Phase 2 Trial for Xaluritamig in Patients With mCRPC and Suboptimal Response to Pluvicto

Thomas Jefferson University is running a phase 2 study of xaluritamig, also known as AMG 509, in adults with metastatic castration-resistant prostate cancer whose disease has shown a suboptimal response to Lu-177 vipivotide tetraxetan (aka 177Lu-PSMA 617) the radioligand therapy better known as Pluvicto. The trial reflects a very specific and clinically important question: what should come next when a patient has already received PSMA-targeted radioligand therapy but still has active, progressing prostate cancer.

Xaluritamig is not a conventional hormone therapy, chemotherapy, or radioligand. It is a STEAP1-directed bispecific T-cell engager designed to bring T cells into close contact with prostate cancer cells expressing STEAP1, thereby redirecting immune attack toward the tumor. That mechanism matters because metastatic castration-resistant prostate cancer remains biologically diverse and often develops resistance to standard androgen-receptor–directed approaches, taxanes, and radioligand therapy. In that setting, a distinct immune-based strategy may offer a new therapeutic lane rather than simply another variant of the same treatment class.

The rationale for this study is especially relevant now that Lu-177 vipivotide tetraxetan has become an important therapy for men with PSMA-positive mCRPC. Although Pluvicto can produce meaningful responses, not every patient benefits equally, and some show only partial or short-lived disease control. A study focused on “suboptimal response” is therefore trying to address a real-world gap: patients who have already proven they are not getting enough benefit from Lu-177 PSMA therapy but still need another active option. That sequencing problem is one of the major challenges in current prostate cancer care, particularly for heavily pretreated patients with limited remaining standard choices.

The broader xaluritamig development program provides the scientific backdrop for this trial. In the first-in-human study, xaluritamig showed encouraging antitumor activity in late-line mCRPC, including PSA and RECIST responses, supporting continued development of STEAP1-targeted T-cell engagers in prostate cancer. Safety, as with many T-cell engagers, is a central issue, and cytokine release syndrome has emerged as a notable class toxicity in the early xaluritamig experience, although it was generally manageable in the reported data. That balance between activity and immune-mediated toxicity is exactly what early-phase studies are designed to define more precisely.

What makes this study particularly interesting is that it is not simply testing xaluritamig in a generic mCRPC cohort. It is focusing on a biologically and clinically enriched subgroup, which can sharpen the relevance of the results. Patients who do not respond well enough to Lu-177 vipivotide tetraxetan may have tumors with aggressive features, heterogeneous target expression, or resistance mechanisms that demand a different therapeutic mechanism. In that sense, the trial is testing not only a drug, but also a treatment sequence hypothesis: whether an STEAP1-directed T-cell engager can rescue disease control after a PSMA-targeted radioligand falls short.

Clinical trial.