Table 1.

Inclusion and exclusion criteria.

Inclusion criteria
1	Adult (⩾18 years) women of any menopausal status or men with histologically or cytologically proven locoregionally recurrent or metastatic breast cancer not amenable to curative treatment (as assessed by the study investigator), and for whom chemotherapy is not indicated
2	ER+ /HER2– in both primary tumor and locoregionally recurrent or metastatic sites (as assessed by IHC or FISH)
3	No previous systemic anti-cancer treatment for their locoregionally recurrent or metastatic disease
4	In pre-/perimenopausal women and men with no prior bilateral orchiectomy, GnRH agonist inhibition is recommended ⩾ 4 weeks prior to randomization
5	Measurable disease evaluable per RECIST v.1.1, 39 or nonmeasurable bone only disease with at least one predominant lytic bone lesion or mixed lytic-blastic lesion a
6	ECOG performance status 0–2
7	Willing and able to provide tumor tissue
8	Capable of giving informed consent
Exclusion criteria
1	Known active brain metastases
2	Diagnosis of any other malignancy (except adequately treated basal or squamous cell cancer or in situ cervical cancer) within 3 years prior to randomization
3	Prior (neo)adjuvant treatment with another SERD
4	Disease recurrence while on, or within 12 months of completion of (neo)adjuvant ET ± CDK4/6 inhibitors
5	Unrecovered acute toxic effects (grade > 1) of prior anti-cancer therapy or surgical procedures
6	Advanced, symptomatic visceral spread; at risk of life-threatening complications in the short term
7	Significant concomitant illness that would adversely affect participation in the study
8	Inadequate hematological, renal, coagulation, or hepatic function
9	Unwilling to use recommended contraception methods, where applicable
10	Participation in any other clinical study within 4 weeks before randomization
11	Major surgery or radiotherapy within 4 weeks before randomization
12	Medical history or ongoing gastrointestinal disorders that may affect the absorption of amcenestrant, letrozole, or palbociclib
13	Treatment with drugs that  • Are known to prolong the QT interval (premenopausal and male participants)  • Are sensitive substrates of P-glycoprotein or breast cancer resistance protein  • Are strong CYP3A inhibitors or inducers (within 2 weeks before first study treatment administration or five elimination half-lives, whichever is longest)  • Have the potential to inhibit UGT (within 2 weeks before first study treatment administration or five elimination half-lives, whichever is longest)  • Have a narrow therapeutic window and are metabolized by CYP3A
14	Known sensitivity or contraindications to any of the study treatments or their excipients

CDK4/6, cyclin-dependent kinase 4 and 6; CYP, cytochrome P450; ECOG, Eastern Cooperative Oncology Group; ER+, estrogen receptor positive; ET, endocrine therapy; FISH, fluorescent in situ hybridization; GnRH, gonadotropin-releasing hormone; HER2–, human epidermal growth factor receptor 2 negative; IHC, immunohistochemistry; RECIST, Response Evaluation Criteria in Solid Tumors; SERD, selective estrogen receptor degrader; UGT, uridine 5′-diphosphoglucuronosyltransferase.

^aPatients with nonmeasurable mixed metastatic (bony-visceral) disease were allowed entry into the study prior to the December 2020 protocol amendment.