Background: Limitations of current approved endocrine therapies (ETs), a mainstay tx for ER+ BC, include incomplete ER signaling inhibition. Novel ETs, such as selective estrogen receptor antagonists and degraders (SERDs), may help overcome this. G, a potent, nonsteroidal, oral (PO) SERD, is well tolerated and has shown robust ER occupancy and encouraging antitumor activity as monotherapy and in combination with the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib (P). MORPHEUS BC (NCT04802759) is evaluating the safety and efficacy of G tx combinations in ER+, HER2– LA/mBC. We present results from the 16-week IA of G and G + CDK4/6i (A or R). Methods: Eligible pts had disease progression on 1–2 lines of ET (including a CDK4/6i) for LA/mBC. Pts were randomized 1:6 (planned n = 15 per arm) to receive G (30 mg PO QD; control arm), G + A (150 mg PO BID), or sequentially, G + R (600 mg PO QD) until disease progression/unacceptable toxicity. The study was not designed to make explicit power and type I error considerations for a hypothesis test. Primary endpoints were safety and objective response rate; other endpoints included progression-free survival, overall survival, clinical benefit rate, disease control rate (DCR), duration of response, and pharmacokinetics. Genetic alterations were defined using baseline circulating tumor DNA. Results: As of Feb 4, 2022, 15 pts were enrolled in the G + A arm; 73% received one prior line of tx in the LA/mBC setting; 27% received prior fulvestrant; 73% had liver metastases at baseline (BL). As of Sept 22, 2022, 11 and 16 (of whom 14 were evaluable) pts were enrolled in the G and G + R arms, respectively; 64%/86% received one prior line of tx in the LA/mBC setting; 73%/36% received prior fulvestrant; 73%/57% had liver metastases at BL. Three pts had a partial response (PR; G + A, n = 1; G + R, n = 2); 19 had stable disease (G, n = 5; G + A, n = 7; G + R, n = 7). DCRs were 36% (G), 40% (G + A), and 50% (G + R). Safety is shown. Conclusions: G combined with a CDK4/6i (A or R) was well tolerated, with no unexpected safety signals. Three PRs were seen in this heavily pretreated population of pts with disease progression post-CDK4/6i tx. This study provides the first data supporting the combinability of G with the CDK4/6is A and R, in addition to P as seen in prior studies. G can therefore be combined with all three approved CDK4/6is. Clinical trial information: NCT04802759.