Randomized Phase II Trial of Targeted Radiation With no Castration for Mcrpc

Phase II Trial of Targeted Radiation With no Castration for Mcrpc

This trial tests if the combination of comprehensive metastasis directed therapy delivered by a precision form of external beam radiotherapy (stereotactic ablative radiotherapy), combined with PSMA targeted radiopharmaceutical therapy and cessation of castration, and then followed by testosterone replacement, is an effective treatment for metastatic castration resistant prostate cancer.

All patients will be treated with stereotactic ablative radiotherapy and PSMA targeted radiopharmaceutical therapy with cessation of castration. Half of patients are randomized to either receive, or not receive, subsequent testosterone replacement.

Study Overview

• Status: Recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Radiation: stereotactic ablative radiotherapy; Drug: Pluvicto; Drug: topical testosterone

Detailed Description

This is a randomized, parallel-arm, two-stage open-label phase 2 study of comprehensive metastasis directed therapy in the form of stereotactic body radiation therapy (SBRT) to all detectable sites of disease plus PSMA targeted radiopharmaceutical therapy (pluvicto), discontinuation of castration, with and without testosterone replacement therapy (TRT) in metastatic castration resistant prostate cancer (mCRPC).

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Matthew B Rettig, MD; Phone Number: (310) 478-3711; Email: matthew.rettig@va.gov
• Study Contact Backup: Name: Nicholas G Nickols, MD PhD; Phone Number: (310) 478-3711; Email: nicholas.nickols@va.gov

Study Locations

• United States
  • California
    • West Los Angeles, California, United States, 90073-1003
      • Recruiting
      • VA Greater Los Angeles Healthcare System, West Los Angeles, CA
      • Contact: Matthew B Rettig, MD; Phone Number: (310) 478-3711; Email: matthew.rettig@va.gov
      • Contact: Nicholas G Nickols, MD PhD; Phone Number: (310) 478-3711; Email: nicholas.nickols@va.gov
      • Principal Investigator: Nicholas George Nickols, MD PhD
  • Illinois
    • Hines, Illinois, United States, 60141-3030
      • Recruiting
      • Edward Hines Jr. VA Hospital, Hines, IL
      • Contact: Abhishek Solanki, MD; Email: abhishek.solanki@va.gov
  • Indiana
    • Indianapolis, Indiana, United States, 46202-2884
      • Recruiting
      • Richard L. Roudebush VA Medical Center, Indianapolis, IN
      • Contact: Ronald Shapiro, MD; Email: ronald.shapiro@va.gov
  • Michigan
    • Ann Arbor, Michigan, United States, 48105-2303
      • Recruiting
      • VA Ann Arbor Healthcare System, Ann Arbor, MI
      • Contact: David Elliott, MD; Email: david.elliott1@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Subject must be 18 years of age or older at the time the Informed Consent is signed
• The subject (or legally acceptable representative if applicable) must provide written informed consent for the trial
• Pathologic diagnosis of prostate cancer of adenocarcinoma histology; presence small cell/neuroendocrine carcinoma is exclusionary

• Metastatic disease as documented by:

  • Osseous metastases detected by technetium-99m (99mTc) planar bone scan or NaF PET scan, or CT scan at some point in patient's history
  • Soft tissue metastases documented on CT or MRI
• PSMA avid metastatic disease as determined by 18F-DCFPyL: at least one lesion with PSMA avidity greater than that of liver (see Prescribing Information for Pluvicto)

• Progressive castration resistant prostate cancer as defined by serum testosterone < 50 ng/mL and one of the following:

  • PSA progression confirmed per Prostate Cancer Clinical Trials Working Group (PCWG3)
  • Radiographic progression of soft tissues according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) modified based on PCWG3, or radiographic progression of bone according to PCWG3
• Prior use of a novel AR signaling inhibitor for 4 weeks, including abiraterone acetate plus prednisone/prednisolone, enzalutamide, apalutamide, and/or darolutamide

NOTE: These AR signaling inhibitors may have been used for mCSPC, M0CRPC, and/or mCRPC.

• ECOG PS grade of 0-2

• 10 metastases detectable on molecular imaging (PSMA and FDG PET) and amenable to SBRT

  • 20% of metastases that are FDG avid but PSMA negative
  • Metastases that are not detectable on PSMA and FDG PET do not count toward the total number of metastases, as they are presumed to represent adequately treated sites of disease
• Life expectancy 6 months

• Adequate organ function:

  • Hemoglobin (hgb) > 8.0 g/dL
  • Absolute neutrophil count (ANC) > 1500/ µL
  • Platelets > 75,000/ µL
  • Total bilirubin 1.5 x ULN OR direct bilirubin ULN for participants with total bilirubin levels >1.5 x ULN
  • ALT and AST 3.0 x ULN ( 5 x ULN for participants with liver metastases) (Child-Pugh class A and B allowed; Child-Pugh class C is excluded)
  • Creatinine < (2.0 mg/dL) during screening evaluation (>2.0 is allowed if EGFR >30 mL/min/1.73 m2)
• Subject must agree to use contraception during the treatment period plus an additional 120 days after the last dose of study treatment and must refrain from donating sperm during this period

Exclusion Criteria:

• Visceral metastases including liver and brain (lung metastases are allowed)
• Small cell/neuroendocrine carcinoma by hematoxylin and eosin light histology (immunohistochemical detection of rare/occasional cells that stain for neuroendocrine markers such as synaptophysin, neuron specific enolase, or chromogranin A is not sufficient to make a diagnosis of small cell/neuroendocrine carcinoma)

