PSMA PET/CT-Guided SBRT Plus Darolutamide in mHSPC (PSMA-DaroRT)

A Multicenter, Prospective, Randomized Controlled Phase II Trial of PSMA PET/CT-Guided Stereotactic Body Radiotherapy Combined With Darolutamide and Androgen Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer

This is a multicenter, randomized, open-label phase 2 study for men with metastatic hormone-sensitive prostate cancer. About 254 participants will first receive 6 months of darolutamide plus androgen deprivation therapy. Participants whose cancer has not progressed and who still have active tumor lesions on prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) will then be randomly assigned to one of two groups. One group will continue darolutamide plus androgen deprivation therapy. The other group will receive stereotactic body radiotherapy (SBRT) to all active tumor lesions identified by PSMA PET/CT, while continuing darolutamide plus androgen deprivation therapy. The main purpose of this study is to find out whether adding PSMA PET/CT-guided SBRT can help participants live longer without tumor growth seen on scans or death. The study will also evaluate prostate-specific antigen (PSA) changes, time to castration-resistant prostate cancer, overall survival, side effects, and quality of life.

Study Overview

• Status: Not yet recruiting
• Conditions: Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)
• Intervention / Treatment: Radiation: Stereotactic Body Radiotherapy (SBRT); Drug: Darolutamide 600 mg twice daily; Drug: Androgen Deprivation Therapy (ADT)

Detailed Description

Metastatic hormone-sensitive prostate cancer is usually treated with systemic therapy, including androgen deprivation therapy and androgen receptor pathway inhibitors such as darolutamide. However, some patients still have active tumor lesions after initial systemic treatment, and these residual lesions may contribute to later disease progression.

This study is designed to test whether adding targeted radiotherapy to residual active tumor lesions can improve disease control. All enrolled participants will first receive 6 months of darolutamide plus androgen deprivation therapy. After this initial treatment period, participants will undergo clinical and imaging assessment, including prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT), to evaluate whether active tumor lesions remain.

Participants who have no disease progression and still have PSMA PET/CT-positive active tumor lesions will be randomly assigned in a 1:1 ratio to one of two groups. Participants in the control group will continue darolutamide plus androgen deprivation therapy. Participants in the experimental group will continue darolutamide plus androgen deprivation therapy and will also receive stereotactic body radiotherapy (SBRT) to all active tumor lesions identified by PSMA PET/CT, including active lesions in the prostate or prostate bed and metastatic sites when appropriate.

This is a multicenter, prospective, randomized, open-label phase 2 study. The study plans to enroll about 254 men with metastatic hormone-sensitive prostate cancer. The main question is whether PSMA PET/CT-guided SBRT, when added to darolutamide and androgen deprivation therapy after 6 months of initial systemic treatment, can increase the proportion of participants who are alive without radiographic disease progression at 3 years after randomization.

Participants will be followed regularly with physical examinations, blood tests including prostate-specific antigen (PSA), testosterone monitoring when required, imaging examinations, assessment of adverse events, and quality-of-life questionnaires. Imaging-based disease progression will be assessed using standard criteria for soft tissue and bone lesions. Safety will be monitored throughout the study, including side effects related to darolutamide, androgen deprivation therapy, and radiotherapy.

The study will also explore whether PSMA PET/CT imaging features, PSA changes, circulating tumor DNA, and molecular features of tumor or blood samples are associated with treatment response, disease progression, or survival outcomes. These exploratory analyses may help identify future biomarkers for selecting patients who are more likely to benefit from combined systemic therapy and PSMA PET/CT-guided radiotherapy.

