Prostate-Specific Membrane Antigen Theranostics in Prostate Cancer - Current State and Evolving Standards.

To review current data for the role of prostate specific membrane antigen (PSMA) radioligand therapy (RLT) for patients with advanced prostate cancer. This review provides an update for multidisciplinary teams on the current and potential future applications of theranostics in prostate cancer. Narrative review focussing on PSMA as a target for RLT, and data using RESULTS: RLT with PSMA is an exciting therapeutic alternative to the existing management options already in use for patients with metastatic castrate-resistant prostate cancer (mCRPC). To date, most evidence exists regarding small-molecule PSMA inhibitors bound to beta-emitting radioisotopes such as 177Lu (Lu-PSMA). Prospective phase II data supports the safety and efficacy of Lu-PSMA in men with heavily pre-treated progressive mCRPC, and several late-phase randomised trials of Lu-PSMA are underway, with many more in the pipeline. Early results are encouraging, indicating that the theranostic approach may play a vital role in management of advanced prostate cancer and perhaps even in much earlier disease states. PSMA RLT is a promising new treatment option for men with mCPRC, and may also have utility in less advanced prostate cancer.

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.

The Promise of Circulating Tumor Cells in Metastatic CRPC

Simple SummaryThe prognosis for metastatic prostate cancer patients remains poor. Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a promising target for both imaging and therapy. In this review paper, we provide an overview of the evidence for PSMA-targeted imaging in prostate cancer, focusing on different imaging modalities and their theranostic applications. We will also review PSMA-targeted radioligand therapy, focusing on lutetium-177 radioligand therapy and alpha-emitting radioligand therapy with actinium-225. Combination regimens with lutetium-177 and other systemic therapy agents will be reviewed. Antibody-based radioimmunotherapy will also be discussed along with other noteworthy radionuclide agents.Introduction: Prostate-specific membrane antigen (PSMA) is a promising novel molecular target for imaging diagnostics and therapeutics (theranostics). There has been a growing body of evidence supporting PSMA theranostics approaches in optimizing the management of prostate cancer and potentially altering its natural history. Methods: We utilized PubMed and Google Scholar for published studies, and clinicaltrials.gov for planned, ongoing, and completed clinical trials in PSMA theranostics as of June 2021. We presented evolving evidence for various PSMA-targeted radiopharmaceutical agents in the treatment paradigm for prostate cancer, as well as combination treatment strategies with other targeted therapy and immunotherapy. We highlighted the emerging evidence of PSMA and fluorodeoxyglucose (FDG) PET/CT as a predictive biomarker for PSMA radioligand therapy. We identified seven ongoing clinical trials in oligometastatic-directed therapy using PSMA PET imaging. We also presented a schematic overview of 17 key PSMA theranostic clinical trials throughout the various stages of prostate cancer. Conclusions: In this review, we presented the contemporary and future landscape of theranostic applications in prostate cancer with a focus on PSMA ligands. As PSMA theranostics will soon become the standard of care for the management of prostate cancer, we underscore the importance of integrating nuclear medicine physicians into the multidisciplinary team.

PSMA Theranostics: A "Must Have" in Every Prostate Cancer Center. Illustration of Two Clinical Cases and Review of the Literature.

Metastatic Burden in Hormone-Naive Prostate Cancer: A Tale of Two Subgroups

Metastatic castration resistant prostate cancer (mCRPC) is a highly mortal disease, requiring safe and effective therapeutic agents to improve the patient outcome. Prostate-specific membrane antigen (PSMA) is over expressed in many prostate cancer cells, and act as target for molecular imaging (MI) and radionuclide therapy (RNT). The introduction of Gallium-68 (68Ga) PSMA- PET/CT in 2012 has changed the management of prostate cancer. In addition to its importance in identifying PSMA expression for selection of patients suitable for PSMA RNT, PSMA- PET/CT showed superior diagnostic accuracy to combined CT and bone scan. Lutetium-177 (177Lu) PSMA-617 is the most investigated PSMA radio ligand for RNT in prostatecancer, it is a radiolabelled small molecule, binds with high affinity to PSMA, enabling beta-particles emissions with short tissue penetration depth (mean range of 0.7 mm and maximum range of 2.1 mm in soft tissue). Since 2014 multiple studies showed a highly impressive therapeutic efficacy and safety of 177Lu-PSMA RNT. The evidence achieved by these studies paved the way to ongoing randomized clinical trials, and currently this therapy is being applied and clinically accepted in many centers worldwide. The aim of this article is to share the practical aspect of PSMA Theranostics for prostate cancer, including patient selection, therapy protocol and follow-up.

Theranostic strategies in prostate cancer: Advances in PSMA PET imaging and radioligand therapy.