• Anti-neoplastic therapies for prostate cancer must be completed > 2 weeks prior to Day 1 (initiation of first dose of PSMA RLT)

  • Investigational agents must have been completed > 4 weeks of Day 1

Note: Participants must have recovered from all AEs due to previous therapies to Grade 1 or baseline

• Participants with Grade 2 neuropathy may be eligible

  • Herbal and non-herbal products that may decrease PSA levels other than medical castration and megestrol (up to 40 mg/day is allowed) for hot flashes
  • Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis

Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

• If a subject has undergone major surgery, they must have recovered adequately from the toxicities or complications from the intervention within 4 weeks prior to starting therapy
• History of non-prostate active malignancy requiring treatment in the 24 months prior to Day 1 except for non-muscle invasive urothelial cancer, non-melanoma skin cancer, or any cancer that in the opinion of the investigator has been adequately treated and will not interfere with study procedures or interpretation of results
• Active infection or conditions requiring treatment with antibiotics
• Symptomatic local recurrence in the setting of prior curative intent therapy (surgery and/or radiation to the prostate)
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Subject is planning to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
• Current or impending cord compression or another indication for urgent palliative radiation therapy

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: Arm 1; Metastasis directed therapy with stereotactic ablative radiotherapy to all detectable sites of disease plus PSMA radiopharmaceutical therapy and discontinuation of castration	Radiation: stereotactic ablative radiotherapy; Metastasis directed; Other Names: SBRT; Drug: Pluvicto; PSMA targeted radiopharmaceutical therapy; Other Names: Lu177-PSMA
Experimental: Arm 2; Metastasis directed therapy with stereotactic ablative radiotherapy to all detectable sites of disease plus PSMA radiopharmaceutical therapy and discontinuation of castration, followed by restoration of physiologic testosterone	Radiation: stereotactic ablative radiotherapy; Metastasis directed; Other Names: SBRT; Drug: Pluvicto; PSMA targeted radiopharmaceutical therapy; Other Names: Lu177-PSMA; Drug: topical testosterone; Topical testosterone 1.62% gel; Other Names: androgel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-month radiographic progression-free survival (rPFS)	6-month radiographic progression-free survival (rPFS) measured by conventional imaging from date of initiation of PSMA radiopharmaceutical therapy	6-months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient reported health-related quality of life measured by Expanded Prostate Cancer Index Composite (EPIC-26)	EPIC-26 contains 26 items in 5 domains (Urinary Incontinence, Urinary Irritative/Obstructive, Bowel, Sexual, and Hormonal). Raw scores are transformed linearly to a 0-100 scale, with higher scores representing better HRQOL.	up to two years
PSA30, PSA50, PSA90, maximal PSA response	This is the rate of PSA response (PSA decrease by 30%, 50%, 90%), and maximal response	up to two years
Time to PSA progression	Time to PSA progression per PCWG3 criteria, from date of initiation of PSMA radiopharmaceutical therapy	up to two years
Objective response rate	Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) from date of initiation of PSMA radiopharmaceutical therapy	up to two years
Time to radiographic progression	Time-to-event, Bone progression by Prostate Cancer Working Group 3 (PCWG3) criteria and/or soft tissue progression by RECIST v1.1, from date of initiation of PSMA radiopharmaceutical therapy	up to two years
PSMA PET response	Measured using Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE)	up to two years
Progression Free Survival	Time-to-event, a composite between time to PSA progression (PCWG3) and/or radiographic progression (PCWG3 for bone, RECIST 1.1 for soft tissue), from date of initiation of PSMA radiopharmaceutical therapy	up to two years
Overall survival	Time-to-event, from date of initiation of PSMA radiopharmaceutical therapy	up to two years
Patient reported health-related quality of life measured by The Functional Assessment of Cancer Therapy-Prostate (FACT-P).	FACT-P includes a general functional status scale (consisting of four subscales: physical wellbeing, social and family wellbeing, emotional wellbeing, and functional wellbeing) and a prostate-cancer-specific subscale. Total score is calculated with general function and prostate-cancer-specific scores, and ranges from 0 to 156 (higher scores indicate better functional status).	up to two years
safety as assessed by physician reported toxicity	Physician reported Common Terminology Criteria for Adverse Events (CTCAE version 5.0)	up to two years

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Nicholas George Nickols, MD PhD, VA Greater Los Angeles Healthcare System, West Los Angeles, CA

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2023
• Primary Completion (Estimated): November 29, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: October 10, 2023
• First Submitted That Met QC Criteria: October 10, 2023
• First Posted (Actual): October 16, 2023

Study Record Updates

• Last Update Posted (Actual): December 31, 2025
• Last Update Submitted That Met QC Criteria: December 29, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: stereotactic body radiotherapy; SBRT; metastatic castration resistant prostate cancer; mCRPC; stereotactic ablative radiotherapy; Metastasis Directed Therapy; Lu177 PSMA; Pluvicto
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Gonadal Steroid Hormones; Gonadal Hormones; Androstenes; Androstanes; Androstenols; Testosterone Congeners; Pluvicto; Testosterone
• Other Study ID Numbers: SPLP-002-23M; 1I01CX002775 (U.S. NIH Grant/Contract: Department of Veterans Affairs)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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