --> 6 | Trial primary completion date: Jul 2023 --> Dec 2023

P1, N=30, Active, not recruiting, Accutar Biotechnology Inc | Recruiting --> Active, not recruiting | Trial completion date: Sep 2023 --> Feb 2024 | Trial primary completion date: Jun 2023 --> Jan 2024

PROTAC ER degrader has a different mechanism of action compared to SERD which may be used in treating fulvestrant-resistant cancers.

Conclusions The RP3D of vepdegestrant 200 mg QD was well tolerated in Japanese patients with ER+/HER2- advanced breast cancer. Vepdegestrant will be evaluated in 2 global, randomized phase 3 studies in patients with ER+/HER2- advanced breast cancer: as second/third-line monotherapy in VERITAC-2 (NCT05654623) and as first-line therapy in combination with palbociclib in VERITAC-3 (NCT05909397).

VERITAC-3 will compare vepdegestrant + palbociclib vs letrozole + palbociclib as 1st-line treatment in pts with ER+/HER2- locoregional recurrent/metastatic breast cancer; no prior treatment in the advanced setting; and no prior treatment in any setting with CDK4/6 inhibitors, vepdegestrant, fulvestrant, elacestrant, or other investigational agents. In the phase 3 portion, pts (N≈1130) will be randomized to vepdegestrant + palbociclib or letrozole + palbociclib. The primary endpoint is PFS by BICR.

In MCF-7 and LCC2 xenograft models, compounds 35s and 35t remarkably suppressed tumor growth without noticeable poisonousness. Finally, this study provided guidance for developing new dual-target antitumor drug candidates for the ERα BC therapy, especially for the resistant variant.

P1b, N=32, Recruiting, Arvinas Estrogen Receptor, Inc. | Trial completion date: Feb 2024 --> Nov 2024 | Trial primary completion date: Aug 2023 --> May 2024

Data support further development of vepdegestrant; the ongoing phase 3 VERITAC-2 study (NCT05654623) is evaluating vepdegestrant 200 mg once daily vs fulvestrant. Table: 390P TRAEs reported in ≥10% of pts overall

P3, N=1180, Recruiting, Pfizer

P2, N=150, Recruiting, Arvinas Inc. | Trial primary completion date: Dec 2023 --> Jul 2024

P1/2, N=215, Recruiting, Arvinas Estrogen Receptor, Inc. | Trial completion date: Feb 2024 --> Sep 2024 | Trial primary completion date: Aug 2023 --> Mar 2024

P1, N=6, Active, not recruiting, Pfizer | Trial completion date: Apr 2023 --> Mar 2024