LuCAB: A phase I/II trial evaluating cabazitaxel in combination with [¹⁷⁷Lu]Lu-PSMA-617 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)

Abstract

TPS278 Background: [177Lu]Lu-PSMA-617 was recently FDA-approved for use in the post-taxane, post-antiandrogen setting in pts with mCRPC. Despite conferring a survival benefit, for many the treatment response is short, and progression is inevitable. One of the likely mechanisms limiting the durability of responses to [177Lu]Lu-PSMA-617 is heterogeneity in tumor PSMA expression. This can be screened for visually using PSMA and FDG PET/CT scans and inspecting for discordant disease, however, micrometastatic disease is unable to be evaluated in this way. In addition, [177Lu]Lu-PSMA-617 may not effectively target micrometastatic disease due to the longer path length of beta emitters. Cabazitaxel has radiosensitizing properties that may enhance the cytotoxic effect of [177Lu]Lu-PSMA-617, whilst also treating any PSMA-negative disease. We hypothesize that the combination of [177Lu]Lu-PSMA-617 and cabazitaxel will be well tolerated and lead to more durable responses. Methods: This single-centre, single-arm phase I/II trial will enrol 32-38 pts with mCRPC to evaluate the safety and preliminary efficacy of cabazitaxel and [177Lu]Lu-PSMA-617 in combination. Up to 6 doses of [177Lu]Lu-PSMA-617 (7.4 GBq) will be administered intravenously every 6 weeks. Cabazitaxel will be given concurrently (dose range 12.5mg/m2 - 20mg/m2), on Day 2 and Day 23 of each 6-week cycle. The dose of cabazitaxel will be escalated using a traditional 3+3 design. Key eligibility criteria include a diagnosis of mCRPC with PSMA-positive disease on PSMA PET/CT (SUVmax ≥15), with no evidence of diffuse marrow disease or sites of discordance on FDG PET/CT. Pts must have progressed after prior docetaxel and a second-generation antiandrogen, have adequate bone marrow and organ function and an ECOG performance status of 0-1. The primary objective is to establish the maximum tolerated dose of cabazitaxel and [177Lu]Lu-PSMA-617. Secondary objectives include measuring the frequency and severity of adverse events, assessment of efficacy through PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective tumor response rate, and evaluation of pain and health-related quality of life over the first 12 months. Bloods will be taken at baseline, during treatment and at progression for ctDNA analysis, the results of which will be correlated with baseline pt and disease characteristics, and response outcomes, to determine biomarkers of treatment response and resistance. Pt recruitment commenced in August 2022 and will continue for 18 months. Clinical trial information: NCT05340374 .

Peculiar Pattern of Response Following [225Ac]Ac-PSMA Therapy: A Case Report with ‘PSA Pseudoregression’ Response Pattern

“…This phenomenon has been elucidated in previous post-therapeutic assessments, with studies revealing discordance in approximately one-fourth of patients [15]. PSA discordance has been recognized in castration-sensitive patients undergoing enzalutamide therapy and is linked to resistance mechanisms [10]. More recently, a similar response pattern in a single mCRPC patient subjected to [ 177 Lu]Lu-PSMA therapy has been witnessed [16].…”

“…However, there is ongoing debate regarding whether a decline of at least 50 % in PSA, compared to any decrease after the first cycle or at any point during treatment, is significantly linked to survival, as different studies have yielded conflicting results [8,9]. It is important to note that some patients may experience radiographic progression before their PSA levels begin to rise [10]. Therefore, PSA alone is rarely used as the sole basis for treatment decisions.…”

“…The identification of molecular factors underpinning such atypical response patterns assumes paramount significance. Genomic aberrations, implicated in radioresistance and PSA discordance, tend to emerge inevitably following prolonged exposure to multiple therapeutic regimens [10]. Unravelling the molecular intricacies behind this unusual pattern may hold vital implications for refining treatment strategies in the context of mCRPC.…”

“…Unravelling the molecular intricacies behind this unusual pattern may hold vital implications for refining treatment strategies in the context of mCRPC. To date, current efforts are focused on implementing translational markers into response evaluation to overcome the acknowledged limitation and enhance reliability [10].…”

Determinants of outcome following PSMA-based radioligand therapy and mechanisms of resistance in patients with metastatic castration-resistant prostate cancer

“…In this study, the median PSA response rate for all pooled subsequent therapies after [ 177 Lu]Lu-PSMA was 12%, suggesting that optimal sequencing of treatments is essential. 14 In the TheraP trial, all patients at enrolment were suitable candidates to receive either [ 177 Lu]Lu-PSMA-617 or cabazitaxel. Despite this, only 32% of patients treated with [ 177 Lu]Lu-PSMA in the trial went on to receive cabazitaxel on disease progression.…”