The purpose of this trial is to investigate the safety and tolerability of TAS3681, to find the maximum tolerated dose (MTD)/recommended dose of TAS3681 (Escalation Phase) and to further evaluate safety and preliminary efficacy of TAS3681 at the MTD/recommended dose (Expansion Phase).

This is a first in human, multinational, Phase 1, open-label study of TAS3681 evaluating safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in patients with metastatic castration-resistant prostate cancer (mCRPC) for which there is no standard therapy. Eligible participants will be enrolled to evaluate safety and determine the MTD/recommended dose for TAS3681, including a preliminary evaluation of food effect and antitumor activity. The study will be conducted in 2 parts, Dose Escalation (Enrollment closed) and Expansion (Enrollment Closed). Patients who are continuing to receive clinical benefit may receive drug in the extension part of the study after escalation and expansion are completed.

Inclusion Criteria:

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:

   I. 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

Exclusion Criteria:

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