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Towards Improving the Efficacy of PSMA-targeting Radionuclide Therapy for Late-stage Prostate Cancer - Combination Strategies

Daria ArbuznikovaMatthias EderAnca-Ligia GrosuPhilipp Tobias MeyerChristian GratzkeConstantinos ZamboglouAnn-Christin Eder

出版	Universität, 2023
URL	http://books.google.com.hk/books?id=grtk0AEACAAJ&hl=&source=gbs_api

註釋Abstract: Purpose of Review
[177Lu]Lu-PSMA-617 is a radiopharmaceutical that emits beta-minus radiation and targets prostate-specific membrane antigen (PSMA)-positive prostate cancer. Despite its clinical success, there are still patients not showing sufficient response rates. This review compiles latest studies aiming at therapy improvement in [177Lu]Lu-PSMA-617-naïve and -resistant patients by alternative or combination treatments.

Recent Findings
A variety of agents to combine with [177Lu]Lu-PSMA-617 are currently under investigation including alpha radiation-emitting pharmaceuticals, radiosensitizers, taxane chemotherapeutics, androgen receptor pathway inhibitors, immune checkpoint inhibitors, and external beam radiation. Actinium-225 (225Ac)-labeled PSMA-targeting inhibitors are the most studied pharmaceuticals for combination therapy or as an alternative for treatment after progression under [177Lu]Lu-PSMA-617 therapy.

Summary
Alpha emitters seem to have a potential of achieving a response to PSMA-targeting radionuclide therapy in both initial non-responders or responders to [177Lu]Lu-PSMA-617 later developing treatment resistance. Emerging evidence for immunostimulatory effects of radiopharmaceuticals and first prospective studies support the combination of [177Lu]Lu-PSMA-617 and immune checkpoint inhibition for late-stage prostate cancer.

Introduction
The lutetium-177 (177Lu)-labeled radiopharmaceutical [177Lu]Lu-PSMA-617 (market name PluvictoTM) has been approved by the US Food and Drug Administration (FDA) [1] and European Medicines Agency (EMA) [2] in 2022 as a last-line therapy for metastatic castration-resistant prostate cancer (mCRPC). Patients can be treated with [177Lu]Lu-PSMA-617 after progression on anti-hormonal therapy with androgen receptor pathway inhibitors (ARPIs) and taxane chemotherapy. The mode of action of [177Lu]Lu-PSMA-617 begins with specific binding of the compound to the prostate-specific membrane antigen (PSMA) [3], a transmembrane protein that is overexpressed in prostate cancer with expression levels rising with higher progression [4, 5]. Upon binding, the pharmaceutical is internalized by PSMA-expressing cells leading to its accumulation and dispersion throughout the cytoplasm [6]. The radiation emitted from 177Lu damages the DNA and other macromolecules, ultimately causing cell death. 177Lu predominantly emits beta-minus particle radiation which has a relatively low linear energy transfer (LET: amount of energy deposited across a unit of traveled particle track) of 0.2 keV/μm [7]. Still, compared to gamma radiation, beta particles emitted from 177Lu have very low tissue penetration ability traveling a mean distance of 0.67 mm [8], thereby damaging only tumor cells in their proximity with limited off-target irradiation of neighboring healthy tissues. The radiation causes single-strand breaks (SSBs) and double-strand breaks (DSBs) in the DNA, either by direct ionization of DNA or indirectly via the formation of highly reactive hydroxyl radicals [9, 10]. These properties render beta-emitting radiopharmaceuticals valuable for the specific targeting of extensively metastasized prostate cancer.

The international, randomized, prospective phase III VISION trial completed the clinical testing phase of [177Lu]Lu-PSMA-617, which led to its FDA and EMA approval for mCRPC. The trial assessed the efficacy of the novel treatment comparing [177Lu]Lu-PSMA-617 plus standard of care (SOC) and SOC only ([11]; NCT03511664). Permitted SOC included ARPIs (e.g., abiraterone, enzalutamide) and excluded, e.g., chemotherapy and immunotherapy due to unknown risks in combination with [177Lu]Lu-PSMA-617. In the radioligand therapy (RLT) arm, patients received a median of five cycles, each at a dose of 7.4 gigabecquerel (GBq) at 6-week intervals. The median overall survival (OS) was significantly better in the RLT arm as compared to SOC only (15.3 months vs. 11.3 months). Patients treated with RLT had a median progression-free survival (PFS) of 8.7 months and those treated with SOC 3.4 months. Of note, a substudy of the trial characterized outcomes depending on the patients' baseline PSMA expression intensity according to positron emission tomography/ computed tomography (PET/CT) imaging. Patients in the highest quartile (whole-body mean standard uptake value (SUV) ≥ 10.2) had a PFS of 14.1 months and those in the lowest quartile (whole body mean SUV 6.0) 5.8 months. This analysis shows that with low-PSMA expression patients do still benefit from PSMA-targeting RLT with 177Lu ([177Lu]Lu-PSMA RLT) [12].brbrThe Australian multicenter, randomized, phase II trial "TheraP" ([13]; NCT03392428) enrolled patients previously receiving docetaxel and in most cases ARPIs. The study compared the efficacy of cabazitaxel, one of the standard subsequent treatment regimens, to [177Lu]Lu-PSMA-617. RLT was administered every 6 weeks for up to six cycles and cabazitaxel once every 3 weeks for up to ten cycles. The primary endpoint was prostate-specific antigen response (PSA: serum marker for biochemical response) and was defined as the proportion of patients achieving a ≥ 50% PSA decline. The response rates were 66% in the RLT arm and 37% in the cabazitaxel arm.br