Prostate Cancer Metastatic Castration Resistant

This is a first-in-human (FIH) open-label, multicenter, dose-escalation and dose-expansion Phase I study of KMV002 in metastatic androgen pathway modulation-resistant (mAPMR) prostate cancer patients. This study consists of two parts: dose escalation (Part 1) and dose expansion (Part 2). Following a screening period, eligible mAPMR patients will be enrolled to receive their assigned regimen of KMV002 (a combination of SN3001C and CpG ODN adjuvant). KMV002 will be given as either a 5-dose or 6-dose regimen.

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with Lutetium-177 (¹⁷⁷Lu-PSMA) is an established treatment for metastatic prostate cancer. Administered intravenously, it enables targeted irradiation of PSMA-expressing tumor cells. However, 30-50% of patients derive limited benefit. This variability could be partly explained by heterogeneity in delivered dose across lesions, leading to under-treatment of certain metastases. The addition of targeted external beam radiotherapy (EBRT) may compensate for this underdosing by delivering a precise dose to insufficiently irradiated lesions. The investigators hypothesize that the addition of adaptive EBRT to ¹⁷⁷Lu-PSMA will reduce the incidence of skeletal-related events (pathologic fracture, spinal cord compression, surgery, or palliative radiotherapy) without increasing toxicity. Adaptive EBRT and RLT for mCRPC (ARREST) is a pragmatic registry-based phase 2, multi-center randomized controlled trial within the PERa prospective cohort (NCT03378856) planned to activate in 2026. Patients receiving standard-of-care (SOC) ¹⁷⁷Lu-PSMA with targetable metastatic burden identified on imaging and suitable for EBRT will be eligible. One hundred and twenty eligible patients will be randomized 1:1 to receive either SOC ¹⁷⁷Lu-PSMA therapy alone (maximum 6 cycles) or combined ¹⁷⁷Lu-PSMA plus adaptive EBRT. Patients in the experimental arm will undergo FDG-PET at study entry and SPECT-CT after each cycle of radioligand therapy. Lesions selected for EBRT boost will be chosen based on a set of criteria that include estimated suboptimal absorbed dose from ¹⁷⁷Lu-PSMA, lesions demonstrating low PSMA but high FDG uptake, symptomatic lesions, and lesions at high risk for skeletal-related events. Selected lesions will receive single-fraction EBRT. The prescribed dose will range from 6-12 Gy, with the goal of achieving a combined total biological effective dose of ≥50 Gy (α/β = 5), while prioritizing dose limits for organs at risk. A maximum treatment time of 60 minutes is permitted for each adaptive EBRT treatment. Patients in the experimental arm who achieve a complete response, as measured by ¹⁷⁷Lu-SPECT-CT and PSA, will pause ARREST treatment and resume at disease progression. The primary endpoint is skeletal-related events at 1 year. Secondary objectives include overall survival, ¹⁷⁷Lu-SPECT-CT and PSA response, toxicity, and quality of life. The sample size is designed to detect a 12-month improvement in the rate of skeletal-related events with a hazard ratio of 0.61, a one-sided alpha of 0.1, and 80% power. ARREST is expected to safely optimize tumor dose, offering a personalized hybrid approach that may lead to improved patient outcomes. In addition, this study will permit further understanding of these two distinct radiation delivery methods and their effects on tissues, thereby refining the relative biological effectiveness model for more precise treatment planning.

This study is a prospective, single arm II clinical trial. The main objective of the study is to evaluate the efficacy and safety of the combination of Sacituzumab Tirumotecan (SKB264) and Tagitanlimab (KL-A167) in the treatment of AVPC (aggressive variant prostate cancer) and NEPC (neuroendocrine prostate cancer).

Prostate cancer is the second most common cause of cancer death in men worldwide. After exhausting guideline-compliant therapies or in accordance with the approval of 177Lu-PSMA-617 (Pluvicto®), patients with metastatic castration-resistant prostate cancer (mCRPC) can be offered radioligand therapy (RLT) that targets the prostate-specific membrane antigen (PSMA). Despite an initially high response rate to PSMA-RLT, the disease often progresses rapidly again. The underlying mechanisms are still poorly understood. Liquid biopsy (LBx) involves the collection and analysis of body fluids, particularly blood. Its major advantage compared to a tissue sample is its non-invasive nature, allowing for multiple samplings, as well as the examination of more than just a single punctured lesion. Among other things, circulating tumor DNA (ctDNA) can be detected in the blood. The aim of this study is to apply LBx before, during, and after PSMA-RLT in patients with mCRPC to determine prognostic factors before therapy and to assess the value of LBx in evaluating treatment response. Furthermore, LBx will be used to gather information on the course of potential tumor heterogeneities and to determine resistance mechanisms against PSMA-RLT. To this end, patients receiving PSMA-RLT will be enrolled in the study at three sites (University Hospital Wuerzburg, University Hospital Augsburg, Klinikum rechts der Isar Munich). The evaluation of clinical and imaging parameters will be carried out centrally at the University Hospital Wuerzburg, while the analysis of LBx will be performed at the University Hospital Augsburg.