RISK-ADAPT Protocol in Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) (RISK-ADAPT)

A Pragmatic Phase 2 Trial of Risk-Adapted Treatment Approaches Including Treatment De-escalation to Minimize Adverse Effects of Hormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer.

This is a prospective, interventional, non-randomized, phase 2 study to assess oncologic outcomes of metastatic hormone-sensitive prostate cancer (mCSPC) patients who receive a risk-adapted treatment approach followed by treatment de-escalation at the Medstar Health network. A pragmatic design will be implemented in order to make the study available to patients at greatest needs from minority populations in the community. Additional assessments include quality-of-life (QoL) and sexual function changes as well as correlative studies. A maximum of 108 patients will be enrolled in this study. We hypothesize that with a risk-adapted treatment approach followed by treatment de-escalation, more than 50% of patients will have radiographic progression-free survival (rPFS) at 36 months. Additionally, we hypothesize that the risk-stratified de-escalation approach will result in fewer treatment-related adverse events and better QoL, compared to historical controls.

Study Overview

• Status: Not yet recruiting
• Conditions: Metastatic Hormone-sensitive Prostate Cancer (mHSPC)
• Intervention / Treatment: Drug: Androgen Deprivation Therapy (ADT); Drug: Androgen Receptor Pathway Inhibitor (ARPI); Radiation: Prostate Radiation; Drug: Docetaxel

• Study Type: Interventional
• Enrollment (Estimated): 108
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Paul D Leger, MD; Phone Number: 202-444-2223; Email: paul.d.leger@gunet.georgetown.edu

Study Locations

• United States
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Georgetown University Medical Center- Lombardi Comprehensive Cancer Center
      • Principal Investigator: Paul Leger, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult patients with metastatic castrate sensitive prostate cancer that are eligible for standard of care (SOC) per treating physician.

   a. Low risk SOC: ADT + ARPI + radiation to the prostate i. For patients with low-risk disease (defined in Section 8.1), prior treatment with ADT or ARPI for up to 8 weeks for mCSPC is permitted; however, prior treatment with docetaxel is not allowed.

   b. High risk SOC: ADT + ARPI +/- docetaxel i. For patients with high-risk disease (defined in Section 8.1), prior treatment with ADT, ARPI, or docetaxel for up to 8 weeks for mCSPC is permitted.

2. Patients who can give informed consent and are willing to comply with follow-up visits and treatment plans.

Exclusion Criteria:

1. Patients for whom, in the opinion of the investigator, participation in the study, use of the drugs outlined in the study, or use of the risk-adapted treatment de-escalation strategy is not appropriate or safe.

2. Patients who have received prior treatment with any of the following:

   1. Chemotherapy other than docetaxel for prostate cancer any time prior to enrollment;
   2. Radiopharmaceuticals for prostate cancer any time prior to enrollment.
3. Patients who have received treatment with radiotherapy (EBRT, brachytherapy, or radiopharmaceuticals) within 2 weeks before prior to the start of study treatment.

4. Patients with prior treatment with an ARPI for non-metastatic disease within 6 months of diagnosis of metastatic disease are not eligible.

   a. Note: Patients who were diagnosed with metastatic disease or more than 6 months after treatment with an ARPI non-metastatic disease are eligible.

5. Patients who had previous (within 28 days before the start of study drug or 4 half-lives of the investigational treatment of the previous study, whichever is longer) or concomitant participation in another clinical study with investigational medicinal product(s).
6. Patients with an inability to swallow oral medications in the opinion of the clinical investigator.
7. Patients with leptomeningeal disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low Risk Prostate Cancer; Low risk patients will receive 6-month doublet therapy with Androgen Deprivation Therapy (ADT) + Androgen Receptor Pathway Inhibitor (ARPI) + prostate radiation with or without radiation to metastatic sites followed by 30 months ARPI monotherapy. At a 36-month timepoint, those who maintain a prostate specific antigen (PSA) ≤ 0.2ng/mL will have the option to either discontinue treatment proceeding with active surveillance or continue on their ARPI until disease progression or intolerable toxicity. Patients who discontinue ARPI will resume ARPI and ADT when the PSA ≥ 2 ng/mL above the lowest PSA on two consecutive checks at least 1 month apart, there is evidence of progressive disease (PD) on conventional scans [CT/MRI imaging per modified RECIST 1.1 or bone scan per Prostate Cancer Clinical Trials Working Group 3 (PCWG3)], clinical symptoms of progression, or if the patient prefers to continue ARPI and ADT.	Drug: Androgen Deprivation Therapy (ADT); ADT, Gonadotropin-releasing hormone (GnRH) agonist or antagonists, as prescribed by the treating physician.; Drug: Androgen Receptor Pathway Inhibitor (ARPI); Darolutamide is the preferred ARPI for this study; however, patients may receive abiraterone, apalutamide, or enzalutamide at the discretion of their oncologist and based on patient preference.; Radiation: Prostate Radiation; prostate radiation, with or without radiation to metastatic sites
Experimental: High Risk Prostate Cancer; High-risk patients will receive triplet therapy with ADT + ARPI + 6 cycles of docetaxel followed by 18-months of ADT + ARPI and then 12-month ARPI monotherapy. If a patient has high-risk disease but, based on the investigator's judgment, has contraindications to docetaxel or is deemed unsuitable for it, they will receive the same treatment regimen as other high-risk patients minus the docetaxel. Then at a 36-month timepoint, those who maintain a PSA ≤ 0.2ng/mL will have the option to either discontinue treatment with active surveillance or continue ARPI until disease progression or intolerable toxicity. Patients who discontinue ARPI will resume ARPI and ADT when the PSA ≥ 2 ng/mL above the lowest PSA (nadir) on two consecutive checks at least 1 month apart, there is evidence of progressive disease (PD) on conventional scans [CT/MRI imaging per modified RECIST 1.1 or bone scan per PCWG3], clinical symptoms of progression, or if the patient prefers to continue ARPI and ADT.	Drug: Androgen Deprivation Therapy (ADT); ADT, Gonadotropin-releasing hormone (GnRH) agonist or antagonists, as prescribed by the treating physician.; Drug: Androgen Receptor Pathway Inhibitor (ARPI); Darolutamide is the preferred ARPI for this study; however, patients may receive abiraterone, apalutamide, or enzalutamide at the discretion of their oncologist and based on patient preference.; Drug: Docetaxel; Docetaxel will be administered as prescribed by the treating physician.; Other Names: Taxotere; Docefrez; Docivyx; BEIZRAY