• Study Type: Interventional
• Enrollment (Estimated): 254
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hao Zeng, MD, PhD; Phone Number: 86 28 85422026; Email: kucaizeng@163.com

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • West China Hospital, Sichuan University

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Male participants aged ≥18 years and <85 years.
• Histologically confirmed prostate adenocarcinoma.
• No neuroendocrine carcinoma, ductal adenocarcinoma, small-cell carcinoma, signet-ring cell carcinoma, or sarcomatoid carcinoma component.
• Metastatic prostate cancer confirmed by imaging or pathological evidence.
• PSMA PET/CT and FDG PET/CT show ≤20 metastatic lesions.
• PSMA PET/CT and FDG PET/CT show concordant tracer uptake activity.
• No prior systemic or local anti-tumor treatment for prostate cancer.
• No prior androgen deprivation therapy.
• No prior first-generation antiandrogen therapy.
• No prior androgen receptor signaling inhibitor therapy, including abiraterone, enzalutamide, apalutamide, rezvilutamide, or darolutamide.
• No prior chemotherapy for prostate cancer.
• No prior radical prostatectomy.
• No prior radiotherapy for prostate cancer.
• Expected survival >12 months.
• Able to understand the study and voluntarily sign written informed consent.
• Able and willing to comply with study visits and protocol procedures.
• Willing to provide tumor tissue, blood, and other biological samples as required by the study protocol.
• Absolute neutrophil count ≥1.5 × 10^9/L.
• Platelet count ≥100 × 10^9/L.
• Hemoglobin ≥90 g/L.
• Total bilirubin ≤1.5 × upper limit of normal.
• Alanine aminotransferase and aspartate aminotransferase ≤2.5 × upper limit of normal.
• Serum albumin ≥20 g/L.
• Serum creatinine ≤1.5 × upper limit of normal or creatinine clearance ≥50 mL/min.
• Eastern Cooperative Oncology Group performance status ≤2.

Exclusion Criteria:

