Testing Interruption of Hormonal Medications in Patients Responding Exceptionally to Therapy for Metastatic Prostate Cancer, (A-DREAM)

Study Overview
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Brief Summary
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This phase II trial examines antiandrogen therapy interruptions in patients with hormone-sensitive prostate cancer that has spread to other places in the body (metastatic) responding exceptionally well to androgen receptor-pathway inhibitor therapy. The usual treatment for patients with metastatic prostate cancer is to receive hormonal medications including a medication to decrease testosterone levels in the body and a potent oral hormonal medication to block growth signals from male hormones (like testosterone) in the cancer cells. Patients whose cancer is responding exceptionally well to this therapy may take a break from these medications according to their doctor's guidance. This trial may help doctors determine if stopping treatment can allow for testosterone recovery.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine the proportion of men who experience 18-month treatment-free interval from therapy with eugonadal testosterone (to >= 150 ng/ml) after treatment interruption. SECONDARY OBJECTIVES: I. To determine time to eugonadal testosterone (> 150 ng/dl). II. To determine duration off-treatment. III. To assess changes in quality of life as follows: To assess changes in patient-reported quality of life as assessed by the Functional Assessment of Cancer Therapy- Prostate (FACT-P) total score from baseline to 24 months after treatment interruption. To assess changes in the FACT-P subscales (i.e., physical well-being, social and family well-being, emotional well-being, functional well-being, and prostate cancer subscale) from baseline to 24 months after treatment interruption. To assess changes in the FACT-P total score and subscales (i.e., physical well-being, social and family well-being, emotional well-being, functional well-being, and prostate cancer subscale) from baseline to the remaining post-baseline time points (i.e., 6, 12, and 18 months) after treatment interruption. OUTLINE: Patients stop both hormonal medications (medication to decrease testosterone levels in the body and potent oral hormonal medication to block growth signals from male hormones in the cancer cells). Patients are then followed every 12 months for symptoms. Patients with an increase in prostate specific antigen (PSA) level to greater than or equal to 5 ng/ml, changes on imaging studies suggesting that their cancer is growing back, or symptoms that the doctor thinks is related to their cancer growing back, resume both hormonal treatments. After completion of study treatment, patients are followed up every 6 months for 10 years from registration or withdrawal from the study or death.

Official Title
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A Phase 2 Trial of ADT Interruption in Patients Responding Exceptionally to AR-Pathway Inhibitor in Metastatic Hormone-Sensitive Prostate Cancer (MHSPC): A-DREAM

Conditions
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Castration-Sensitive Prostate Carcinoma, Metastatic Prostate Carcinoma, Stage IV Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8

Intervention / Treatment
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* Other: Pharmacotherapy Discontinuation
* Other: Follow-Up
* Other: Questionnaire Administration
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic or clinical diagnosis of metastatic prostate cancer Must have had evidence of metastatic disease by bone scan, or nodal or visceral lesions on computed tomography (CT) or magnetic resonance imaging (MRI) prior to starting on intense antiandrogen therapy (ADT) Radiographic evidence of disease is not required at the time of enrollment No metastases to liver or to brain, as these represent aggressive variant disease biology for which intermittent treatment may not be favored Must currently be receiving intense ADT for metastatic hormone sensitive prostate cancer (mHSPC) Testosterone suppression (TS) with luteinizing hormone releasing hormone (LHRH)-agonist or LHRH-antagonist AND An approved secondary androgen receptor pathway inhibitor (ARPI) abiraterone, enzalutamide, or apalutamide (or darolutamide if approved for this indication) Must have remained on testosterone suppression for metastatic disease continuously (without treatment breaks) for 540-750 days (approximately 18 to 24 months) from time of first dose of LHRH agonist or antagonist by time of registration. A period of anti-androgen treatment prior to LHRH agonist or antagonist initiation is not included in the 540 - 750 days (approximately 18 to 24 months) Must have received treatment with ARPI for at least 360 days in total by time of A032101 registration. Treatment breaks from ARPI of up to 28 days are permitted (for example peri-procedural or for management of a temporary adverse event) as long as PSA did not rise while holding therapy Prior TS in the context of neoadjuvant/concurrent/adjuvant treatment with local therapy is permitted. Prior course(s) of intermittent TS for biochemical-only recurrence is permitted. However, if the patient previously received TS, metastatic progression for which intense ADT was initiated must have occurred during an off-treatment interval and with testosterone >= 150 ng/dL Prior local therapy for prostate cancer (either before or after diagnosis of metastatic disease) is permitted. Prior treatment with docetaxel chemotherapy for up to 6 cycles is permitted. Prior radiation therapy to metastatic sites (either for symptom palliation or for ablation of oligometastatic disease) is permitted Exclusion Criteria: No history of surgical castration No history of ARPI use prior to diagnosis of mHSPC for which the patient is currently receiving intense ADT (such as in the neoadjuvant setting with prior local therapy) No current or prior treatment with experimental agents for metastatic hormone-sensitive prostate cancer Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Prior to initiating intense ADT Prostate specific antigen (PSA) >= 5 ng/ml Testosterone >= 150 ng/dl. Patients are permitted to enroll if testosterone was not measured prior to initiating intense ADT for mHSPC if they did not previously receive TS and were not known or suspected to be hypogonadal at the time At time of enrollment to A032101 PSA < 0.2 ng/ml ** PSA values (measured in the same laboratory) must be stable or falling for 3 consecutive measurements - i.e. any PSA rise must be followed by a decrease in PSA that is further decreased or stable on a 3rd measurement. Any patient with 2 consecutive rises in PSA values since achieving castrate level of testosterone is not eligible Testosterone < 50 ng/dl No current participation in a clinical study that does not allow for TS or ARPI interruption No patients with a currently active second malignancy * Patients with non-melanomatous skin cancer, superficial bladder cancer, cancer not needing active therapy for at least 2 years, cancer for which the treating investigator deems the subject

