Metastatic Castration-resistant Prostate Cancer
Conditions
Keywords
mCRPC, ARB, Radiopharmaceutical
Brief 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.
Detailed description
The hypothesis investigators will test in this study is whether layering radium-223 following 16 weeks of enzalutamide or darolutamide exposure in patients demonstrating a biochemical response improves disease outcomes. By adding radium-223 following a potential bone flare phenomenon \[after first 12-14 weeks of therapy with an androgen receptor blocker (ARB)\], including patients expected to have durable response to systemic therapy, and mandating the use of bone protective agents during treatment, the investigators aim to demonstrate an optimal time to add radium-223 in the mCRPC landscape.
Interventions
DRUGEnzalutamide during Lead-in Period
Participants will receive 12 weeks open-label lead-in ARB (enzalutamide) that will continue after double-blind randomization to radium-223 or placebo.
DRUGLead-in Enzalutamide followed by Radium-223/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.
DRUGLead-in Enzalutamide followed by Placebo/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.
DRUGDarolutamide during Lead-in Period
Participants will receive 12 weeks open-label lead-in darolutamide that will continue after double-blind randomization to radium-223 or placebo.
DRUGLead-in Darolutamide followed by Radium-223/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.
DRUGLead-in Darolutamide followed by Placebo/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.
Sponsors
Bayer
Carolina Urologic Research Center
Tulane University
Barbara Ann Karmanos Cancer Institute
MANA RBM
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Masking of Radium-223 or placebo only
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.
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Symptomatic Skeletal Event-free Survival (SSE-FS) | approximately 1 year and 8 months | SSE-FS is a composite endpoint, composed of 4 events that indicate disease progression: * the first use of external-beam radiation therapy to relieve skeletal tumor-related symptoms * the occurrence of new symptomatic pathologic bone fractures. * the occurrence of new symptomatic spinal cord compression * a tumor-related orthopedic surgical intervention |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | approximately 1 year and 8 months | Number of subjects who survived between RT2 randomization through data cut-off. |
| Time to Chemotherapy Initiation | approximately 1 year and 8 months | Number of subjects who began docetaxel or cabazitaxel treatment during the study. |
| Radiographic Progression-free Survival (rPFS) | approximately 1 year and 8 months | Number of subjects with bone scan progression per PCWG3 criteria, and/or progression by CT/MRI per RECIST 1.1 criteria, or death from any cause following RT2. Radiological progression is interpreted by local assessment only. |
| Safety Profile of Androgen Receptor Blocker (ARB) Therapy With or Without Radium-223. | approximately 1 year and 8 months | Safety profile of androgen receptor blockers (enzalutamide or darolutamide) with or without radium-223; number of participants with treatment-related adverse events as assessed by CTCAE v5.0. Reported only in the AE reporting module. |
| Occurrence of AESI: Bone Fractures (Pathologic and Non-pathologic) | approximately 1 year and 8 months | Assess occurrence of AESI: fractures (pathologic and non-pathologic). |
Countries
United States
Participant flow
Recruitment details
Recruitment occurred from Jun 2020- Jul 2021 at selected medical centers that specialized in the treatment of advanced prostate cancer.
Pre-assignment details
23 subjects signed ICF. 2/23 subjects screen failed without reporting any adverse events and received no study treatments. 21/23 subjects signing ICF met all entry criteria and were randomized to Lead-in ARB (R1). 5 subjects discontinued the study during Lead-in ARB. Although 16 subjects randomized to R2, 2 of the subjects randomized to Enzalutamide + Placebo did not receive any cycles due to the early termination of the study and are reported only in the Lead-in Enzalutamide safety group.
