Combination of talazoparib and enzalutamide for advanced prostate cancer after abiraterone

Inclusion Criteria:

1. Male age 18 or older.
2. Histological diagnosis of prostate adenocarcinoma without neuroendocrine differentiation or small cell features.
3. Willing and able to provide written informed consent to participate in the study. Written consent must be given before registration, according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) / Good clinical practice (GCP), and national/local regulations.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
5. Willing to provide tumor biopsies during the study. Note: At study entry, the pre-treatment new tumor biopsy (fresh-frozen and Formalin-fixed and paraffin-embedded (FFPE) material) could be replaced by an archived tumor biopsy upon agreement from the study chief investigator if such biopsy has been taken after progression to metastatic castration resistance and has both archived fresh-frozen material and a FFPE block with a minimum tumor content over 30 percent. Still the patient must be amenable and willing to undergo a new mandatory post-treatment biopsy.
6. Willing to provide blood samples for biomarker analysis.
7. Willing to give consent to sequencing of DNA damage repair (DDR) genes for analysis of the prevalence of somatic and germline aberrations in DNA damage repair genes.
8. Metastatic (M1) prostate cancer documented by bone scan, or soft tissue disease documented by computed tomography (CT), or magnetic resonance imaging (MRI).
9. Asymptomatic or minimally symptomatic prostate cancer at screening.
10. Estimated life expectancy of greater than or equal to 6 months from screening.
11. Ongoing androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone (GnRH) agonist or antagonist for participants who have not undergone bilateral orchiectomy must be in place before screening and must continue throughout the study.

12 .Disease progression after at least 12 weeks of treatment with a prior androgen-receptor signalling inhibitor (ARPi), including abiraterone acetate or a direct AR inhibitor, such as enzalutamide, apalutamide, or darolutamide, for metastatic hormone-sensitive prostate cancer. Note: Patients who previously received Enzalutamide can be recruited but up to a maximum of 6. Those patients will be included directly into the experimental arm. Progression is defined as:

a. PSA rise of greater than or equal to 25 percent and an absolute increase of greater than or equal to 2 ng/mL above nadir (or baseline for participants with no PSA decline), confirmed by a second PSA value at least 3 weeks later.

and / or b. Limited radiographic progression: maximum of 2 new bone metastases, no new soft tissue metastasis and less than 50 percent increase in the size of measurable soft tissue lesions.

13\. Participants who have received prior docetaxel must meet the following criteria:

a. Received a maximum of 6 cycles of docetaxel for mHSPC and b. Received the last dose of docetaxel equal or higher than 6 months prior to randomization.

14\. Participants who have received prior Lu177-PSMA must meet the following criteria:

a. Received a maximum of 6 cycles of docetaxel for mHSPC. b. Received the last dose of Lu177-PSMA equal or higher than 6 months prior to randomization 15. Adequate organ function within 28 days before the first study treatment on Day 1, defined by the following:

1. Haemoglobin greater than or equal to 10 g/dL, no blood transfusions within 14 days before obtaining the haematology laboratory tests at screening,
2. Platelets greater than or equal to 100,000/μL no platelets transfusions within 14 days before obtaining the haematology laboratory tests at screening,
3. Neutrophils greater than or equal to 1500/μL, no growth factors given within 14 days before obtaining the haematology laboratory tests at screening,
4. Serum creatinine less than1.5X ULN or calculated creatinine clearance greater than or equal to 50 mL/min
5. Albumin greater than 3 g/dL,
6. AST or ALT less than 2.5 × ULN (less than 5 × ULN if liver function abnormalities are due to hepatic metastasis).
7. Total serum bilirubin less than 1.5 × ULN (less than 3 × ULN for participants with documented Gilbert syndrome or for whom indirect bilirubin concentrations suggest an extrahepatic source of elevation). 16. Ability to swallow study medication tablets and comply with study requirements.

   17\. Agrees to use a condom and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant, starting contraception at screening and continue throughout the study period and for 3 months after the final treatment administration, (during the treatment period and for at least 90 days after last dose of enzalutamide or at least 120 days after las dose of talazoparib, whichever occurs later) unless the patient is unable to maintain intercourse due to the androgen deprivation.

