3215 - Trial in Progress: Randomized Phase II Trial of Targeted Radiation with No Castration for Treatment of Metastatic Castration-Resistant Prostate Cancer

12:45pm - 02:00pm PT

Hall F

Screen: 3

POSTER

Presenter(s)

Sasha Ebrahimi, MD, PhD - UCLA Radiation Oncology, Los Angeles, CA

S. Ebrahimi¹, G. Berenji², M. Rettig^2,3, and N. G. Nickols^1,2; ¹Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, ²VA Greater Los Angeles Health System, Los Angeles, CA, ³Department of Medical Oncology, University of California, Los Angeles, Los Angeles, CA

Purpose/Objective(s):

Patients with metastatic castration-resistant prostate cancer (mCRPC) are conventionally maintained on lifelong androgen deprivation therapy (ADT) despite resistance to castration and its well-documented adverse effects. Recently, androgen receptor-independent therapies such as PSMA-targeted radioligand therapy (RLT) have demonstrated efficacy and are now standard of care. Additionally, metastasis-directed therapy (MDT) with stereotactic body radiation therapy (SBRT) provides durable local control with minimal toxicity.

This study investigates whether a non-hormonal treatment approach can improve oncologic outcomes while preserving quality of life. The hypothesis is that comprehensive MDT with SBRT and PSMA RLT without ongoing castration therapy will enhance treatment efficacy and improve quality-of-life scores for mCRPC patients.

Materials/Methods:

This is a randomized, open-label, Phase II trial enrolling 60 patients across multiple sites. Eligible patients must have mCRPC with serum testosterone <50 ng/mL and PSA, soft tissue, or bone progression (RECIST 1.1/PCWG3). Active disease visible on PSMA PET must have at least one lesion SUV = liver uptake. Disease burden is limited to =10 active sites on PSMA and FDG PET, all amenable to SBRT, with =20% FDG-avid but PSMA-negative metastases. Exclusion criteria include visceral (liver/brain) metastases, prior PSMA RLT or radium-223 treatment, small cell/neuroendocrine prostate cancer, or impending spinal cord compression. Prior PARP inhibitors, sipuleucel-T, or pembrolizumab are allowed.

Following ADT discontinuation, patients are randomized 1:1 into two arms: (1) PSMA RLT (¹⁷⁷Lu vipivotide tetraxetan) for 2 cycles with intervening SBRT in 1–5 fractions delivered to all sites of active disease, or (2) the same treatment but with daily transdermal testosterone gel initiated if post-treatment imaging is consistent with no active sites of disease.

The primary endpoint is 6-month rPFS, assessed by conventional imaging from PSMA RLT initiation. Secondary endpoints include safety and toxicity (CTCAE v5.0), PSA response rates (PSA30, PSA50, PSA90), time to PSA progression (PCWG3), objective response rate (RECIST 1.1 for soft tissue, PCWG3 for bone lesions), and quality of life (EPIC-26, FACT-P). Exploratory endpoints are genomic alterations (tumor DNA NGS) and molecular imaging (PSMA and FDG PET/CT) associations with response. 26 patients per arm are needed to detect an absolute 25% increase in an expected 6-month rPFS (from 50% to 75%) with 82% power at a = 0.04.

Results:

TBD.

Conclusion:

This trial challenges the conventional indefinite ADT paradigm in mCRPC by assessing whether a non-hormonal approach combining PSMA RLT and SBRT without ongoing testosterone suppression can improve oncologic outcomes and quality of life. If successful, this study may establish a novel treatment framework for mCRPC management.