Darolutamide With Radium-223 or Placebo and the Effect on Radiological Progression-Free Survival for Patients With mCSPC

A Phase III Randomized Study Comparing the Combination of Darolutamide With Radium-223 or Placebo and the Effect on Radiological Progression-Free Survival for Patients With Metastatic Castration-Sensitive Prostrate Cancer (mCSPC)

The goal of this clinical trial is to compare the combination of Darolutamide with Radium-223 or placebo and the effects on radiological progression-free survival for patients with Metastatic Castration-Sensitive Prostrate Cancer (mCSPC)

The main questions it aims to answer are:

• Radiological progression-free survival (rPFS) in mCSPC
• Overall Survival (OS)
• Symptomatic skeletal event-free survival (SSE-FS)
• Initiation of subsequent antineoplastic therapy
• Safety

Participants will have visits at baseline, treatment is once a month for up to 6 months, and long term follow up will continue until the participant dies, withdraws consent, and/or study is terminated.

A novel treatment strategy combining darolutamide and radium-223 is considered for subjects with mCSPC. Response to treatment is monitored every 12 weeks using a continuous measurement. The main scientific question concerns the comparison of radium-223 to placebo and is best addressed by a randomized clinical trial. Use of placebo in this study is considered ethical, as provision is made for subjects to discontinue their treatment and switch to radium-223 due to lack of efficacy on unblinding where it influences current treatment decisions. Switch to rescue medication is an intercurrent event, after which it is still possible to collect the variable measurements as described in sections on study endpoints below. This is also the case after other intercurrent events such as discontinuation of radium-223 treatment due to an adverse event, but not for intercurrent events such as death unrelated to study IP or disease, subject loss to follow-up, or subject withdrawal from all study treatments and procedures.

Inclusion Criteria:

1. Patient is able and willing to provide informed consent.

2. Metastatic castration-sensitive prostate cancer (mCSPC) at screening with histologically or cytologically confirmed diagnosis of prostate adenocarcinoma.

3. Men ≥ 18 years.

4. ECOG performance status of 0, 1 or 2 at screening.

5. Metastatic to bone with ≥ 2 bone metastases (area of increased uptake on 99mTc methylene diphosphonate bone scan); equivocal lesions on the bone scan must be confirmed by standard X-ray, CT, or MRI.

6. Ongoing ADT by Investigator's choice with luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or bilateral orchiectomy for less than 120 days prior to randomization. ADT treatment should be on a stable dose without interruptions of at least 4 weeks prior to first dose of blinded IP.

7. On bone health agents with at least one dose of BHA prior to first dose of blinded IP.

8. Adequate bone marrow and organ function as defined by:

   1. Hemoglobin ≥ 9.0 g/dL
   2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
   3. Platelets ≥ 100 x 109/L (participant must not have received any growth factor within 4 weeks or a blood transfusion within 7 days of the hematology laboratory sample obtained at Screening)
   4. Serum creatinine ≤2 x upper limit of normal ULN
   5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 1.5 x upper limit of normal (ULN)
   6. Total bilirubin < 1.5 x ULN, unless the participant a diagnosis of Gilbert's disease or a similar syndrome involving slow conjugation of bilirubin; in participants with Gilbert's, the total bilirubin should be < 3 x ULN and the elevation should be seen in the unconjugated or indirect bilirubin measurement)
   7. Albumin ≥ 2.5 g/dL

9. Fertile male participants, 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 blinded IP, and not father a child or donate sperm during this period.

10. No known contraindication to any study treatment (darolutamide, radium-223, and/or Investigator's choice ADT).

Exclusion Criteria:

1. Pathological finding consistent with small cell carcinoma of the prostate.

2. Prior treatment for mCSPC [excluding ADT ≤120 days and first-generation ARI (bicalutamide, nilutamide or flutamide) for ≤120 days when initiating ADT], with the exception of Metastases Directed Therapy (MDT) with EBRT/SBRT (at least 2 bone metastases must be untreated). Prior treatment for localized prostate cancer is allowed (all treatments must have been completed ≥ 1 year prior to randomization)

3. Treatment for mCSPC with ADT starting >120 days prior to randomization.

4. Treatment for mCSPC with first generation ARI (bicalutamide, nilutamide or flutamide) starting >120 days prior to randomization.

5. Prior hemi-body or whole-body external radiotherapy.

   a. Other types of prior external radiotherapy and brachytherapies are allowed, if more than 28 days prior to randomization.

6. Prior therapy with radionuclides (e.g., including but not limited to radium-223, strontium-89, samarium-153), including prior therapy with investigational radionuclides (e.g., including but not limited to iodine-131, rhenium-186, rhenium- 188, thorium- 277, actinium-225 and lutetium-177).

7. Prior treatment with:

   • Second-generation androgen receptor (AR) inhibitors such as enzalutamide, darolutamide, apalutamide or other investigational AR inhibitors.
   • Cytochrome P 17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as antineoplastic treatment for prostate cancer.
   • Chemotherapy including docetaxel or immunotherapy for prostate cancer.
   • Use of systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/day within 28 days prior to randomization.

8. Current involvement in any drug or device trial involving investigational agent or medical device within the last 28 days prior to randomization.

9. Any prior investigational agent for nmCSPC/mCSPC.

10. Known hypersensitivity to compounds related to darolutamide, or radium-223, or to CT and/or MRI contrast media.

11. A blood transfusion ≤ 28 days prior to randomization.

12. Major surgical procedures ≤ 28 days or minor surgical procedures ≤7 days prior to randomization. No waiting period is required following port-a-cath placement.

13. Superscan on 99mTc methylene diphosphonate bone scan.