MK5684-U01A

An individual is eligible for inclusion in the study if the individual meets all of the following criteria:

Type of Participant and Disease Characteristics

1. Histologically- or cytologically-confirmed (if acceptable according to local health authority regulations) adenocarcinoma of the prostate without small cell histology. The diagnosis must be stated in a pathology report and confirmed by the investigator.

2. Prostate cancer progression and was receiving ADT (or post bilateral orchiectomy) within 6 months before screening. Prostate cancer progression determined by the investigator through 1 of the following:

• PSA progression shown by local laboratory values, as defined by a minimum of 2 consecutive rising PSA levels with an interval of ≥ 1 week between each assessment, where PSA at screening must be ≥ 1 ng/mL. Refer to Section 8.2.2 for further details.

Note: A PSA level obtained during the screening period can count as the confirmatory second rising PSA.

• Radiographic disease progression in soft tissue based on RECIST 1.1, with or without PSA progression.

• Radiographic disease progression in bone per PCWG, defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression.

3. Disease progression under the following conditions if the participant received first generation anti-androgen therapy as last treatment therapy prior to screening:

• Evidence of progression > 4 weeks since the last flutamide treatment.

• Evidence of progression > 6 weeks since the last bicalutamide or nilutamide treatment.

4. Current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue disease shown by CT/MRI.

5. Prior treatment with 1 to 2 NHA (eg, abiraterone acetate, enzalutamide, apalutamide, darolutamide) for nmHSPC, mHSPC, nmCRPC, or mCRPC, and have disease progression during or after treatment with at least the most recent NHA treatment (treatment duration needs to be at least 8 weeks, or at least 14 weeks for participants with bone progression).

Note: Participants may have received abiraterone acetate and docetaxel or darolutamide and docetaxel for nmHSPC, mHSPC, or nmCRPC. However, participants must have received no more than 6 cycles of docetaxel and had no radiographic disease progression while receiving docetaxel.

6. Received no more than 1 taxane-based chemotherapy regimen for mCRPC and has had PD during or after treatment. If docetaxel chemotherapy has been used more than once (eg, once for mHSPC and once for mCRPC), it will be considered as 1 therapy. Prior taxane-based chemotherapy for mCRPC is allowed if ≥ 4 weeks have elapsed from the last dose of most recent taxane-based chemotherapy before the date of allocation/randomization.

Note: Participants who have not received a taxane-based chemotherapy regimen for mCRPC are eligible.

7. Ongoing androgen deprivation with serum testosterone < 50 ng/dL (< 1.7 nM). If the participant is currently being treated with LHRH agonists or antagonists (in participants who have not undergone orchiectomy), this therapy must have been initiated at least 4 weeks before the date of allocation/randomization, and treatment must be continued throughout the study.

8. Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses for ≥ 4 weeks before the date of allocation/randomization.

Demographics

9. Is at least 18 years of age at the time of providing the informed consent.

Assigned Male Sex at Birth

10. If capable of producing sperm, the participant agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue

contraception for each study intervention is:

- MK-5684: 7 days

- Olaparib: 90 days

- Docetaxel: 90 days

- Cabazitaxel: 90 days

• Refrains from donating sperm

PLUS either:

• Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent

OR

• Uses contraception as detailed below unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview) as detailed below:

- Uses a penile/external condom when having penile-vaginal intercourse with a nonparticipant of childbearing potential who is not currently pregnant PLUS partner use of an additional contraceptive method, as a condom may break or leak.

Note: Participants capable of producing ejaculate whose partner is pregnant or breastfeeding must agree to use a penile/external condom during each episode of sexual activity in which the partner is at risk of drug exposure via ejaculate.

- Contraceptive use by participants capable of producing sperm should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.

Refer to Appendix 8 for country-specific requirements.

