A Phase IIIB Study to Evaluate the Use of Capivasertib in Combination With Fulvestrant in Patients With Advanced Breast Cancer Who Have Relapsed/Progressed on ET and CDK4/6 Inhibitor Reflecting Real World Clinical Practice in Spain

Phase IIIb, multicentre, single arm, Spain study assessing effectiveness/safety of capivasertib+fulvestrant in locally advanced (inoperable) or metastatic HR+/HER2- BC with the PIK3CA/AKT1/PTEN-altered following recurrence or progression on or after endocrine therapy and CDK4/6 inhibitor. Capivasertib will be administered as 400mg BD, 4 days on 3 days off in combination with fulvestrant at the approved dose of monthly 500mg (2 × 5mL IV), with an additional loading dose in Cycle 1.

Key Inclusion Criteria

Histologically confirmed HR+/HER2- breast cancer (primary or metastatic):

• HR+ defined as ER+ with or without PRg+
• HER2- defined as IHC 0 or 1+, or IHC 2+/ISH-

Patient with tumours harbouring at least one PIK3CA/AKT1/PTEN qualifying alteration detected by a validated test (including NGS on tissue, cell block, or if tissue/cell block is not available, on ctDNA, as per protocol requirements. If alteration is initially detected by a method other than NGS, NGS on tissue/cell block must be performed within 45 days unless not available, which must be documented.)

Metastatic or locally advanced disease with radiological or objective evidence of recurrence or progression.

Patients must have received treatment with an ET in combination with CDK4/6i and have:

• Radiological evidence of breast cancer recurrence or progression while on, or within 12 months of the end of (neo)adjuvant treatment with an ET with CDK4/6i, OR
• Radiological evidence of progression while on prior ET with CDK4/6i administered as a treatment line for locally advanced or metastatic breast cancer.

Informed consent

Eastern Cooperative Oncology Group (ECOG)/ World Health Organisation (WHO) performance status ≤ 2 at enrollment (not more than 20% of patients with ECOG PS2 will be allowed).

Reproduction:

• Women of childbearing potential (WOCBP) patients with ovarian suppression induced by LHRH agonist should agree to use 2 forms of highly effective methods of accepted contraception to prevent pregnancy.
• Male patients should use barrier contraception.

Key Exclusion Criteria

History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥2 years before the first dose of study intervention and of low potential risk for recurrence.

Disease burden making the patient ineligible for endocrine therapy per the investigator judgement.

Unresolved toxicities from prior therapy greater than CTCAE grade 1.

Leptomeningeal metastases or symptomatic, unstable, or steroid-dependent brain metastases.

HbA1c ≥8.0% (63.9 mmol/mol).

Inadequate bone marrow reserve or organ function.

Severe or uncontrolled systemic diseases, uncontrolled hypertension, active infections including hepatitis B, hepatitis C, HIV, and confirmed COVID-19.

Known abnormalities in coagulation.

Refractory nausea, vomiting, malabsorption syndrome, chronic gastrointestinal diseases, inability to swallow formulated product, or significant bowel resection.

Previous allogenic bone marrow or solid organ transplant.

Known immunodeficiency syndrome.

Unknown or non-altered PIK3CA/AKT1/PTEN-status.

Evidence of dementia altered mental status or any psychiatric condition.

Pregnant women.

Participants with significant QT interval prolongation or a history of related cardiac conditions, including arrhythmias or recent cardiac procedures.

Prior/concomitant therapy:

• More than 2 lines of endocrine therapy or in combination with CDK4/6i for inoperable locally advanced or metastatic disease.
• More than 1 line of chemotherapy for inoperable locally advanced or metastatic disease. Adjuvant and neoadjuvant chemotherapy are not classed as lines of chemotherapy for ABC.

AKT1, PIK3CA and mTOR inhibitors not allowed.

Adequate washout or dose reduction may be required for some CYP3A.

Participation in another clinical study with a study intervention.