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

Prior treatment

• 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
• 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).
• Concomitant use of P-gp inhibitors or inducers or BCRP inhibitors (see Appendix A)

Other illness

• Any psychological condition potentially hampering compliance with the study protocol
• Known persistent (\>4 weeks) ≥ Grade 2 toxicity from prior cancer therapy (except for alopecia grade 2)
• 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

Lab values

• Women who have a positive pregnancy test (urine/serum) and/or who are breastfeeding

Other

• 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)

• 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