Study of TAS3681 in Metastatic Castration Resistant Prostate Cancer

Open to males ages 18 years and up

1. Male ≥18 years of age
2. Histological or cytological evidence of metastatic castrate resistant prostate cancer (excluding neuroendocrine differentiation and small cell histology) who are castration resistant and have:
   1. Dose escalation: documented progression defined in PCWG3 and/or intolerance to abiraterone and/or enzalutamide therapy, as well as 1 or more chemotherapies.
   2. Expansion:
   3. Group A: documented progression after abiraterone or enzalutamide and chemotherapy consisting of no more than 2 prior taxane-based therapies

   ii. Group B: documented progression after only abiraterone or enzalutamide therapy without any chemotherapy

   iii. Measurable disease per RECIST 1.1 and/or bone metastases

3. ECOG performance status of ≤1 on Day 1 Cycle 1
4. Ongoing androgen deprivation with serum testosterone <50 ng/dL
5. Expansion Phase only: willingness to undergo baseline core biopsies, if feasible
6. Ability to take medication orally
7. Adequate organ function
8. Agree to use effective contraception during the study and for 30 days after the last dose of TAS3681
9. Willing to comply with scheduled visits and procedures

1. QTcF ≥ 450 ms, history of QTc prolongation or predisposition for QTc prolongation or family history of sudden cardiac death or QT prolongation
2. History or presence of heart failure or left ventricular dysfunction with ejection fraction <40% within the previous 6 months; if >6 months cardiac function within normal limits and free of cardiac-related symptoms
3. History or presence of atrial fibrillation, atrial flutter, or paroxysmal supraventricular tachycardia; the presence or history of ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia
4. Presence of cardiac pacemaker or implantable cardioverter-defibrillator
5. History or presence of bradycardia or conduction abnormalities
6. History or presence of cardiac arrest or unexplained syncope
7. Hypokalemia
8. History of myocardial infarction or severe unstable angina

9. Any medication administered within 2 weeks prior to 1st dose of TAS3681 that is known to prolong the QT interval or be arrhythmogenic

   10. Received G-CSF, radiotherapy for extended field, anticancer chemotherapy,

   investigational agents, or major surgery within 4 weeks of study drug administration; receipt of anticoagulant or CYP3A inhibitor within 2 weeks of study drug administration

   11. Serious illness or medical condition that could affect the safety or tolerability of

   study treatments

   12. Received prior treatment with TAS3681 13. User of herbal products 14. Any condition or reason that in the opinion of the investigator, interferes with the

   ability of the participant to participate in the trial

   15. To be eligible to participate in the food effect assessment (Escalation Phase only),

   participants must not have a history or presence of any clinically significant abnormality involving the gastrointestinal tract and an inability to fast for a minimum of 8 hours