• Current or prior history of another primary malignancy.
• History of another malignancy within 3 years that differs from the study cancer in primary site or histology.
• History of papillary thyroid carcinoma is allowed if it is well controlled.
• History of basal cell carcinoma of the skin is allowed if it is well controlled.
• History of squamous cell carcinoma of the skin is allowed if it is well controlled.
• History of cervical carcinoma in situ is allowed if it is well controlled.
• Prior radical prostatectomy.
• Prior external beam radiotherapy.
• Prior radical or ablative local therapy for prostate cancer.
• Prior treatment with an androgen receptor signaling inhibitor, including abiraterone, enzalutamide, apalutamide, rezvilutamide, or darolutamide.
• Prior chemotherapy for prostate cancer.
• Major surgery within 4 weeks before enrollment.
• Serious trauma within 4 weeks before enrollment.
• Contraindication to radiotherapy.
• Spinal cord compression.
• Active enteritis.
• Severe pelvic infection.
• Inability to maintain the required body position for radiotherapy.
• History of allergy to PET/CT tracer.
• Nuclear medicine assessment showing super bone imaging.
• Marked discordance between PSMA PET/CT and FDG PET/CT findings.
• Disease progression during the 6-month run-in period of androgen deprivation therapy plus darolutamide before randomization.
• Unacceptable toxicity during the 6-month run-in period of androgen deprivation therapy plus darolutamide before randomization.
• No active tumor lesion on PSMA PET/CT after the 6-month run-in period.
• Allergy to any component of the study treatment.
• Active or poorly controlled serious infection.
• Human immunodeficiency virus infection.
• Acute or chronic active hepatitis B infection, defined as positive hepatitis B surface antigen with hepatitis B virus DNA >1 × 10^3/mL.
• Acute or chronic active hepatitis C infection, defined as positive hepatitis C virus antibody with hepatitis C virus RNA >15 IU/mL.
• Active pulmonary tuberculosis.
• Other serious infectious disease.
• New York Heart Association class III or IV congestive heart failure.
• Persistent symptomatic arrhythmia.
• Uncontrolled atrial fibrillation.
• Left ventricular ejection fraction below the lower limit of normal on repeated echocardiographic assessments.
• Uncontrolled hypertension, defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg.
• Arterial thrombotic, embolic, or ischemic event within 6 months before enrollment.
• Myocardial infarction within 6 months before enrollment.
• Unstable angina within 6 months before enrollment.
• Cerebrovascular accident within 6 months before enrollment.
• Transient ischemic attack within 6 months before enrollment.
• Medical condition requiring warfarin or coumarin anticoagulation therapy.
• Uncontrolled hypercalcemia, defined as ionized calcium >1.5 mmol/L, total calcium >12 mg/dL, or corrected serum calcium above the upper limit of normal.
• Symptomatic hypercalcemia requiring continuous bisphosphonate therapy.
• Uncontrolled adrenal insufficiency.
• History of abdominal fistula within 6 months before enrollment.
• History of gastrointestinal perforation within 6 months before enrollment.
• History of intra-abdominal abscess within 6 months before enrollment.
• Severe non-healing wound.
• Severe non-healing ulcer.
• Gastrointestinal disease that may impair absorption.
• Active peptic ulcer disease.
• Uncontrolled nausea.
• Uncontrolled vomiting.
• Uncontrolled diarrhea.
• History of small bowel resection that may impair drug absorption.
• Other acute or chronic disease, psychiatric disorder, or laboratory abnormality that may increase the risk associated with study participation or study treatment.
• Other acute or chronic disease, psychiatric disorder, or laboratory abnormality that may interfere with interpretation of study results.
• Any other medical or psychological condition that, in the investigator's judgment, may affect participant safety, compliance, or study integrity.
• Any condition that, in the investigator's judgment, makes the participant unsuitable for this study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PSMA PET/CT-Guided SBRT + Darolutamide + ADT; After a 6-month run-in period of darolutamide plus androgen deprivation therapy, eligible participants without disease progression and with residual PSMA PET/CT-positive active tumor lesions will receive PSMA PET/CT-guided stereotactic body radiotherapy to all active tumor lesions while continuing darolutamide plus androgen deprivation therapy.	Radiation: Stereotactic Body Radiotherapy (SBRT); Stereotactic body radiotherapy will be delivered in the experimental arm after the 6-month run-in period of darolutamide plus androgen deprivation therapy. Radiotherapy will target all residual PSMA PET/CT-positive active tumor lesions, while participants continue darolutamide plus androgen deprivation therapy. Target lesions may include active lesions in the prostate or prostate bed and metastatic sites. Dose and fractionation will be selected according to lesion location, lesion size, and organ-at-risk constraints as specified in the study protocol.; Drug: Darolutamide 600 mg twice daily; Darolutamide will be administered orally at 600 mg twice daily with food during the 6-month run-in period in combination with androgen deprivation therapy. After randomization, darolutamide will be continued in both treatment groups according to the assigned treatment strategy. Treatment may be interrupted or dose-reduced according to protocol-defined toxicity management rules.; Drug: Androgen Deprivation Therapy (ADT); Androgen deprivation therapy will be maintained throughout study treatment in both groups. The method of androgen deprivation therapy will be selected by the investigator according to the participant's clinical condition and may include surgical castration or medical castration with a luteinizing hormone-releasing hormone agonist or antagonist. Treatment will aim to maintain castrate testosterone levels according to the study protocol.