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiological progression-free survival (rPFS)	rPFS is defined as the time from the first dose of systemic therapy for mCSPC to the first documented radiological progression in soft tissue or bone, based on CT, MRI, or NM bone scan, using Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) for soft-tissue metastases and Prostate Cancer Working Group 3 (PCWG3) criteria for bone metastases, or death from any cause.	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	OS is defined as the time from the date of treatment to death from any cause. OS at 5 years is defined as being alive at 5 years after starting of ADT.	5 years
rPFS using PSMA PET/CT scan combined with PSA response	This is defined at the time from the first dose of systemic therapy for mCSPC to the time to progressive disease as measured by PSMA PET/CT scan (RECIP 1.0) combined with PSA response	5 years
Time to initiation of subsequent antineoplastic therapy	Time to initiation of subsequent antineoplastic therapy is defined as the time from initiation of ADT to subsequent antineoplastic therapy for prostate cancer.	5 years
Disease progression within 5 years of starting ADT for mCSPC	The number of patients with disease progression at 5 years	5 years
Symptomatic skeletal event free (SSE) survival	SSE survival is defined as the time from first dose of systemic therapy for mCSPC to the first occurrence of SSE or death from any cause, whichever comes first. An SSE is defined as external beam radiation therapy (EBRT) to relieve skeletal symptoms, or new symptomatic pathologic bone fracture, or occurrence of spinal cord compression or tumor-related orthopedic surgical intervention, whichever comes first.	5 years
Time to pain progression	Time from start date of ADT to the first date a subject experiences a pain progression. Pain will be assessed using the PEG Scale (Pain, Enjoyment, General Activity) Questionnaire	5 years
Adverse Events	Number of patients with an AE that resulted in treatment discontinuation.	5 years
Quality-of-life changes- NCCN/FACT-FPSI-17	Patients with changes to quality of life ans sexual function as measured by National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy (FACT) Prostate Cancer Symptom Index - 17 Item Version (NCCN/FACT-FPSI-17). Score rage 0 to 68, a score of "0" is a severely symptomatic patient and the highest possible score is an asymptomatic patient.	3 months, 6 months, 9 month, 1 year
Quality-of-life changes-BPI-SF	Patients with changes to quality of life as measured by Brief Pain Inventory-Short Form (BPI-SF). Score range 0 to 10; a low score equals less pain severity and less pain interference, a higher score equals higher pain severity and interference.	3 months, 6 months, 9 month, 1 year
Development of osteoporosis	The number of patients that develope osteoporosis within 5 years on study	5 years
Development of osteopenia	The number of patients that develope osteopenia within 5 years on study	5 years
Prevalence of gynecomastia	The number of patients who develop Grade 1 to 3 Gynecomastia;	5 years

Collaborators and Investigators

• Sponsor: Georgetown University
• Collaborators: Lantheus Medical Imaging
• Investigators: Principal Investigator: Paul D Leger, MD, Georgetown University

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): August 1, 2032
• Study Completion (Estimated): August 1, 2032

Study Registration Dates

• First Submitted: June 8, 2026
• First Submitted That Met QC Criteria: June 8, 2026
• First Posted (Actual): June 12, 2026

Study Record Updates

• Last Update Posted (Actual): June 12, 2026
• Last Update Submitted That Met QC Criteria: June 8, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Organic Chemicals; Pharmacologic Actions; Chemical Actions and Uses; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Taxoids; Cyclodecanes; Diterpenes; Docetaxel; Androgen Antagonists
• Other Study ID Numbers: STUDY00010158

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes