Clinical Pharmacology, Genentech, Inc., South San Francisco, CA, USA.
Discovery Oncology, Genentech, Inc., South San Francisco, CA, USA.
Expert Opin Investig Drugs. 2022 Jun;31(6):515-529. doi: 10.1080/13543784.2021.1983542. Epub 2021 Oct 25.
The selective estrogen receptor degrader (SERD) and full receptor antagonist provides an important therapeutic option for hormone receptor (HR)-positive breast cancer. Endocrine therapies include tamoxifen, a selective estrogen receptor modulator (SERM), that exhibits receptor agonist and antagonist activity, and aromatase inhibitors that block estrogen biosynthesis but which demonstrate acquired resistance. Fulvestrant, the only currently approved SERD, is limited by poor drug-like properties. A key focus for improving disease management has been development of oral SERDs with optimized target occupancy and potency and superior clinical efficacy.
Using PubMed, clinicaltrials.gov, and congress websites, this review explored the preclinical development and clinical pharmacokinetics from early phase clinical studies (2015 or later) of novel oral SERDs, including giredestrant, amcenestrant, camizestrant, elacestrant, and rintodestrant.
Numerous oral SERDs are in clinical development, aiming to form the core endocrine therapy for HR-positive breast cancer. Through property- and structure-based drug design of estrogen receptor-binding, antagonism, degradation, anti-proliferation, and pharmacokinetic properties, these SERDs have distinct profiles which impact clinical dosing, efficacy, and safety. Assuming preliminary safety and activity data are confirmed in phase 3 trials, these promising agents could further improve the management, outcomes, and quality of life in HR-positive breast cancer.
选择性雌激素受体降解剂（SERD）和完全受体拮抗剂为激素受体（HR）阳性乳腺癌提供了重要的治疗选择。内分泌治疗包括他莫昔芬，一种选择性雌激素受体调节剂（SERM），具有受体激动剂和拮抗剂活性，以及芳香酶抑制剂，可阻断雌激素生物合成，但会产生获得性耐药。目前唯一获批的 SERD 药物氟维司群受限于较差的药物特性。改善疾病管理的一个关键重点是开发具有优化的靶标占有率和效力以及卓越临床疗效的口服 SERD。
本综述通过使用 PubMed、clinicaltrials.gov 和会议网站，探讨了新型口服 SERD 的临床前开发和临床药代动力学，这些新型口服 SERD 包括 giredestrant、amcenestrant、camizestrant、elacestrant 和 rintodestrant，其早期临床研究（2015 年或之后）结果均已发表。
许多口服 SERD 正在临床开发中，旨在成为 HR 阳性乳腺癌的核心内分泌治疗药物。通过对雌激素受体结合、拮抗、降解、抗增殖和药代动力学特性的基于结构和性质的药物设计，这些 SERD 具有不同的特征，这会影响临床用药剂量、疗效和安全性。假设这些有前景的药物在 3 期试验中初步确认了安全性和活性数据，那么这些药物可能会进一步改善 HR 阳性乳腺癌的管理、结果和生活质量。
