Key inclusion criteria for both phases:

          1. Adult females (pre- and/or post-menopausal), and adult males.

          2. Histologically confirmed HR+/ HER2- breast cancer determined from the most recent
             tumour sample (primary or metastatic) per the American Society of Clinical Oncology
             and College of American Pathologists guideline. To fulfil the requirement of HR+
             disease, a breast cancer must express ER with or without co-expression of progesterone
             receptor.

          3. Eligible for palbociclib and fulvestrant therapy as per investigator assessment.

          4. Adequate organ and bone marrow functions.

          5. Consent to provide a mandatory FFPE tumour sample.

        Inclusion criteria only for phase III:

          1. Radiologic measurable relapse during neoadjuvant / adjuvant endocrine therapy or
             evidence of relapse within 12 months of completion of adjuvant therapy or disease
             progression during the initial 12 months of 1L endocrine therapy in locally advanced
             unresectable or metastatic breast cancer.

          2. Received up to a maximum of 1 lines of prior chemotherapy in the advanced setting.

        Key exclusion criteria for both phases:

          1. History of another primary malignancy except for malignancy treated with curative
             intent with no known active disease ≥ 5 years before the first dose of study
             intervention and of low potential risk for recurrence.

          2. Radiotherapy with a wide field of radiation within 4 weeks prior to study treatment
             initiation and/or radiotherapy with a limited field of radiation for palliation within
             2 weeks prior to study treatment initiation. Patients who received prior radiotherapy
             to ≥25% of bone marrow are not eligible independent of when it was received.

          3. Major surgery (excluding placement of vascular access) within 4 weeks of the first
             dose of study treatment.

          4. Persistent toxicities (CTCAE Grade >1) caused by previous anticancer therapy,
             excluding alopecia. Participants with irreversible toxicity that is not reasonably
             expected to be exacerbated by study intervention may be included (eg, hearing loss)
             after consultation with the AstraZeneca study physician.

          5. Spinal cord compression, brain metastases or leptomeningeal metastases unless
             asymptomatic, treated and stable and not requiring steroids within 4 weeks prior to
             study treatment initiation.

          6. Any of the following cardiac criteria at screening:

               1. . Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 consecutive
                  ECGs

               2. . Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting ECG (eg, complete left bundle branch block, third-degree heart block)

               3. . Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events

               4. . Experience of any of the following procedures or conditions in the preceding 6
                  months: coronary artery bypass graft, angioplasty, vascular stent, myocardial
                  infarction, angina pectoris, congestive heart failure New York Heart Association
                  (NYHA) grade ≥ 2

               5. . Uncontrolled hypotension

               6. . Cardiac ejection fraction outside institutional range of normal or < 50%
                  (whichever is higher)

          7. Any of these clinically significant abnormalities of glucose metabolism at screening:

               1. . diabetes mellitus type I or type II requiring insulin treatment

               2. . HbA1c ≥ 8.0% (63.9 mmol/mol)

          8. Previous allogeneic bone marrow transplant or solid organ transplant.

        Key exclusion criteria for the phase III only:

        1. Prior treatment with CDK4/6 inhibitors (any setting), a SERD (including unlicensed
        SERDs), allosteric mTOR inhibitors (e.g. everolimus), PI3K inhibitors (e.g. alpelisib) or
        AKT inhibitors.