• Patients must have histologically and/or cytologically confirmed, advanced / metastatic breast cancer, ER \>10% and not HER2 overexpressing/amplified as per ASCO/CAP criteria. Patients with locally advanced or inflammatory disease without distant metastases that is potentially resectable or treatable with curative intent are not eligible

• All patients must have a formalin fixed paraffin embedded tissue block (from primary or metastatic tumour) available and must have provided informed consent for the release of the block

• Patients must have had objective disease progression demonstrated on (defined as while taking or within 8 weeks of the last dose) first line CDK4/6i + ET for MBC. Patients who discontinued CDK4/6i + ET without disease progression more than 8 weeks prior to objective disease progression (toxicity, patient request) are not eligible. Patients must have received at least 24 weeks of first line CDK4/6i + ET therapy

• Presence of clinically and/or radiologically documented disease. All radiology studies must be performed within 21 days prior to enrollment (within 28 days if negative). All patients must have measurable disease as defined by RECIST 1.1.

• The criteria for defining measurable disease are as follows:

‣ Chest x-ray ≥ 20 mm

⁃ CT scan (with slice thickness of 5 mm) ≥ 10 mm: longest diameter

⁃ Physical exam (using calipers) ≥ 10 mm

⁃ Lymph nodes by CT scan ≥ 15 mm: measured in short axis

• Patients must be ≥ 18 years of age

• Patients must have an ECOG performance status 0 or 1

• Patients must have a life expectancy ≥ 3 months.

• Hemoglobin ≥90 g/L\*

• Absolute neutrophils ≥ 1.5 x 10\^9/L (1500/µL)

• Platelets ≥ 100 x 109/L (100 x 10\^3/µL)

• Bilirubin ≤ 1.5 x ULN (upper limit of normal)\*\*

• AST \& ALT ≤ 2.5 x ULN

• ≤ 5.0 x ULN if patient has liver metastases

• Serum creatinine ≤ 1.5 x ULN, Creatinine clearance ≥50 mL/min

• All patients must have received at least 24 weeks of prior CDK4/6i in combination with first line ET for advanced or metastatic disease and have had disease progression on or within 8 weeks of the last dose of CDK4/6i. Patients who have progressed on, or within 12 months of completion of adjuvant therapy with an aromatase inhibitor may be treated with fulvestrant instead of an aromatase inhibitor combined with CDK4/6 inhibitor.

∙ In addition, the following systemic therapies may have been given after CDK4/6i / ET prior to screening / enrollment to this study:

• For enrollment to second line substudies:

• \- An additional single agent non-fulvestrant/SERD endocrine therapy in the palliative setting is permitted provided patient remains eligible for and can access fulvestrant treatment. Patients who have received prior fulvestrant/SERD are not eligible for fulvestrant containing substudies. Contact CCTG in case of any other prior endocrine therapy other than an aromatase inhibitor or tamoxifen.

• For enrollment to third line substudies:

‣ Non-SERD endocrine therapy and targeted agents alone or in combination.

⁃ Patients who have received a prior targeted agent may not be eligible for substudies that contain the same class of agent. Contact CCTG.

⁃ Note: if a patient has not had fulvrestrant/SERD prior to enrollment to 3rd line: substudy, single agent fulvestrant/SERD must be given prior to enrollment (unless not possible for reasons such as fulvestrant/SERD not standard of care / not funded in province, patient cannot receive intramuscular injection; contact CCTG for other scenarios).

• Patients may also have received adjuvant/neoadjuvant systemic therapies; however cytotoxic chemotherapy or antibody drug conjugates (ADC) in the palliative setting are not permissible.

• Patients receiving LHRH agonists (for example premenopausal patients) may continue, but may not start LHRH agonist within 12 weeks of enrollment.

• Consult CCTG for other scenarios (for example where short course of other ET is given prior to CDKi + ET, patients who have received investigational drugs, vaccines or immunotherapies) as certain patients may be eligible.

• All reversible prior toxicity related to prior therapies must have recovered to grade ≤ 1 (consult CCTG in the case of irreversible toxicity) and have adequate washout as follows (screening may occur during the washout period): Longest of the following (for questions or any proposed variance, please discuss with CCTG prior to patient enrollment): Two weeks; 5 half-lives for investigational agents; standard cycle length of standard therapies

• Patients must not have received a transfusion (platelets or red blood cells) or colony stimulating factors ≤ 4 weeks prior to initiating treatment substudy therapy.

• Surgery: Prior surgery is permitted provided that a minimum of at least 28 days have elapsed between any major surgical procedure and date of enrollment, and that wound healing has occurred.

• Radiation: Prior external beam radiation is permitted provided a minimum of 28 days (4 weeks) have elapsed between the last dose of radiation and date of enrollment. Exceptions may be made for low-dose, non-myelosuppressive radiotherapy after consultation with CCTG. Concurrent radiotherapy is not permitted.

• Patients must be registered and provide consent prior to blood collection for screening. The screening blood sample cannot be sent for analysis prior to screening registration.

• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to both screening registration as well as enrollment to a specific substudy to document their willingness to participate.

• Patients must be accessible for treatment and follow up. Patients enrolled on this trial must be treated and followed at the participating centre

• In accordance with CCTG policy, substudy treatment is to begin within 2 working days of patient enrollment.

• Women/men of childbearing potential must have agreed to use a highly effective contraceptive method.