This study aimed to investigate the oncological outcomes and toxicity profile of 177Lu-PSMA-I&T radioligand therapy (RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC), as well as our initial experience in metastatic hormone-sensitive prostate cancer (mHSPC). A total of 38 consecutive patients with metastatic prostate cancer (33 mCRPC and 5 mHSPC) received 177Lu-PSMA-I&T RLT, with a median of 2 cycles per patient (range, 1-7). Response to RLT was evaluated based on prostate-specific antigen (PSA) changes and imaging response. Clinical progression-free survival and overall survival were used to report oncological outcomes. Toxicity was assessed using the Common Toxicity Criteria for Adverse Events criteria. In mCRPC, 22 (69%), 18 (56%), and 11 (34%) patients achieved any PSA decline, PSA response of ≥30%, and PSA response of ≥50%, respectively. The clinical progression-free survival and overall survival after the first cycle of RLT were 6.3 and 21.4 months, respectively. In mHSPC, 177Lu-PSMA-I&T RLT resulted in excellent PSA response (93.0%-99.9%) in all cases. Clinical progression and cancer-related mortality occurred in only 1 case. Toxicity profile was favorable in both mHSPC and mCRPC. 177Lu-PSMA-I&T RLT demonstrated favorable PSA response (≥30%) in over half of the patients with mCRPC and excellent PSA response in all patients with mHSPC. Toxicity profile was favorable in both mHSPC and mCRPC settings. Further studies are needed to evaluate the role of 177Lu-PSMA-I&T RLT in the management of metastatic prostate cancer.

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that has become central to prostate cancer (PCa) diagnostics and treatment. Beyond its enzymatic role in folate and glutamate metabolism, PSMA is upregulated in advanced PCa, where it contributes to angiogenesis, tumour progression, and therapeutic resistance. This review integrates current understanding of PSMA biology with an emphasis on the role of PSMA expression and the hallmarks of cancer-proliferative signalling, metabolic adaptation, and evasion of cell death. While PSMA has revolutionised theranostic strategies in PCa, its utility as a sole biomarker is limited in select cases such as neuroendocrine differentiation and discordant disease biology. To address these challenges, we highlight emerging biomarkers and novel imaging markers that complement PSMA, including genomic alterations, circulating tumour markers, and exosomal microRNAs. Advances in radiomics and dual-tracer positron emission tomography (PET) further refine patient selection by capturing aggressive low-PSMA phenotypes. Furthermore, PSMA-PET is showing promise in other malignancies, including renal cell carcinoma (RCC) and glioblastoma multiforme (GBM), where neovasculature expression may extend its theranostic applications beyond PCa. By situating PSMA within this broader biomarker landscape, we outline opportunities for theranostic integration, including predictive models, combination therapies and expansion into non-prostate malignancies. Understanding the biology of PSMA in conjunction with novel biomarkers provides a framework for optimising theranostic applications and advancing personalised cancer care.

Targeting Metastatic Hormone Sensitive Prostate Cancer: Chemohormonal Therapy and New Combinatorial Approaches.

