Radioligand Targets for PSMA-Low and PSMA-Negative Prostate Cancer

Updated October 2026.

¹⁷⁷Lu-PSMA-617 (Pluvicto) proved that radioligand therapy works in metastatic castration-resistant prostate cancer. It also exposed the target's ceiling. In the phase 3 VISION trial, 126 of 1,003 screened patients (12.6%) were ineligible on PSMA PET, either because they had no PSMA-positive disease or because at least one sizeable metastasis was PSMA-negative (Sartor et al., NEJM 2021). Among those who are treated, low baseline PSMA uptake predicts poor response, and PSMA expression can be lost as the disease progresses.

That leaves a well-defined clinical gap and a commercially attractive one: patients who have already been selected by molecular imaging, who are already in nuclear-medicine care, and who need a second handle. This guide compares the targets being pursued for that gap, and what each one needs to prove.

A triage map, not clinical guidance. Program stages change quickly. Verify trial status and expression data for any target before acting on it.

What a "second target" for prostate cancer has to do

A target for PSMA-low disease has to clear the usual radioligand criteria, plus two that are specific to this setting:

1. Expression that doesn't track PSMA. A target that is lost alongside PSMA (for example, one that is also driven by androgen-receptor signalling) helps less in exactly the patients who need it. The most valuable candidates are expressed in PSMA-low lesions, or in a distinct subtype such as neuroendocrine prostate cancer.
2. A normal-tissue profile compatible with patients who may have already received PSMA radioligand therapy. Kidney, salivary gland and bone marrow dose from prior ¹⁷⁷Lu-PSMA treatment is already spent. A second agent that also loads those organs leaves little room. See how normal-tissue expression maps to dosimetry risk.

STEAP1: high prevalence, imaging-validated

Six-transmembrane epithelial antigen of the prostate 1 is a multi-pass membrane protein that is broadly expressed in prostate cancer, including castration-resistant disease. Immuno-PET with the ⁸⁹Zr-labelled anti-STEAP1 antibody MSTP2109A showed strong uptake in both bone and soft-tissue lesions, with most biopsied lesions confirmed positive (UroToday, SNMMI 2024 review). The STEAP1 × CD3 T-cell engager xaluritamig has validated the target clinically in another modality.

Open question for radioligands: STEAP1 is a multi-pass protein with small extracellular loops, which constrains binder design. Most radiopharmaceutical work to date is antibody-based, which brings long circulation and marrow exposure.

Profile: STEAP1

KLK2 (hK2): the most clinically advanced alpha program

Human kallikrein 2 is highly prostate-restricted, which is the source of both its appeal and its risk. Janssen's JNJ-69086420 is an ²²⁵Ac-labelled anti-hK2 antibody. In its phase 1 study in mCRPC, doses of at least 150 µCi produced a PSA50 response rate of 45.6%. Treatment-related adverse events led 9 of 57 patients (15.8%) to discontinue, and 4 treatment-related deaths were reported. Interstitial lung disease and thrombocytopenia were dose-limiting (ASCO 2024 abstract).

Open question: hK2 expression is androgen-receptor driven, like PSMA, so its value in AR-independent or neuroendocrine disease is limited. The safety profile reflects a long-circulating antibody carrying an alpha emitter as much as the target itself.

Profile: KLK2

CD46: expressed in PSMA-deficient models

CD46 is a complement-regulatory protein that is overexpressed in prostate cancer, and it is notable for being expressed in PSMA-low and neuroendocrine models. Preclinically, the ²²⁵Ac-labelled anti-CD46 antibody [²²⁵Ac]DOTA-YS5 suppressed growth in both PSMA-positive and PSMA-deficient xenografts. The same study saw kidney toxicity at higher activities, which the authors attributed to redistribution of the daughter isotope ²¹³Bi (Bidkar et al., Clin Cancer Res 2023).

Open question: CD46 is expressed on most nucleated normal cells. Tumor-to-normal contrast, not expression alone, decides whether it works.

Profile: CD46

B7-H3 (CD276): broad expression, pan-tumor upside

B7-H3 is an immune-checkpoint family protein that is overexpressed in prostate cancer and many other solid tumors, with relatively limited normal-tissue expression. It is being pursued with ADCs and antibody-based radiopharmaceuticals. A B7-H3 program would not be prostate-specific, which can be an advantage for portfolio value.

Profile: B7-H3

GRPR: a peptide-receptor complement to PSMA

Gastrin-releasing peptide receptor is a GPCR expressed mainly in earlier-stage, androgen-dependent prostate cancer, where it is often complementary to PSMA. It has well-developed peptide antagonist chemistry, such as RM2, and PSMA/GRPR heterodimers are in development. Its expression tends to fall in advanced castration-resistant disease, which limits it as a salvage target. Pancreatic uptake is the dosimetry concern to watch.

Profile: GRPR

DLL3: the neuroendocrine prostate cancer target

Delta-like ligand 3 is expressed on neuroendocrine prostate cancer (and small-cell lung cancer) but not on prostate adenocarcinoma, and it is rarely co-expressed with PSMA or STEAP1 (UroToday, PSMA and Beyond 2025). That makes it the clearest target for the treatment-emergent neuroendocrine subtype, which PSMA agents miss almost entirely. DLL3 is already clinically validated in small-cell lung cancer by the T-cell engager tarlatamab.

Profile: DLL3

FAP: target the stroma instead

Fibroblast activation protein sits on cancer-associated fibroblasts, not on tumor cells, so its expression doesn't depend on the tumor's PSMA status. The trade-off is short tumor retention for many small-molecule FAP inhibitors, and the need to deliver dose from the stroma to tumor cells. That favors longer-range beta emitters over alpha emitters.

Profile: FAP

Side by side

Run this screen against your own constraints. Nuclens ranks every cell-surface protein for a prostate cancer indication by tumor expression, internalization, shedding and clinical precedent, with sources for every score. Rank PSMA-low prostate cancer targets free →

How to choose between them

• For PSMA-low adenocarcinoma, prioritize targets whose expression doesn't depend on the androgen receptor (CD46, B7-H3). Then let normal-tissue contrast decide.
• For treatment-emergent neuroendocrine disease, DLL3 is the leading candidate. Expect a smaller but highly underserved population.
• For combination or sequencing with PSMA agents, look at cumulative kidney, salivary gland and marrow dose before tumor expression.
• For an alpha emitter, favor internalizing targets with homogeneous expression. For a beta emitter, crossfire tolerates more heterogeneity. See alpha vs beta emitters for target selection.

Next, see every candidate ranked on our prostate cancer radioligand targets page, or run your own screen with your isotope, organ limits and novelty bar.

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