Active Comparator: Darolutamide + ADT; After a 6-month run-in period of darolutamide plus androgen deprivation therapy, eligible participants without disease progression and with residual PSMA PET/CT-positive active tumor lesions will continue darolutamide plus androgen deprivation therapy without local radiotherapy.	Drug: Darolutamide 600 mg twice daily; Darolutamide will be administered orally at 600 mg twice daily with food during the 6-month run-in period in combination with androgen deprivation therapy. After randomization, darolutamide will be continued in both treatment groups according to the assigned treatment strategy. Treatment may be interrupted or dose-reduced according to protocol-defined toxicity management rules.; Drug: Androgen Deprivation Therapy (ADT); Androgen deprivation therapy will be maintained throughout study treatment in both groups. The method of androgen deprivation therapy will be selected by the investigator according to the participant's clinical condition and may include surgical castration or medical castration with a luteinizing hormone-releasing hormone agonist or antagonist. Treatment will aim to maintain castrate testosterone levels according to the study protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-Year Radiographic Progression-Free Survival (rPFS)	Radiographic progression-free survival (rPFS) is defined as the time from randomization to radiographic disease progression or death from any cause, whichever occurs first. Progression is assessed using RECIST 1.1 for soft tissue and PCWG3 criteria for bone lesions. The 3-year rPFS rate will be estimated using the Kaplan-Meier method.	From randomization to 3 years after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Radiographic Progression-Free Survival (o-rPFS)	Overall radiographic progression-free survival is defined as the time from the first dose of induction therapy with darolutamide plus androgen deprivation therapy to the first occurrence of radiographic disease progression or death from any cause, whichever occurs first. Radiographic progression will be assessed according to RECIST 1.1 for soft-tissue lesions and PCWG3 criteria for bone lesions.	From first dose of induction therapy to radiographic progression or death, assessed up to 60 months
PSA Progression-Free Survival (PSA-PFS)	PSA progression-free survival is defined as the time from randomization to PSA progression per PCWG3 criteria or death from any cause, whichever occurs first. For participants with a PSA decline from baseline, PSA progression is defined as a ≥25% increase and an absolute increase of ≥2 ng/mL from the PSA nadir, confirmed by a second consecutive value obtained ≥3 weeks later. For participants without a PSA decline from baseline, PSA progression is defined as a ≥25% increase from baseline with an absolute increase of ≥2 ng/mL after 12 weeks of treatment.	From randomization to PSA progression or death, assessed up to 60 months
Time to Castration-Resistant Prostate Cancer (CRPC)	Time to castration-resistant prostate cancer is defined as the time from randomization to the development of castration-resistant prostate cancer under castrate testosterone levels, defined as serum testosterone <50 ng/dL or <1.7 nmol/L. Castration-resistant prostate cancer is defined by biochemical progression, radiographic progression, or unequivocal clinical progression according to protocol-defined criteria.	From randomization to development of castration-resistant prostate cancer, assessed up to 60 months
Overall Survival (OS)	Overall survival is defined as the time from randomization to death from any cause.	From randomization to death from any cause, assessed up to 60 months
PSA Response Rate (≥50% Decline From Baseline)	PSA response rate is defined as the proportion of participants who achieve a ≥50% decline in serum PSA from baseline (at randomization) at any time during treatment, confirmed by at least one repeat measurement approximately 4 weeks later.	From randomization to PSA response, assessed up to 36 months
Best Percent Change in PSA From Baseline	Best percent change in PSA from baseline is defined as the maximum percent decrease from baseline PSA at randomization to the lowest observed PSA value during follow-up.	From randomization up to 36 months
PSA Nadir	PSA nadir is defined as the lowest serum PSA value observed from randomization through the end of prespecified follow-up.	From randomization up to 36 months
Time to PSA Nadir	Time to PSA nadir is defined as the time from randomization to the date when the lowest serum PSA value is first observed.	From randomization up to 36 months
Incidence and Severity of Adverse Events	Safety will be assessed by the incidence and severity of treatment-emergent adverse events, treatment-emergent serious adverse events, adverse events of special interest, darolutamide-related adverse events, adverse events leading to treatment discontinuation, and adverse events with fatal outcome. Adverse events will be graded according to CTCAE v6.0.	From first study treatment to 30 days after the last study treatment or radiotherapy, whichever occurs later
Quality of Life (EORTC QLQ-C30)	Quality of life will be assessed using EORTC QLQ-C30 questionnaires. Scores and changes from baseline over time will be summarized and compared between treatment groups.	Baseline at randomization and prespecified follow-up visits up to 36 months
Quality of Life (QLQ-PR25)	Quality of life will be assessed using EORTC QLQ-PR25 questionnaires. Scores and changes from baseline over time will be summarized and compared between treatment groups.	Baseline at randomization and prespecified follow-up visits up to 36 months
Quality of Life (EQ-5D)	Quality of life will be assessed using EQ-5D questionnaires. Scores and changes from baseline over time will be summarized and compared between treatment groups.	Baseline at randomization and prespecified follow-up visits up to 36 months

