A Study Comparing ARB With Radium-223 vs ARB Therapy With Placebo and the Effect Upon Survival for mCRPC Patients
Condition: Metastatic Castration-resistant Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: Enzalutamide during Lead-in Period; Lead-in Enzalutamide followed by Radium-223/Enzalutamide; Lead-in Enzalutamide followed by Placebo/Enzalutamide; Darolutamide during Lead-in Period; Lead-in Darolutamide followed by Radium-223/Darolutamide; Lead-in Darolutamide followed by Placebo/Darolutamide
Intervention description: Participants will receive 12 weeks open-label lead-in ARB (enzalutamide) that will continue after double-blind randomization to radium-223 or placebo.; After a 12-week lead-in period of open-label enzalutamide, participants will be randomized to double-blind radium-223 or placebo. Participants will continue on their randomized, open-label enzalutamide.; After a 12-week lead-in period of open-label enzalutamide, participants will be randomized to double-blind radium-223 or placebo. Participants will continue on their randomized, open-label enzalutamide.; Participants will receive 12 weeks open-label lead-in darolutamide that will continue after double-blind randomization to radium-223 or placebo.; After a 12-week lead-in period of open-label darolutamide, participants will be randomized to double-blind radium-223 or placebo. Participants will continue on their randomized, open-label darolutamide.; After a 12-week lead-in period of open-label darolutamide, participants will be randomized to double-blind radium-223 or placebo. Participants will continue on their randomized, open-label darolutamide.
Intervention MeSH terms: Radium Ra 223 dichloride
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: 12 week lead-in open-label androgen-receptor blocker (ARB) followed by up to 6 cycles of double-blind Radium-223 or placebo.
Masking: Double (Participant, Investigator)
Masking description: Masking of Radium-223 or placebo only
Enrollment: 23.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: mCRPC; ARB; Radiopharmaceutical

Summary:

      This is a randomized, multi-center, double-blind, Phase III study of radium-223 plus
      enzalutamide or darolutamide compared to enzalutamide or darolutamide treatment plus placebo.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Able and willing to provide informed consent.

          2. Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma.

          3. Men ≥ 18 years.

          4. ECOG performance status of 0 or 1 at screening.

          5. Metastatic to bone with ≥ 2 bone metastases (area of increased uptake on 99mTc bone
             scan); equivocal lesions on the bone scan must be confirmed by standard X-ray, CT, or
             MRI.

          6. Patients must have progressive metastatic castration-resistant prostate cancer (mCRPC)
             at screening and on androgen deprivation therapy (ADT) as evidenced by either:

               1. For patients who manifest disease progression solely as a rising
                  prostate-specific antigen (PSA) level - documentation of a sequence of two rising
                  PSA values at a minimum of 1-week apart with the Screening value ≥1 ng/ml (see
                  Appendix D);

               2. For patients with disease progression manifested in the bone, irrespective of
                  progression by rising PSA - defined by the appearance of 2 or more new skeletal
                  lesions demonstrated by 99Tc bone imaging. Ambiguous results should be confirmed
                  by other imaging modalities than bone scan and x-ray (e.g.: CT-scan or MRI).

               3. For patients with disease progression manifested at nodal sites, irrespective of
                  progression by rising PSA - progression defined per RECIST 1.1.

          7. Ongoing ADT with luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or
             bilateral orchiectomy.

          8. Use of bone health agents (denosumab or zoledronic acid or other bisphosphonates)
             starting any time prior to R1 unless contraindicated or considered not in the best
             interest of the patient. A waiver must be approved by the medical monitor if bone
             health agents cannot be used. Bone health agents should be continued throughout both
             RT1 and RT2 treatment periods.

          9. Adequate bone marrow and organ function as defined by:

               1. Hemoglobin ≥ 10.0 g/dL

               2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

               3. Platelets ≥ 100 x 109/L

               4. Serum creatinine ≤ 1.95 mg/dL

               5. Estimated creatinine clearance >/= 30 mL/min by Cockroft-Gault calculation

               6. Alanine aminotransferase (ALT) ≤ 175 U/L

               7. Aspartate aminotransferase (AST) ≤ 100 U/L

               8. Total bilirubin ≤ 1.8 mg/dL (unless the patient a diagnosis of Gilbert's disease
                  or a similar syndrome involving slow conjugation of bilirubin; in patients with
                  Gilbert's, the total bilirubin should be less than 6 mg/dL if patient has
                  Gilbert's and the elevation should be seen in the unconjugated or indirect
                  bilirubin measurement)

               9. LDH ≤ 224 U/L at screening.

              10. Albumin ≥ 2.5 g/dL

         10. Fertile male patients, defined as all males physiologically capable of conceiving
             offspring with female partners of child-bearing potential, must be willing to use
             condoms plus spermicidal agent during the study treatment period and for 6 months
             after the last dose of study drug, and not father a child or donate sperm during this
             period.