Informed Consent

11. The participant (or legally acceptable representative) has provided documented informed consent for the study.

Additional Categories

12. Tumor tissue from a fresh core or excisional biopsy from soft tissue not previously irradiated. Samples from tumors progressing at a prior site of radiation are allowed. Participants with bone-only or bone-predominant disease may provide a bone biopsy sample. Tumor sample is preferably obtained within 12 months of screening; however, if a recent sample is not available, participants may provide a tumor tissue sample obtained greater than 12 months from screening. FFPE tissue blocks are preferred to slides. Other exceptions may be considered after Sponsor consultation.

Note: Details pertaining to tumor tissue submission are in the Laboratory Manual.

13. Participants who have AEs due to previous anticancer therapies must have recovered to ≤ Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have ≤ Grade 2 neuropathy are eligible.

14. HIV-infected participants must have well controlled HIV on ART, defined as:

a. Participants on ART must have a CD4+ T-cell count ≥ 350 cells/mm3 at the time of screening.

b. Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening.

c. It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months.

d. Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study.

e. The combination ART regimen must not contain any antiretroviral medications that interact with CYP3A4 inhibitors/inducers/substrates (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-druginteractions-table-substrates-inhibitors-and-inducers).

Refer to Appendix 8 for country-specific requirements

15. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to randomization.

Note: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention.

Hepatitis B screening tests are not required unless:

- Known history of HBV infection

- As mandated by local health authority.

Refer to Appendix 8 for country-specific requirements

16. Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening.

Note: Participants must have completed curative antiviral therapy at least 4 weeks prior to randomization.

Hepatitis C screening tests are not required unless:

- Known history of HCV infection

- As mandated by local health authority.

17. Has an ECOG PS of 0 or 1 assessed within 7 days before the date of randomization.

18. Has a life expectancy > 3 months.

19. Adequate organ function as defined in the following table (Table 6). Specimens must be collected within 10 days before the start of study intervention.

Table 6 Adequate Organ Function Laboratory Values

System Laboratory Value

Haematological

Absolute neutrophil count (ANC) ≥ 1500/µL

Platelets ≥ 100,000/µL

Haemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/La

Renal

Measured or calculated creatinine clearanceb ≥ 51 mL/min

Hepatic

Total bilirubin ≤ 1.5 × ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN

AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases)

Coagulation

International normalized ratio (INR) OR prothrombin time (PT)

Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); CrCl=creatinine clearance; ULN=upper limit of normal.

a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.

b Cockcroft-Gault CrCl formula = [[140 – age (yr)] × weight(kg)] / [72 × serum Cr (mg/dL) × F] where F = 1 for participants assigned male sex at birth. As an alternative, CrCl can be determined from a 24-hour urine collection. 

An individual must be excluded from the study if the individual meets any of the following criteria:

Medical Conditions

1. Presence of gastrointestinal condition (eg, malabsorption), that might affect the absorption of study medication.

2. Is unable to swallow capsules/tablets.

3. History of pituitary dysfunction.

Note: Exceptions may be considered after Sponsor consultation.

4. Poorly controlled diabetes mellitus.

5. Clinically significant abnormal serum potassium or sodium level.

6. Has any of the following at Screening Visit:

• Hypotension: systolic BP < 110 mmHg, or

• Uncontrolled hypertension: systolic BP ≥ 160 mmHg or diastolic BP ≥ 90 mmHg, in 2 out of 3 recordings with optimized antihypertensive therapy.

7. Active or unstable cardio/cerebro-vascular disease, including thromboembolic events. Examples: recent (within 6 months) myocardial infarction, coronary artery bypass graft or symptomatic cerebrovascular accident or congestive heart failure (New York Heart Association Class III-IV).

8. History or family history of long QTc syndrome.

9. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions as judged by the investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF interval prolongation > 470 msec, electrolyte disturbances, etc), or has congenital long QT syndrome.