Participants by arm
| Arm | Count |
|---|---|
| Lead-in Enzalutamide Followed by Radium-223/Enzalutamide 12-week lead-in of open-label Enzalutamide followed by radium-223. Participants continued on their randomized, open-label Enzalutamide. | 5 |
| Lead-in Darolutamide Followed by Radium-223/Darolutamide 12-week lead-in of open-label Darolutamide followed by radium-223. Participants continued on their randomized, open-label Darolutamide. | 5 |
| Lead-in Enzalutamide Followed by Placebo/Enzalutamide 12-week lead-in of open-label Enzalutamide followed by placebo. Participants continued on their randomized, open-label Enzalutamide. | 6 |
| Lead-in Darolutamide Followed by Placebo/Darolutamide 12-week lead-in of open-label Darolutamide followed by placebo. Participants continued on their randomized, open-label Darolutamide. | 5 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| R1- Lead-in ARB Treatment (12 Weeks) | Adverse Event | 0 | 0 | 1 | 1 |
| R1- Lead-in ARB Treatment (12 Weeks) | Did not meet R2 entry criteria | 1 | 1 | 0 | 1 |
| R1- Lead-in ARB Treatment (12 Weeks) | Randomized R2 (no cycles given) | 0 | 0 | 2 | 0 |
| R2- ARB Treatment With Ra-223 or Placebo | Physician Decision | 0 | 0 | 1 | 0 |
| R2- ARB Treatment With Ra-223 or Placebo | Sponsor Decision | 4 | 4 | 2 | 3 |
Baseline characteristics
| Characteristic | Lead-in Enzalutamide Followed by Radium-223/Enzalutamide | Lead-in Darolutamide Followed by Radium-223/Darolutamide | Lead-in Enzalutamide Followed by Placebo/Enzalutamide | Lead-in Darolutamide Followed by Placebo/Darolutamide | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 5 Participants | 6 Participants | 4 Participants | 20 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Concomitant use of bone health agents (osteoclast inhibitors) | 5 Participants | 5 Participants | 6 Participants | 5 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 4 Participants | 6 Participants | 4 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 4 Participants | 5 Participants | 5 Participants | 19 Participants |
| Region of Enrollment United States | 5 participants | 5 participants | 6 participants | 5 participants | 21 participants |
| Sex/Gender, Customized Males | 5 participants | 5 participants | 6 participants | 5 participants | 21 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 | 0 / 4 | 0 / 4 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 4 / 4 | 2 / 3 | 4 / 4 | 4 / 4 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 1 / 4 | 0 / 3 | 0 / 4 | 1 / 4 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Symptomatic Skeletal Event-free Survival (SSE-FS)
SSE-FS is a composite endpoint, composed of 4 events that indicate disease progression: * the first use of external-beam radiation therapy to relieve skeletal tumor-related symptoms * the occurrence of new symptomatic pathologic bone fractures. * the occurrence of new symptomatic spinal cord compression * a tumor-related orthopedic surgical intervention
Time frame: approximately 1 year and 8 months
Population: No analysis was performed. Outcome measure includes only number (%) of subjects that met primary endpoint (occurrence of SSE-FS).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lead-in Enzalutamide Only (no Cycles) | Symptomatic Skeletal Event-free Survival (SSE-FS) | 0 Participants |
| Lead-in Darolutamide Only (no Cycles) | Symptomatic Skeletal Event-free Survival (SSE-FS) | 0 Participants |
| Lead-in Enzalutamide Followed by Radium-223/Enzalutamide | Symptomatic Skeletal Event-free Survival (SSE-FS) | 0 Participants |
| Lead-in Darolutamide Followed by Radium-223/Darolutamide | Symptomatic Skeletal Event-free Survival (SSE-FS) | 0 Participants |
| Lead-in Enzalutamide Followed by Placebo/Enzalutamide | Symptomatic Skeletal Event-free Survival (SSE-FS) | 2 Participants |
| Lead-in Darolutamide Followed by Placebo/Darolutamide | Symptomatic Skeletal Event-free Survival (SSE-FS) | 1 Participants |
Secondary
Occurrence of AESI: Bone Fractures (Pathologic and Non-pathologic)
Assess occurrence of AESI: fractures (pathologic and non-pathologic).
Time frame: approximately 1 year and 8 months
Population: No analysis was performed. Outcome measure includes only number (%) of subjects with AESI.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lead-in Enzalutamide Only (no Cycles) | Occurrence of AESI: Bone Fractures (Pathologic and Non-pathologic) | 0 Participants |
| Lead-in Darolutamide Only (no Cycles) | Occurrence of AESI: Bone Fractures (Pathologic and Non-pathologic) | 0 Participants |
| Lead-in Enzalutamide Followed by Radium-223/Enzalutamide | Occurrence of AESI: Bone Fractures (Pathologic and Non-pathologic) | 1 Participants |
| Lead-in Darolutamide Followed by Radium-223/Darolutamide | Occurrence of AESI: Bone Fractures (Pathologic and Non-pathologic) | 0 Participants |
| Lead-in Enzalutamide Followed by Placebo/Enzalutamide | Occurrence of AESI: Bone Fractures (Pathologic and Non-pathologic) | 0 Participants |
| Lead-in Darolutamide Followed by Placebo/Darolutamide | Occurrence of AESI: Bone Fractures (Pathologic and Non-pathologic) | 0 Participants |
Secondary
Overall Survival (OS)
Number of subjects who survived between RT2 randomization through data cut-off.
