ASCO GU 2025: Beyond PSMA-Targeted Agents for Advanced Disease

(UroToday.com) The 2025 GU ASCO annual meeting featured a prostate cancer session and a presentation by Dr. William Kelly discussing beyond PSMA-targeted agents for advanced disease. Dr. Kelly notes that there are several important considerations for targets for radioligand therapy:

Accessibility:
- Does the cell membrane possess an extracellular moiety?
  - Cell surface or transmembrane glycoproteins, carbohydrates, cell surface receptors, growth factor receptors, transporters, enzymes
- The tumor microenvironment has attractive targets: CAFs, TAMs, TILs, neo-angiogenesis, hypoxia
High specificity:
- Target overexpressed in malignant tumors (local or metastatic)
- Little or no expression in normal tissues (on/off target toxicity)
Correlation:
- Reliable marker of overall tumor burden
- Ideally, a target for both imaging and therapy
Stable expression
- Target cell population across different conditions and stages of differentiation
- Considerations: lineage plasticity, treatment effects, and understanding a target’s functional relevance

The selection of a carrier system, linker, and radionuclide are critical for a successful radioligand therapy:

Dr. Kelly emphasized that there are many promising targets for prostate cancer, as highlighted in the following figure:

Dr. Kelly then discussed several of these important targets, starting with CD46, which is a negative regulator of the complement system, helping early cancer cells avoid immune detection. CD46 is overexpressed in prostate cancer, including primary disease, CRPC, and neuroendocrine prostate cancer. Expression increases after ADT and previous studies have established that abiraterone or enzalutamide upregulates CD46. 225Ac-DOTA-YS5 radioimmunotherapy suppressed PSMA positive and deficient models, and FG-3246 is a novel antibody drug conjugate to CD46 in clinical trials (phase 1 with mCRPC with clinical activity).

DLL3 inhibits the Notch signaling pathway and is highly expressed in small cell lung cancer and neuroendocrine tumors, but is not expressed on the surface of normal cells. Expression in prostate cancer includes 76.6% of neuroendocrine prostate cancer and 12.5% of adenocarcinoma. Additionally, it correlates with aggressive clinical features such as RB-1 loss. At ASCO 2024, Dr. Aggarwal presented results of a phase 1b study of tarlatamab, a half-life extended bispecific T-cell engager targeting DLL3, in de novo or treatment emergent neuroendocrine prostate cancer:

Initial results noted that DLL3+ patients had a partial response rate of 22%, disease control rate of 56%, and median progression free survival of 3.75 months.

Human kallikrein 2 (hK2) is expressed across different prostate cancer stages, including homogenous expression in non-metastatic and metastatic castration sensitive prostate cancer, with increased heterogeneity in mCRPC. hK2 in mCRPC is found in 67.6% of bone lesions, 65.7% of lymph nodes, and 33.5% of liver, with good intra-patient and intra-lesion homogeneity. Whole-body and SPECT/CT scans confirmed accumulation of the hK2-targeting antibody to prostate cancer tumors in patients with mCRPC, and radioligand therapy, T-cell engager, and CAR-T cell therapies are in development. JNJ-69086420 is an hK2-targeted, humanized monoclonal antibody conjugated to ²²⁵Ac:

hK2 is regulated by androgen receptor signaling, similar to PSA, and is encoded by KLK2, with high membranous expression in prostate cancer, and exists in both a secreted and membrane-associated form. JNJ-69086420 preferentially binds to the membrane-associated form of hK2 and delivers alpha-particle radiation to prostate tumor cells. Early clinical assessment of JNJ-69086420 in 75 patients noted deep and durable PSA responses. At a 250 uCi dose level, there was a PSA50 rate of 44%, a PSA90 rate of 9%, and 18% had a RECIST objective response rate:

From a safety standpoint, there was persistent grade 3/4 thrombocytopenia on a fixed dosing schedule at cumulative doses of >500 uCi, however, there was only one (3.8%) grade 3 thrombocytopenia following a single 250-400 uCi dose:

Dr. Kelly then discussed STEAP1, which belongs to the STEAP family of metalloreductases that can form homotrimers or heterotrimers with other STEAP proteins. STEAP1 is detected in low levels in normal prostate, with weak cytoplasmic expression in normal liver, testis, thyroid, and lung macrophages. It also is elevated in 88% of mCRPC samples by IHC, and metastatic lesions express higher levels of STEAP1 than primary tumors. STEAP1 showed evidence of clinical activity in a phase 1 study of the STEAP-1 antibody drug conjugate vandortuzumab vedotin (DSTP3086S).¹

In 2024, Dr. Kelly’s team reported the first-in-human study of Xaluritamig monotherapy dose exploration for patients with mCRPC, primarily taxane pretreated.² There were 97 patients that received ≥1 IV dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. The maximal tolerated dose was identified as 1.5 mg IV weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (72%), fatigue (45%), and myalgia (34%). Cytokine release syndrome occurred primarily during cycle 1 and improved with premedication and step dosing:

PSA and RECIST responses across cohorts were encouraging, with a 49% PSA50, 24% objective response rate, and with greater frequency at target doses ≥0.75 mg (59% PSA50, 41% objective response rate). The following represents the best PSA percentage change from baseline and the best percentage change in tumor size:

Antitumor activity of Xaluritamig has also been observed against both soft tissue and bone disease:

Dr. Kelly then discussed combining radioligand therapy and immunotherapy in an attempt to turn prostate cancer from a “cold” tumor to a “hot” tumor:

From a priming standpoint (immunotherapy radioligand therapy; radioligand therapy immunotherapy), Dr. Kelly discussed a phase I trial assessing single dose ¹⁷⁷Lu-PSMA-617 followed by maintenance pembrolizumab in patients with mCRPC. This showed an objective response rate of 56%, thus the interpretation of this approach is that a single priming dose of ¹⁷⁷Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in mCRPC.

From a synergy standpoint (immunotherapy + radioligand therapy) Dr. Kelly highlighted the PRINCE phase I trial of ¹⁷⁷Lu-PSMA-617 in combination with pembrolizumab in patients with mCRPC, which demonstrated no new safety signals and promising activity. Second, the EVOLUTION phase II study assessed ¹⁷⁷Lu-PSMA-617 + ipilimumab + nivolumab for mCRPC. From a salvage standpoint (immunotherapy or radioligand therapy stable disease to progressive disease switching to the other treatment approach after progression), Dr. Kelly highlighted the phase 2a feasibility study of sequential targeting of PSMA and STEAP-1 with ¹⁷⁷Lu-PSMA-617 and Xaluritamig in patients with mCRPC:

There are several challenges for novel targeted agents, including tumor heterogeneity, lineage plasticity, and functional relevance of the target, which requires enhanced imaging, blood/urine based monitoring (ie. ctDNA, exosomes), and relevant pre-clinical models:

Finally, Dr. Kelly highlighted the treatment landscape for prostate cancer in 2025 and beyond:

Dr. Kelly concluded his presentation by discussing beyond PSMA-targeted agents for advanced disease with the following take-home points:

There are several promising non-PSMA targets that have high sensitivity, good correlation to tumor burden, and stable expression (ie. CD46, DLL3, STEAP1, and hK2/KLK2) which could be used as monotherapy or potentially in combination with immunotherapies
Opportunities to improve radioligand based therapies are to better understand tumor heterogeneity, lineage plasticity and target functional relevance through enhanced imaging, blood based monitoring, and novel pre-clinical models

Presented by: William K. Kelly, DO, Thomas Jefferson University Hospital, Philadelphia, PA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.

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