Collaborators and Investigators

• Sponsor: West China Hospital
• Collaborators: Bayer
• Investigators: Principal Investigator: Hao Zeng, MD, PhD, West China Hospital

Publications and helpful links

General Publications

• Parker CC, James ND, Brawley CD, Clarke NW, Hoyle AP, Ali A, Ritchie AWS, Attard G, Chowdhury S, Cross W, Dearnaley DP, Gillessen S, Gilson C, Jones RJ, Langley RE, Malik ZI, Mason MD, Matheson D, Millman R, Russell JM, Thalmann GN, Amos CL, Alonzi R, Bahl A, Birtle A, Din O, Douis H, Eswar C, Gale J, Gannon MR, Jonnada S, Khaksar S, Lester JF, O'Sullivan JM, Parikh OA, Pedley ID, Pudney DM, Sheehan DJ, Srihari NN, Tran ATH, Parmar MKB, Sydes MR; Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018 Dec 1;392(10162):2353-2366. doi: 10.1016/S0140-6736(18)32486-3. Epub 2018 Oct 21.
• Phillips R, Shi WY, Deek M, Radwan N, Lim SJ, Antonarakis ES, Rowe SP, Ross AE, Gorin MA, Deville C, Greco SC, Wang H, Denmeade SR, Paller CJ, Dipasquale S, DeWeese TL, Song DY, Wang H, Carducci MA, Pienta KJ, Pomper MG, Dicker AP, Eisenberger MA, Alizadeh AA, Diehn M, Tran PT. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020 May 1;6(5):650-659. doi: 10.1001/jamaoncol.2020.0147.
• Malaspina S, Ettala O, Tolvanen T, Rajander J, Eskola O, Bostrom PJ, Kemppainen J. Flare on [18F]PSMA-1007 PET/CT after short-term androgen deprivation therapy and its correlation to FDG uptake: possible marker of tumor aggressiveness in treatment-naive metastatic prostate cancer patients. Eur J Nucl Med Mol Imaging. 2023 Jan;50(2):613-621. doi: 10.1007/s00259-022-05970-y. Epub 2022 Sep 26.
• Rans K, Charlien B, Filip A, Olivier H, Julie DH, Cederic D, Herlinde D, Benedikt E, Karolien G, Annouschka L, Nick L, Kenneth P, Carl S, Koen S, Hans V, Ben V, Steven J, Gert M. SPARKLE: a new spark in treating oligorecurrent prostate cancer: adding systemic treatment to stereotactic body radiotherapy or metastasectomy: key to long-lasting event-free survival? BMC Cancer. 2022 Dec 12;22(1):1294. doi: 10.1186/s12885-022-10374-0.
• Bossi A, Foulon S, Maldonado X, Sargos P, MacDermott R, Kelly P, Flechon A, Tombal B, Supiot S, Berthold D, Ronchin P, Kacso G, Salem N, Calabro F, Berdah JF, Hasbini A, Silva M, Boustani J, Ribault H, Fizazi K; PEACE-1 investigators. Efficacy and safety of prostate radiotherapy in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 x 2 factorial design. Lancet. 2024 Nov 23;404(10467):2065-2076. doi: 10.1016/S0140-6736(24)01865-8.
• Boeve LMS, Hulshof MCCM, Vis AN, Zwinderman AH, Twisk JWR, Witjes WPJ, Delaere KPJ, Moorselaar RJAV, Verhagen PCMS, van Andel G. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2019 Mar;75(3):410-418. doi: 10.1016/j.eururo.2018.09.008. Epub 2018 Sep 25.

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): August 1, 2031
• Study Completion (Estimated): October 1, 2031

Study Registration Dates

• First Submitted: June 7, 2026
• First Submitted That Met QC Criteria: June 14, 2026
• First Posted (Actual): June 16, 2026

Study Record Updates

• Last Update Posted (Actual): June 16, 2026
• Last Update Submitted That Met QC Criteria: June 14, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: SBRT; Androgen Deprivation Therapy; Darolutamide; PSMA PET/CT; Metastasis-Directed Therapy
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Investigative Techniques; Therapeutics; Surgical Procedures, Operative; Pharmacologic Actions; Chemical Actions and Uses; Radiotherapy; Stereotaxic Techniques; Neurosurgical Procedures; Androgen Antagonists; darolutamide; Radiosurgery
• Other Study ID Numbers: WCH-URO-2026-449

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Individual participant data (IPD) sharing has not been decided at this time. Any future sharing will be considered after study completion and publication, subject to IRB/ethics approval, applicable regulations, participant privacy protections, and data use agreements. Requests, if allowed, would require submission of a research proposal and will be evaluated by the study team.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes