Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective

Abstract

Estrogen receptor-positive (ER+) is the most common subtype of breast cancer. Endocrine therapy is the fundamental treatment against this entity, by directly or indirectly modifying estrogen production. Recent advances in novel compounds, such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), or phosphoinositide 3-kinase (PI3K) inhibitors have improved progression-free survival and overall survival in these patients. However, some patients still develop endocrine resistance after or during endocrine treatment. Different underlying mechanisms have been identified as responsible for endocrine treatment resistance, where ESR1 gene mutations are one of the most studied, outstanding from others such as somatic alterations, microenvironment involvement and epigenetic changes. In this scenario, selective estrogen receptor degraders/downregulators (SERD) are one of the weapons currently in research and development against aromatase inhibitor- or tamoxifen-resistance. The first SERD to be developed and approved for ER+ breast cancer was fulvestrant, demonstrating also interesting activity in ESR1 mutated patients in the second line treatment setting. Recent investigational advances have allowed the development of new oral bioavailable SERDs. This review describes the evolution and ongoing studies in SERDs and new molecules against ER, with the hope that these novel drugs may improve our patients’ future landscape.

Overcoming Cancer Drug Resistance Utilizing PROTAC Technology

“…Thus, the strategy to combat this mechanism of resistance was to eliminate ERα expression, which led to the discovery of a new class of drugs called selective ER degraders (SERDs). Currently, fulvestrant ( Figure 4 ) is the only SERD approved by the FDA, but numerous new compounds are under clinical development ( Hernando et al, 2021 ). In both animal models and clinical settings, SERDs have proven to be effective in countering several resistance mechanisms to SERMs ( Lu and Liu, 2020 ).…”

Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role

“… 106 Notably, both of these drugs contain an acrylic acid side chain, whereas many of the novel oral SERDs discussed above were created with a basic amino side chain to optimize ER degradation across multiple breast cancer cell lines. 107 Similarly, clinical development of AZD9496 was discontinued in favor of AZD9833 that was optimized for absorption and activity. Differences in chemical structure, efficacy, and side effects between agents will likely play a significant role in determining which drugs ultimately enter clinical practice.…”

Role of PI3K/Akt/mTOR pathway in mediating endocrine resistance: concept to clinic

“…To date, published data from clinical trials have used fulvestrant, AI, or tamoxifen as the ET backbone to mTOR, Akt, or PI3K inhibition. Fulvestrant is the only SERD that is licensed for clinical practice but novel, oral SERDs are now in clinical development with improved pharmacokinetics and bioavailability [ 180 ]. Four agents have already entered phase III testing; amcenestrant, camizestrant, and giredestrant are examined in combination with palbociclib in the AMEERA-5, SERENA-4, and persevERA breast cancer trials respectively, while elacestrant monotherapy is tested vs. fulvestrant or AI in patients who progressed on CDK4/6i (EMERALD trial) [ 181 ].…”