The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted in the identification of bis-phenol chromene <b>17ha</b>. In a tamoxifen-resistant breast cancer xenograft model, <b>17ha</b> (ER-α degradation efficacy = 97%) demonstrated tumor regression, together with robust reduction of intratumoral ER-α levels. However, despite superior oral exposure, <b>5a</b> (ER-α degradation efficacy = 91%) had inferior activity. This result suggests that optimizing ER-α degradation efficacy leads to compounds with robust effects in a model of tamoxifen-resistant breast cancer. Compound <b>17ha</b> (GDC-0927) was evaluated in clinical trials in women with metastatic estrogen receptor-positive breast cancer.