Bicalutamide and Abemaciclib in Inoperable or Metastatic Androgen Receptor-positive Triple-negative Breast Cancer

Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study specificprocedures, sampling and analysis. If a patient declines to participate in anyvoluntary exploratory research of the study, there will be no loss of benefit to thepatient and she will not be excluded from other aspects of the study

2. Women aged at least 18 years

3. The patient has a biopsy-confirmed diagnosis of recurrent, unresectable, locallyadvanced, or metastatic AR+ TNBC

4. AR+ assessed locally and defined as ≥1% of cells staining on IHC of lastrecurrent/metastatic breast cancer specimen

5. Local biopsy confirmation of last recurrent/metastatic site with positive IHCfor ER and/or PR in ≤10% of cells and negative for HER2 per ASCO/CAP-guidelines

6. Prior invasive (metastatic) breast cancer with positive IHC for ER and/or PR in >10% of cells is allowed, provided the last biopsy of recurrent/metastaticdisease has positive IHC for ER and/or PR in ≤10% of cells

7. Prior invasive (metastatic) HER2-positive breast cancer per ASCO/CAP-guidelinesis not allowed

8. The patient has measurable disease per RECIST 1.1 or evaluable bone-onlydisease with lytic or mixed component that is progressive as evidenced onpre-treatment baseline imaging

9. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 with nodeterioration over the previous 2 weeks and minimum life expectancy of 12 weeks

10. The patient must have had prior treatment with at least 1 prior cytostatic regimenin advanced setting. There is no upper limit for prior treatment lines in advancedsetting.

• Patients with 1-10% cells with positive IHC for ER in the lastrecurrent/metastatic site must be treated with at least one line of endocrinetherapy in advanced setting.

• Patients with known germline BRCA1/2 pathogenic variants should have receivedprevious treatment with PARP inhibitors in the early/locally advanced ormetastatic setting, unless contraindicated.

• Prior treatment with palbociclib or ribociclib is allowed, provided at least 6months have elapsed between last administration and start of study treatment

6. Patients must have recovered (Common Terminology Criteria for Adverse Events [CTCAE]Grade ≤1) from the acute effects of prior anticancer treatment except for residualGrade 2 alopecia, anemia or peripheral neuropathy prior to randomization. A washoutperiod of at least 21 days is required between last chemotherapy dose and first doseof study drug (provided the patient did not receive radiotherapy).

7. Patients who received radiotherapy must have completed and fully recovered from theacute effects of radiotherapy. A washout period of at least 14 days is requiredbetween end of radiotherapy and randomization.

8. In females of child-bearing potential, a negative serum or urine pregnancy testwithin 7 days prior to starting treatment is required. Women of child-bearingpotential must agree to use a highly effective method of contraception prior tostudy entry, for the duration of study participation (in addition to theLHRH-agonist), and for 3 weeks following completion of abemaciclib and for 130 daysfollowing completion of bicalutamide.

A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy; or

• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., hashad menses at any time in the preceding 12 consecutive months).

Exclusion Criteria:

1. Treatment with any of the following: a. Any experimental treatment in a clinical trial within the last 30 days or 5half-lives, whichever is longer, prior to randomization. b) Currently enrolled in any other type of medical research (for example: medicaldevice) judged by the sponsor not to be scientifically or medically compatible withthis study. c. Any other chemotherapy, immunotherapy or anticancer agents within 21 days of thefirst dose of study treatment d. Treatment with palbociclib or ribociclib within 6months of the first dose of study treatment e. Any prior exposure to abemaciclib f.Any prior exposure to anti-androgen therapy (bicalutamide, abiraterone, and/orenzalutamide)

2. Major surgery (excluding placement of vascular access) within 4 weeks of the firstdose of study treatment

3. Spinal cord compression, leptomeningeal carcinomatosis, or brain metastases - unlessasymptomatic, treated, stable at baseline imaging and not requiring corticosteroids >10 mg prednisolone daily (or equivalent) for at least 2 weeks prior to start ofstudy treatment

4. Concurrent use of endocrine therapy (tamoxifen, anastrozole, letrozole, exemestane,oral contraceptive pills)

5. The patient has serious and/or uncontrolled preexisting medical condition(s) that,in the judgment of the investigator, would preclude participation in this study (forexample, interstitial lung disease, severe dyspnea at rest or requiring oxygentherapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min],history of major surgical resection involving the stomach or small bowel, orpreexisting Crohn's disease or ulcerative colitis or a preexisting chronic conditionresulting in baseline Grade 2 or higher diarrhea).