         11. The treating site investigator deems RT1 (Enzalutamide or Darolutamide) treatment safe
             and feasible.

             Subjects must meet the remaining inclusion criteria in order to be qualified for the
             second randomization (R2). Only subjects that complete the initial 12 weeks of run-in
             RT1 should be evaluated. Prior inclusion criteria do not need to be re-evaluated:

         12. Patients must have a documented ≥ 30% decline of PSA at any time during the 12 weeks
             of RT1.

         13. Patients must have no evidence of visceral metastatic disease at the time of RT2
             randomization

         14. Ongoing treatment with RT1 and bone health agents at time of RT2 randomization.

         15. The treating site investigator deems RT2 (Ra-223 dichloride) treatment safe and
             feasible.

        Exclusion Criteria:

          1. Pathological finding consistent with small cell carcinoma of the prostate.

          2. Prior chemotherapy for CRPC. Prior docetaxel for hormone-sensitive disease is
             permitted under the following conditions: started within 3 months of ADT initiation,
             given for a maximum of 6 cycles and progression occurred > 6 months after the last
             dose of docetaxel.

          3. Prior treatment for mCRPC or CRPC. However, the following therapies are permitted and
             not exclusionary: Sipuleucel-T, 5-alpha-reductase inhibitors, estrogens, or older
             antiandrogens (such as flutamide, bicalutamide, or nilutamide).

          4. Prior treatment for more than 2 months with CYP17 inhibitors (e.g. abiraterone or
             orteronel).

          5. Prior treatment for more than 2 months with agents inhibiting androgen receptor
             signaling (e.g. enzalutamide, apalutamide, or darolutamide).

          6. Prior hemibody or whole-body external radiotherapy. Other types of prior external
             radiotherapy and brachytherapies are allowed.

          7. Prior therapy with radionuclides (e.g., radium-223, strontium-89, samarium-153,
             rhenium-186, rhenium-188, actinium-225 and lutetium-177).

          8. Current involvement in any drug or device trial involving investigational agent or
             medical device within the last 28 days prior to R1.

          9. In general, any prior investigational agent for nmCRPC/mCRPC; however, may be reviewed
             by medical monitor/PIs for waiver consideration, on a case-by-case basis.

         10. Hypersensitivity to compounds related to enzalutamide, darolutamide, or Ra-223.

         11. A blood transfusion ≤ 28 days prior to R1.

         12. Major surgical procedures ≤ 28 days or minor surgical procedures ≤7 days prior to R1.
             No waiting period is required following port-a-cath placement.

         13. Patients with visceral metastases, clinical evidence of central nervous system
             metastases, or leptomeningeal tumor spread as demonstrated via CT/MRI of chest,
             abdomen, pelvis, and CNS (if needed). CT/MRI of the CNS only performed if suspicion of
             CNS metastases or leptomeningeal tumor spread. Nodules < 1 cm alone will not be
             considered visceral metastases. Renal masses < 3 cm will not be considered
             exclusionary.

         14. Serious active infection at the time of screening or another serious underlying
             medical condition that would impair the ability of the patient to receive protocol
             treatment.

         15. Presence of other active cancers, or history of treatment for invasive cancer ≤2 years
             of R1. Patients with Stage I/II cancer who have received definitive local treatment
             and are considered unlikely to recur are eligible. All patients with previously
             treated in situ carcinoma (i.e., non-invasive) and superficial bladder cancer are
             eligible, as are patients with history of non-melanoma skin cancer.

         16. Any other serious or unstable illness, or medical, social, or psychological condition,
             that could jeopardize the safety of the subject and/or his/her compliance with study
             procedures, or may interfere with the subject's participation in the study or
             evaluation of the study results.