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (discontinue hormonal medication, follow up)<br>Patients stop both hormonal medications (medication to decrease testosterone levels in the body and potent oral hormonal medication to block growth signals from male hormones in the cancer cells). Patients are then followed every 12 months for symptoms. Patients with an increase in PSA level to greater than or equal to 5 ng/ml, changes on imaging studies suggesting that their cancer is growing back, or symptoms that the doctor thinks is related to their cancer growing back, resume both hormonal treatments. | Other: Pharmacotherapy Discontinuation<br>* Stop hormonal medications (Abiraterone, Enzalutamide, Apalutamide, Leuprolide, Goserelin, Degarelix, Relugolix)<br>* Other names: Medication Discontinuation;Other: Follow-Up<br>* Undergo follow-up<br>Other: Questionnaire Administration<br>* Ancillary studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-free with eugonadal testosterone (> 150 ng/dl) | The proportion of men who experience 18-month treatment-free interval from therapy with eugonadal testosterone (to >= 150 ng/ml) after treatment interruption will be calculated for the study cohort. | At 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to eugonadal testosterone | The median time to eugonadal testosterone (> 150 ng/dl) will be computed by the cumulative incidence function. | Up to 10 years | 
| Duration off-treatment | The median time off-treatment. | Up to 10 years | 
| Radiographic progression-free survival | The median time to radiographic progression or death (whichever occurs first) will be computed by the Kaplan-Meier estimator. | Up to 10 years | 
| Time to next treatment | The median time to the first subsequent treatment will be computed by the cumulative incidence function. | Up to 24 months | 
| Overall survival | The median survival time will be computed by the Kaplan-Meier estimator. Survival time defined as from treatment interruption per protocol to death due to any cause or censored at date last known alive. | Assessed up to 10 years | 
| Cancer-specific survival | The median survival time will be computed by the cumulative incidence function. Cancer-specific survival as defined as from treatment interruption per protocol to death attributable to cancer or its treatment in the opinion of the treating investigator or censored at date last known alive. | Assessed up to 10 years | 
| Non-cancer specific survival | The median survival time will be computed by the cumulative incidence function. Non-cancer-specific survival as defined as from treatment interruption per protocol to death not attributable to cancer or its treatment in the opinion of the treating investigator or censored at date last known alive. | Up to 10 years | 
| Prostate specific antigen (PSA) progression-free survival | The median PSA progression free survival time will be computed by the Kaplan-Meier estimator. PSA progression free survival as defined as from treatment interruption per protocol to the first PSA failure (two consecutive increases in PSA of 25% and >= 2 ng/mL above nadir) or death. | Assessed up to 10 years |