6. As judged by the investigator, any evidence of severe or uncontrolled systemicdiseases, including active bleeding diatheses, or active infection includinghepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening forchronic conditions is not required.

7. Any of the following cardiac criteria:

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

9. Any clinically important abnormalities in rhythm, conduction or morphology ofresting ECG (eg, complete left bundle branch block, third degree heart block)

10. Any factors that increase the risk of QTc prolongation or risk of arrhythmicevents such as heart failure, hypokalemia, congenital long QT syndrome, familyhistory of long QT syndrome or unexplained sudden death under 40 years of ageor any concomitant medication known to prolong the QT interval

11. Personal history of syncope of cardiovascular etiology, ventricular arrhythmia (of pathologic origin including, but not limited to, ventricular tachycardiaand ventricular fibrillation), or sudden cardiac arrest.

12. Experience of any of the following procedures or conditions in the preceding 6months: coronary artery bypass graft, angioplasty, vascular stent, myocardialinfarction, angina pectoris, congestive heart failure NYHA Grade 2 or greater

13. Uncontrolled hypotension - Systolic BP <90mmHg and/or diastolic BP <50mmHg

14. Known left ventricular ejection fraction (LVEF) below lower limit of normal forsite

15. Prior history of DVT/PE or embolic stroke, unless currently on therapeuticanticoagulation

16. Inadequate bone marrow reserve or organ function as demonstrated by any of thefollowing laboratory values:

17. Absolute neutrophil count < 1.5 x 109/L

18. Platelet count < 100 x 109/L

19. Hemoglobin < 8 g/dL (Patients may receive transfusions to achieve thishemoglobin level at the discretion of the investigator. Initial treatment mustnot begin earlier than the day after the erythrocyte transfusion.)

20. Alanine aminotransferase > 3 times the upper limit of normal (ULN)

21. Aspartate aminotransferase > 3 times ULN

22. Total bilirubin > 1.5 times ULN (patients with Gilbert's syndrome with a totalbilirubin ≤2.0 times ULN and direct bilirubin within normal limits arepermitted)

23. Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 ml/min (measured or calculated per local institutional practice); confirmation ofcreatinine clearance is only required when creatinine is > 1.5 times ULN

24. Known proteinuria 3+ on dipstick analysis or >500mg/24 hours

25. Sodium or potassium outside normal reference range for site

26. Liver disease such as cirrhosis, chronic active hepatitis, or chronic persistenthepatitis. Patients who are hepatitis B Core antibody IgG positive are allowed toparticipate if taking and compliant with daily oral hepatitis B prophylacticmedications

27. Severely impaired lung function defined as spirometry and DLCO that is 50% of thenormal predicted value and/or 02 saturation that is 89% or less at rest on room airand/or serious /uncontrolled preexisting medical condition(s) that, in the judgmentof the investigator, would preclude participation in this study (for example,interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy).

28. Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN

29. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability toswallow the formulated product, or previous significant bowel resection that wouldpreclude adequate absorption of abemaciclib and/or bicalutamide

30. Patients with an active bleeding diathesis

31. The patient has active systemic bacterial infection (requiring intravenous [IV]antibiotics at time of initiating study treatment), fungal infection, or detectableviral infection (such as known human immunodeficiency virus positivity or with knownactive hepatitis B or C [for example, hepatitis B surface antigen positive].Screening is not required for enrollment.

32. History of hypersensitivity or allergic reaction to abemacliclib, bicalutamide orgoserelin, or drugs with a similar chemical structure or class

33. Judgment by the investigator that the patient should not participate in the study ifthe patient is unlikely to comply with study procedures, restrictions andrequirements

34. Co-administration with strong CYP3A4 inducers (e.g., phenytoin, rifampin,carbamazepine, St John's Wort, bosentan, efavirenz, etravirine, modafinil, andnafcillin) or strong CYP3A4 inhibitors (e.g., clarithromycin, indinavir,itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir,posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, andvoriconazole). See Appendix 4 for complete list.

35. Other invasive malignancies within the past 3 years except for adequately treatedcarcinoma of the cervix or basal or squamous cell carcinomas of the skin.

36. Female patients who are pregnant or breast feeding/lactating, or females ofreproductive potential who are not using effective birth control methods. Hormonalcontraceptives are not acceptable as a method of contraception.

37. Patients with hereditary problems of galactose intolerance, total lactasedeficiency, or glucose-galactose malabsorption