   18\. Subjects must not donate sperm starting at screening and throughout the study period and for 3 months after the final abiraterone acetate administration.

   19\. Subject agrees not to participate in another interventional study while with experimental medical products or anticancer drugs not approved in this setting on treatment in this study. Exceptions could be allowed for protocols investigating the survival or quality of life impact of common routine or conventional drugs (i.e. acetylsalicylic acid, statins, oral antidiabetic drugs) as long as they do not intefere with the study treatment and the evaluation of the main study arms.

   20\. Willing and able to comply with all scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

1. Prior ARPi treatment for less than 12 weeks or disease progression (either PSA or radiographic progression) within 6 months of starting abiraterone or ARi.
2. Known or suspected brain metastasis or active leptomeningeal disease.
3. Symptomatic or impending spinal cord compression or cauda equina syndrome.
4. Use of opiate analgesia for pain from prostate cancer with average Brief pain inventory (BPI) questionnaire score higher than or equal to 6 and/or uncontrolled prostate cancer-related pain requiring increasing doses of opiates within 4 weeks prior to randomization
5. Prior treatment with more than one ARPi. This will include abiraterone, enzalutamide, apalutamide, or darolutamide, which are treatments with demonstrated PFS and/or OS benefit in mHPSC, as well as any other novel AR or androgen synthesis directed therapy (with the exception on LHRH/GnRH analogues and/or antagonists). Note: Patients who started on one ARPi and switched to another due to toxicity will only be eligible after prior discussion with the study chair, provided that they were on the first ARPi (other than enzalutamide) for a very limited period of time and can document that they were responding - without PSA rise or worsening symptoms - at the moment they were switched to the second ARPi. Inclusion of such cases will require written notification and approval from the study chair or co-chair.
6. Therapeutic radiation therapy within, 14 days (7 days for limited-field palliative radiotherapy) prior to study enrolment, or participants who have not recovered from radiotherapy-related toxicities to grade less than or equal to 1 according to NCI-CTCAE v.5.0.
7. Major surgery within 4 weeks prior to randomization or participants who have not recovered from the side effects of any major surgery.
8. Administration of an investigational therapeutic or invasive surgical procedure (not including surgical castration) within 30 days of Cycle 1 Day 1 or currently enrolled in an investigational study.
9. History of seizure or any condition that may predispose to seizure (i.e., prior significant brain trauma, brain vascular malformation, etc) or subjects that have had an unexplained loss of consciousness or transient ischemic attacks within 1 year previous to scheduled day 1 of treatment.
10. Congenital long QT syndrome or ECG at screening with QT interval corrected using Fridericia's formula (QTcF) greater than 500 milliseconds.
11. Participants with clinically significant cardiovascular disease including but not limited to any of the following:

    1. Stroke, transient ischemic attack, unstable angina pectoris or documented myocardial infarction within 12 months prior to study entry.
    2. Symptomatic pericarditis or clinically significant pericardial effusion or myocarditis
    3. Documented congestive heart failure (New York Heart Association Class, NYHA functional classification III-IV)
    4. Uncontrolled, persistent hypertension defined as systolic blood pressure greater than 170mmHg or diastolic blood pressure greater than100mmHg. Subjects with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
12. Participants with any of the following cardiac conduction abnormalities:

    1. Ventricular arrhythmias except for benign premature ventricular contractions
    2. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication.
    3. Conduction abnormality requiring a pacemaker.
    4. Other cardiac arrhythmia not controlled with medication.
13. Any clinically significant gastrointestinal disorder affecting absorption (i.e., extensive small bowel resection, active inflammatory bowel disease).
14. Active or symptomatic viral hepatitis or chronic liver disease.
15. Known/possible hypersensitivity, allergies to enzalutamide, talazoparib or any of capsule excipients.
16. Other malignancy except:

    1. Carcinoma in situ or non-melanoma skin cancer.
    2. A cancer diagnosed and treated greater than or equal to 5 years before randomization with no subsequent evidence of recurrence.
17. Any condition or situation which, in the opinion of the investigator, would put the subject at risk, may confound study results, or interfere with the subject's participation in this study.