10. MDS/AML or features suggestive of MDS/AML.

11. History or current condition of adrenal insufficiency (eg, Addison’s disease).

12. Has a history of (noninfectious) pneumonitis requiring steroids, or current pneumonitis.

13. HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric Castleman’s Disease.

Prior/Concomitant Therapy

14. Received an anticancer mAb within 4 weeks before the date of randomization or has not recovered to Grade ≤ 1 or baseline from AEs due to a mAb administered more than 4 weeks before the date of randomization/allocation.

Note: Treatment with denosumab as SOC for bone metastases is permitted.

15. Undergone major surgery, including local prostate intervention (except prostate biopsy), within 28 days before the date of randomization/allocation, and has not recovered from the toxicities and/or complications.

16. Used herbal or medicinal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA (eg, saw palmetto, megesterol acetate) within 4 weeks before the date of randomization/allocation.

17. Received treatment with 5-α reductase inhibitors (eg, finasteride, dutasteride), oestrogens, and/or cyproterone within 4 weeks before the date of randomization/allocation.

18. Received an aldosterone antagonist (eg, spironolactone, eplerenone, canrenone, potassium canrenoate) and phenytoin within 4 weeks prior to the first dose of study intervention.

19. Is on an unstable dose of thyroid hormone therapy within 6 months prior to the first dose of study intervention.

20. Received a whole blood transfusion in the last 120 days before the date of randomization. Packed red blood cells and platelet transfusions are acceptable if not given within 28 days before the date of randomization.

21. Received prior systemic anticancer therapy including investigational agents within 4 weeks before the date of randomization/allocation.

22. Received prior radiotherapy within 2 weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids.

Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease is permitted. The last palliative radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention.

23. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.

Refer to Section 6.5 for information on COVID-19 vaccines.

24. Systemic use of the following medications within 2 weeks prior to the first dose of study intervention:

• Strong or moderate CYP3A4 inhibitors or inducers or a P-gp inhibitor. A list of strong inhibitors or inducers of CYP3A4 and inhibitors of P-gp can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-druginteractions-table-substrates-inhibitors-and-inducers.

NOTE: A 5-week washout period for phenobarbital and a 3-week washout period for other CYP3A4 inducers prior to the first dose of olaparib is required.

25. Received prior targeted small molecule therapy or NHA treatment within 4 weeks prior to the first dose of study intervention as follows:

• Abiraterone acetate + prednisone or darolutamide within 2 weeks

• Enzalutamide or apalutamide within 3 weeks.

Prior/Concurrent Clinical Study Experience

26. Known hypersensitivity to the components or excipients in olaparib, cabazitaxel, docetaxel, polysorbate 80, fludrocortisone, dexamethasone, prednisone, or MK-5684.

27. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.

Diagnostic Assessments

28. Has a “superscan” bone scan, defined as an intense symmetric activity in the bones and diminished renal parenchymal activity on baseline bone scan such that the presence of additional metastases in the future could not be evaluated.

29. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.

30. Known additional malignancy that is progressing or has required active treatment within the past 3 years.

Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.

31. Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable and have not required steroid treatment for at least 14 days before the first dose of study intervention.

32. Active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed.

33. Active infection requiring systemic therapy.

Note: Participants with HBV and HIV are eligible as defined in Section 5.1. Refer to Appendix 8 for country-specific requirements.

34. Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection.

Note: Hepatitis B and C screening tests are not required unless:

- Known history of HBV and HCV infection

- As mandated by local health authority.

Refer to Appendix 8 for country-specific requirements.

35. History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant’s participation for the full duration of the study, such that it is not in the best

interest of the participant to participate, in the opinion of the treating investigator.

36. Known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.

Other Exclusions

37. Is to father children within the projected duration of the study, starting with the screening visit through the duration (days) after the last dose of study intervention listed in inclusion criterion #10.

38. Participants who have not adequately recovered from major surgery or have ongoing surgical complications. 

Research Nurse: Elizabeth Coates (x2031) Elizabeth.Coates@LTHTR.nhs.uk