Time frame: approximately 1 year and 8 months
Population: No analysis was performed. Outcome measure includes only number (%) of subjects with who survived.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lead-in Enzalutamide Only (no Cycles) | Overall Survival (OS) | 4 Participants |
| Lead-in Darolutamide Only (no Cycles) | Overall Survival (OS) | 3 Participants |
| Lead-in Enzalutamide Followed by Radium-223/Enzalutamide | Overall Survival (OS) | 4 Participants |
| Lead-in Darolutamide Followed by Radium-223/Darolutamide | Overall Survival (OS) | 4 Participants |
| Lead-in Enzalutamide Followed by Placebo/Enzalutamide | Overall Survival (OS) | 3 Participants |
| Lead-in Darolutamide Followed by Placebo/Darolutamide | Overall Survival (OS) | 3 Participants |
Secondary
Radiographic Progression-free Survival (rPFS)
Number of subjects with bone scan progression per PCWG3 criteria, and/or progression by CT/MRI per RECIST 1.1 criteria, or death from any cause following RT2. Radiological progression is interpreted by local assessment only.
Time frame: approximately 1 year and 8 months
Population: No analysis was performed. Outcome measure includes only number (%) of subjects who experienced radiological progression.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lead-in Enzalutamide Only (no Cycles) | Radiographic Progression-free Survival (rPFS) | 0 Participants |
| Lead-in Darolutamide Only (no Cycles) | Radiographic Progression-free Survival (rPFS) | 0 Participants |
| Lead-in Enzalutamide Followed by Radium-223/Enzalutamide | Radiographic Progression-free Survival (rPFS) | 0 Participants |
| Lead-in Darolutamide Followed by Radium-223/Darolutamide | Radiographic Progression-free Survival (rPFS) | 0 Participants |
| Lead-in Enzalutamide Followed by Placebo/Enzalutamide | Radiographic Progression-free Survival (rPFS) | 1 Participants |
| Lead-in Darolutamide Followed by Placebo/Darolutamide | Radiographic Progression-free Survival (rPFS) | 1 Participants |
Secondary
Safety Profile of Androgen Receptor Blocker (ARB) Therapy With or Without Radium-223.
Safety profile of androgen receptor blockers (enzalutamide or darolutamide) with or without radium-223; number of participants with treatment-related adverse events as assessed by CTCAE v5.0. Reported only in the AE reporting module.
Time frame: approximately 1 year and 8 months
Population: No analysis was performed. Outcome measure includes only number (%) of subjects followed for safety. Safety data reported in AE section.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lead-in Enzalutamide Only (no Cycles) | Safety Profile of Androgen Receptor Blocker (ARB) Therapy With or Without Radium-223. | 4 Participants |
| Lead-in Darolutamide Only (no Cycles) | Safety Profile of Androgen Receptor Blocker (ARB) Therapy With or Without Radium-223. | 2 Participants |
| Lead-in Enzalutamide Followed by Radium-223/Enzalutamide | Safety Profile of Androgen Receptor Blocker (ARB) Therapy With or Without Radium-223. | 4 Participants |
| Lead-in Darolutamide Followed by Radium-223/Darolutamide | Safety Profile of Androgen Receptor Blocker (ARB) Therapy With or Without Radium-223. | 4 Participants |
| Lead-in Enzalutamide Followed by Placebo/Enzalutamide | Safety Profile of Androgen Receptor Blocker (ARB) Therapy With or Without Radium-223. | 3 Participants |
| Lead-in Darolutamide Followed by Placebo/Darolutamide | Safety Profile of Androgen Receptor Blocker (ARB) Therapy With or Without Radium-223. | 3 Participants |
Secondary
Time to Chemotherapy Initiation
Number of subjects who began docetaxel or cabazitaxel treatment during the study.
Time frame: approximately 1 year and 8 months
Population: No analysis was performed. Outcome measure includes only number (%) of subjects who started docetaxel or cabazitaxel treatment during the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lead-in Enzalutamide Only (no Cycles) | Time to Chemotherapy Initiation | 0 Participants |
| Lead-in Darolutamide Only (no Cycles) | Time to Chemotherapy Initiation | 0 Participants |
| Lead-in Enzalutamide Followed by Radium-223/Enzalutamide | Time to Chemotherapy Initiation | 0 Participants |
| Lead-in Darolutamide Followed by Radium-223/Darolutamide | Time to Chemotherapy Initiation | 0 Participants |
| Lead-in Enzalutamide Followed by Placebo/Enzalutamide | Time to Chemotherapy Initiation | 0 Participants |
| Lead-in Darolutamide Followed by Placebo/Darolutamide | Time to Chemotherapy Initiation | 0 Participants |