Phase 2 Trial: Deruxtecan in Neuroendocrine Prostate Cancer

A new phase 2 clinical trial will investigate ifinatamab deruxtecan (I-DXd), an experimental B7-H3-targeted antibody-drug conjugate (ADC), in men with metastatic neuroendocrine prostate cancer (NEPC). The multicenter study plans to enroll 30 patients with either de novo neuroendocrine disease or neuroendocrine transformation that developed during treatment for prostate cancer.

Neuroendocrine transformation represents a particularly challenging form of treatment resistance. Some prostate cancers progressively lose their dependence on androgen receptor signaling and acquire neuroendocrine characteristics, making conventional hormone-directed therapies less effective. Ifinatamab deruxtecan offers a different therapeutic approach: it targets B7-H3, also known as CD276, a cell-surface protein frequently expressed in aggressive prostate cancers, and delivers a cytotoxic payload that inhibits topoisomerase I, causing DNA damage that may lead to cancer cell death.

An important feature of the trial is its relatively broad definition of neuroendocrine disease.

Patients may qualify for the trial if their tumors show neuroendocrine features, specific neuroendocrine markers, or mutations in at least two of three genes: RB1, TP53 and PTEN. However, patients selected solely on the basis of these mutations will make up no more than 30% of those evaluated for treatment effectiveness. This broader approach may help researchers identify which patients are most likely to benefit from B7-H3-targeted therapy.

Participants must have metastatic disease with measurable soft-tissue lesions and previous systemic treatment. Patients with de novo NEPC must previously have received platinum-based chemotherapy, while those with treatment-emergent NEPC must have undergone androgen deprivation therapy and treatment with at least one androgen receptor pathway inhibitor. Prior cytotoxic chemotherapy is also generally required in the latter group, although the protocol permits certain exceptions.

The primary endpoint is objective response rate (ORR), measured through radiographic tumor responses. Secondary endpoints include response duration, radiographic progression-free survival, overall survival, safety and PSA responses in patients with baseline PSA above 5 ng/mL. Particularly interesting are the circulating tumor DNA (ctDNA) analyses, which will assess reductions in tumor DNA fraction and conversion from detectable to undetectable ctDNA. Investigators will also examine B7-H3 expression, intratumoral heterogeneity and the co-expression of other cell-surface targets to better understand which tumor populations respond or escape treatment.

Clinical trial.