FUnctional Selection of Advanced Breast Cancer Patients for Talazoparib Treatment Using the REpair Capacity (RECAP) Test

This is a single arm, prospective multicenter study among patients with advanced breast cancer with RECAP-based HRD phenotype who will be treated with talazoparib, a strong PARP inhibitor. After signing informed consent, metastatic breast cancer patients will undergo an ultrasound (or CT-) guided biopsy in order to obtain at least two biopsies from a metastatic lesion to determine the HR status by the RECAP test and a blood withdrawal for ctDNA isolation. HR proficient (HRP) patients will receive anti-tumor therapy (non study drug) on discretion of their treating physician; only the response on treatment will be registered. Approximately 30% of screened patients will have an HRD tumor and thus will be eligible to start talazoparib monotherapy until PD or unacceptable side effects. The primary endpoint is PFS at four months. Additional endpoints will include overall response rate and overall survival. Upon progression, patients will be kindly asked for consent to perform another biopsy (optional) and blood withdrawal in order to prove reversibility of the RECAP test outcome (from HRD to HRP) and explore potential mechanisms of resistance (both in tissue and ctDNA).

Inclusion criteria

• WHO performance status 0-2
• Locally advanced breast cancer without options for treatment with curative intent or metastatic breast cancer
• Objective progressive disease (PD) according to RECIST within 4 months prior to study entry
• The breast cancer must be either

• high grade (Bloom & Richardson grade 3) ER positive (>10%) and HER2 negative primary breast cancer, or
• triple negative (ER<10%, PR<10% and HER2 negative), or
• any Bloom & Richardson grading and receptor status and also

• at least one metastatic lesion must have a proven HRD phenotype based on a RECAP test not treated with anticancer therapy thereafter or
• the patient must have a proven germline or somatic BRCA1 and/or BRCA2 mutation The Bloom & Richardson grading is always based on the primary tumor. The receptor status can be based on the primary tumor or a metastatic lesion whichever comes latest.
• The site of the metastatic lesion (or primary tumor in case it is still in situ) should be easily amendable for biopsy. NB lung metastases (high risk of hemato/pneumo-thorax) and bone metastases (not suitable for RECAP test because calcifications interfere with experimental procedures) are excluded. The local guidelines will be used for stopping and r estarting of anticoagulation. Bilirubin <1.5 ULN (except elevated bilirubin due to Gilbert's disease or a similar syndrome involving slow conjugation of bilirubin) and both AST and ALT <5x ULN in case a liver biopsy is planned.
• The tumor must be HRD, defined as HRD identified by the RECAP test determined just before the start of potential Talazoparib treatment within this study (also in case a proven germline BRCA1/2 mutation is present).
• Maximum of four prior lines of chemotherapy for advanced disease; Patients who received platinum compounds are eligible if they have had at least a progression free interval of four months.
• Measurable or evaluable disease according to RECIST 1.1 criteria (appendix 2)
• Life expectancy ≥ 3 months
• Hemoglobin ≥ 10 g/dL (6,2 mmol/L) and ANC of ≥ 1.5 x 109 /L
• Platelets >100 x 10e9/L
• Hepatic function as defined by total serum bilirubin ≤ 1. 5 x ULN (except elevated bilirubin due to Gilbert's disease or a similar syndrome involving slow conjugation of bilirubin), ASAT and ALAT < 3 x ULN or <5 x ULN in case of liver metastasis
• Adequate renal function as defined by either serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min (by Cockcroft-Gault formula)
• Negative pregnancy test (urine/serum) for female patients with childbearing potential
• Written informed consent

Exclusion criteria

• Any psychological condition potentially hampering compliance with the study protocol
• Any treatment with investigational antitumor drugs within 28 days prior to receiving the first dose of investigational treatment; or within 21 days for standard chemotherapy; or within 14 days for weekly scheduled chemotherapeutic regimens or endocrine therapy
• Radiotherapy within the last four weeks prior to receiving the first dose of investigational treatment; except 1 or 2 x 8 Gy for pain palliation, then seven days interval after the last radiation should be maintained
• Known persistent (>4 weeks) ≥ Grade 2 toxicity from prior cancer therapy (except for alopecia grade 2)
• Symptomatic brain or leptomeningeal metastases. Patients completely free of symptoms and without corticosteroids for at least four weeks after adequate treatment by resection and/or irradiation could be eligible (consult PI).
• Women who have a positive pregnancy test (urine/serum) and/or who are breastfeeding
• Unreliable contraceptive methods. Women and men enrolled in this trial must agree to use a reliable contraceptive method throughout the study (adequate contraceptive methods are: intra-uterine devices or systems, condom or other barrier contraceptive measures, sterilization and true abstinence)
• Concomitant use of P-gp inhibitors or inducers or BCRP inhibitors (see Appendix A)
• Any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
• Uncontrolled infectious disease (such as Human Immunodeficiency Virus HIV-1 or HIV-2 infection) or known active hepatitis B or C
• Recent myocardial infarction (< six months) or unstable angina