Summary

This phase II trial studies how well talazoparib works for the treatment of breast cancer with a BRCA 1 or BRCA 2 gene mutation that has spread to other places in the body (metastatic). Talazoparib is a study drug that inhibits (stops) the normal activity of certain proteins called “poly (ADP-ribose) polymerases” also called “PARPs”. PARPs are proteins that help repair deoxyribonucleic acid (DNA) mutations. PARP inhibitors, such as talazoparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. PARPs are needed to repair mistakes that can happen in DNA when cells divide. If the mistakes are not repaired, the defective cell will usually die and be replaced. Cells with mistakes in their DNA that do not die can become tumor cells. Tumor cells may be killed by a study drug, like talazoparib, that stops the normal activity of PARPs. Talazoparib may be effective in the treatment of metastatic breast cancer with BRCA1 or BRCA2 mutations.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate the efficacy of talazoparib, as assessed by progression-free survival in patients with metastatic breast cancer harboring deleterious somatic BRCA 1 or 2 mutations, as detected by circulating cell-free deoxyribonucleic acid (cfDNA) or metastatic tumor tissue biopsy.

SECONDARY OBJECTIVES:
I. To evaluate the objective response rate (ORR) in patients with metastatic breast cancer and deleterious somatic BRCA 1 or 2 mutations treated with talazoparib.
II. To evaluate the safety/tolerability, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grading, in patients with metastatic breast cancer harboring deleterious somatic BRCA 1 or 2 mutations, as detected by cfDNA or metastatic tumor tissue biopsy.
III. To prospectively monitor serial changes in BRCA mutant allelic fraction (MAF) by cfDNA in response to treatment with talazoparib, and correlate results with outcomes in patients with metastatic somatic BRCA cfDNA or tumor tissue mutant breast cancer. (exploratory objective)
IV. To assess the impact of pre-existing resistance mutations at baseline, particularly BRCA reversion mutations, based on pre-treatment cfDNA or metastatic tumor tissue analysis, on clinical outcomes with talazoparib, in patients with somatic BRCA mutant metastatic breast cancer. (exploratory objective)
V. To compare paired pre-and post-treatment liquid biopsies (and metastatic tissue biopsy if done prior to trial entry), and to identify potential novel targets for future combination studies. (exploratory objective)
VI. Determine the rate of positivity of the Cancer Risk B (CR-B) assay in patients with somatic BRCA mutations in cell-free DNA or metastatic tumor tissue biopsy who are not known to be germline BRCA1/2 carriers, and correlate CR-B positivity with talazoparib response. (Exploratory objective)

OUTLINE:
Patients receive talazoparib orally (PO) once daily (QD). Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, 90 days, then every 3 months up to 2 years.

Eligibility

1. Metastatic breast cancer with deleterious somatic BRCA 1 or 2 mutations detectable by cell-free circulating tumor DNA, by Clinical Laboratory Improvement Act (CLIA) certified clinical assay (including but not restricted to MGH-Snapshot cfDNA assay, Guardant360, Foundation One) or by a CLIA certified tumor tissue genotyping assay performed on a metastatic breast cancer specimen (including but not restricted to MGH-Snapshot assay, Foundation One, Caris). The eligibility of a given assay and/or BRCA mutation could be discussed with the primary investigator (Dr. Vidula) and senior investigator (Dr. Bardia), who will provide the final discretion * Patients with germline BRCA 1 or 2 mutations will not be eligible * Patients with only a VUS (variant of unknown significance), or non-functional BRCA mutation, without a deleterious somatic BRCA 1 or 2 mutation will not be eligible
2. The following disease subtypes are eligible: * Triple negative breast cancer (defined as estrogen receptor [ER] < 1%, progesterone receptor [PR] < 1%, HER2 negative, as per American Society of Clinical Oncology [ASCO] College of American Pathologists [CAP] guidelines), with disease progression on at least one prior chemotherapy regimen in the metastatic setting * Hormone receptor positive, HER2 negative disease with disease progression on at least one prior endocrine therapy in the metastatic setting or be considered inappropriate for endocrine therapy
3. Patients must have evaluable or measurable disease
4. Any number of prior lines of therapy are allowed
5. Patients may have received prior platinum based chemotherapy (0-1 prior platinum based therapy). However, the patient must not have progressed while on platinum treatment (any setting), or within 6 months after end of treatment (neoadjuvant and/or adjuvant)
6. At least two weeks from last systemic therapy for breast cancer, with recovery of all treatment related toxicity to grade 1 or less. Subjects with =< grade 2 neuropathy are an exception to this criterion
7. At least two weeks from last radiation therapy, with recovery of all treatment related toxicity to grade 1 or less
8. >= 18 years of age on day of signing informed consent
9. Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
10. Absolute neutrophil count (ANC) >= 1,500 /mcL (within 10 days prior to treatment initiation)
11. Platelets >= 100,000 / mcL (within 10 days prior to treatment initiation)
12. Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (within 10 days prior to treatment initiation)
13. Measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 15 mL/min (within 10 days prior to treatment initiation)
14. Serum total bilirubin =< 1.5 X institutional upper limit of normal (ULN) OR direct bilirubin =< institutional ULN for subjects with total bilirubin levels > 1.5 ULN (within 10 days prior to treatment initiation)
15. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional ULN OR =< 5 X institutional ULN for subjects with liver metastases (within 10 days prior to treatment initiation)
16. Prior central nervous system (CNS) disease is allowed if stable for at least one month since whole brain radiation therapy in patients who received whole brain radiation, or 2 weeks since stereotactic radiotherapy in patients who received stereotactic radiotherapy. Patients should not be requiring steroids. Patients whose CNS disease was surgically treated may be enrolled if stable for at least one month after surgery, and not requiring steroids
17. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
18. Female subjects of childbearing potential must use an acceptable form of birth control per treating physician discretion or be surgically sterile, or abstain from heterosexual activity for the course of the study through 7 months after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
19. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy. Additionally, male patients may not donate sperm during the duration of the study and through 7 months after the last dose of study therapy
20. Willing and able to provide written informed consent