The Role of Theranostics in Prostate Cancer

70 Background: 177-Lutetium Prostate-specific membrane antigen (Lu-PSMA) therapy is under current scientific investigation and aims to become an established part in treatment of metastatic castration resistant prostate cancer (mCRPC). However, real-world evidence in treatment comparison is scant. Methods: We relied on the FRAMCAP database and compared cabazitaxel vs. Lu-PSMA therapy in mCRPC patients regarding progression-free (PFS) and overall (OS). Sensitivity analyses addressed 2 nd to 4 th line mCRPC patients to approximate current Phase-III patient selection criteria. Results: Of 373 mCRPC patients, 14% received cabazitaxel vs. 65% Lu-PSMA vs. 21% both. Patients undergoing Lu-PSMA therapy were significantly older (median 72 vs. 66 years, p<0.01) and displayed a higher proportion of ECOG ≥2 (12 vs. 5.0%, p=0.1), relative to cabazitaxel patients. Rates of PSA50 were 32% vs. 0% for Lu-PSMA vs. cabazitaxel. In outcome analyses, significant superior median PFS was observed for Lu-PSMA vs. cabazitaxel (13.4 vs. 7.1 months, p<0.001), even after multivariable adjustment (HR: 0.38, p<0.001). Regarding OS, rates also significantly differed with median OS of 14.7 vs. 16.5 vs. 29.6 months for cabazitaxel vs. Lu-PSMA vs. both treatments (p<0.01). In sensitivity analyses of 2 nd to 4 th line mCRPC, PFS rates and median OS rates for cabazitaxel vs. Lu-PSMA vs. both therapies qualitatively remained the same compared to the entire cohort. Conclusions: In real-world setting, Lu-PSMA provides significantly better PFS and qualitatively better OS rates compared to cabazitaxel chemotherapy and should therefore be considered as a valuable treatment option for advanced mCRPC patients according to the EMA-approval. Characteristics of 296 metastatic castration resistant prostate cancer (mCRPC) patients stratified according to treatment of cabazitaxel vs. 177 - Lutetium- prostate-specific membrane antigen radioligand therapy (Lu-PSMA). Characteristic N Overall,N = 296 1 CabazitaxelN = 52 (18%) 1 Lu-PSMA,N = 244 (82%) 1 p-value 2 Age at mCRPC, years 192 71 (64, 76) 66 (58, 71) 72 (66, 78) <0.001 PSA at m CRPC, ng/ml 141 18 (6, 72) 63 (12, 144) 15 (6, 64) 0.044 Number of CRPC lines 296 3 (2, 4) 4 (3, 5) 3 (2, 4) <0.001 Cycles systemic treatment 229 3 (2, 6) 5 (3, 6) 3 (2, 6) 0.031 PSA response, % 39 20 (0, 66) 15 (0, 23) 25 (0, 68) 0.3 PSA50 39 11 (28%) 0 (0%) 11 (32%) 0.3 PSA90 39 5 (13%) 0 (0%) 5 (15%) 0.9 ECOG status at mCRPC 109 0.10 0 52 (48%) 14 (70%) 38 (43%) 1 45 (41%) 5 (25%) 40 (45%) >=2 12 (11%) 1 (5%) 11 (12%) Cardiovascular disease 183 66 (36%) 13 (35%) 53 (36%) 0.9 Gleason Score 8-10 259 181 (70%) 39 (80%) 142 (68%) 0.10 De Novo mHSPC 290 161 (56%) 33 (63%) 128 (54%) 0.2 High volume mHSPC 146 99 (68%) 24 (73%) 75 (66%) 0.5 Metastatic sites at mCRPC 130 0.8 M1a 14 (11%) 3 (13%) 11 (10%) M1b 104 (80%) 20 (83%) 84 (79%) M1c 12 (9%) 1 (4%) 11 (10%) Treatment mHSPC 126 0.034 ADT mono 25 (20%) 4 (20%) 21 (20%) ARSI 58 (46%) 4 (20%) 54 (51%) Docetaxel 34 (27%) 10 (50%) 24 (23%) Triplet 3 (2%) 1 (5%) 2 (2%) Other 6 (5%) 1 (5%) 5 (5%) Treatment 1st line mCRPC 296 <0.001 ADT mono 29 (10%) 6 (12%) 23 (9%) Chemotherapy 53 (18%) 19 (37%) 34 (14%) Lu-PSMA 28 (10%) 0 (0%) 28 (11%) ARSI 163 (55%) 26 (50%) 137 (56%) PARPi +/- ARSI 1 (0.3%) 0 (0%) 1 (0.4%) Radium 20 (7%) 0 (0%) 20 (8%) None/Other/NA 2 (1%) 1 (2%) 1 (0.4%) Treatment 2nd line mCRPC 296 <0.001 Chemotherapy 69 (23%) 27 (52%) 42 (17%) Lu-PSMA 73 (25%) 0 (0%) 73 (30%) ARSI 114 (39%) 25 (48%) 89 (36%) PARPi+/- ARSI 5 (2%) 0 (0%) 5 (2%) Radium 13 (4%) 0 (0%) 13 (5%) None/Other/NA 22 (7%) 0 (0%) 22 (9%) 1 Median (IQR); n (%). 2 Wilcoxon rank sum test; Fisher’s exact test; Pearson’s Chi-square test. PSA: Prostate-specific antigen, ECOG: Eastern Cooperative Oncology group, mHSPC: metastatic hormone-sensitive prostate cancer, ADT: Androgen deprivation therapy, ARSI: Androgen receptor signaling inhibitor, PARPi: poly-(ADP-ribose)-polymerase inhibitors, NA: Unknown.

Prostate-specific membrane antigen (PSMA)-based images, which visually quantify PSMA expression, are used to determine prostate cancer micrometastases. This study evaluated whether a circulating tumor cell (CTC)-based transcript platform, including PSMA mRNA, could help identify potential prognostic markers in prostate cancer. We prospectively enrolled 21 healthy individuals and 247 patients with prostate cancer [localized prostate cancer (LPCa), n = 94; metastatic hormone-sensitive prostate cancer (mHSPC), n = 44; and metastatic castration-resistant prostate cancer (mCRPC), n = 109]. The mRNA expression of six transcripts [PSMA, prostate-specific antigen (PSA), AR, AR-V7, EpCAM, and KRT 19] from CTCs was measured, and their relationship with biochemical recurrence (BCR) in LPCa and mCRPC progression-free survival (PFS) rate in mHSPC was assessed. PSA-PFS and radiological-PFS were also calculated to identify potential biomarkers for predicting androgen receptor signaling inhibitor (ARSI) and taxane-based chemotherapy resistance in mCRPC. CTC detection rates were 75.5%, 95.3%, and 98.0% for LPCa, mHSPC, and mCRPC, respectively. In LPCa, PSMA [hazard ratio (HR), 3.35; P = 0.028) and PSA mRNA (HR, 1.42; P = 0.047] expressions were associated with BCR. Patients with mHSPC with high PSMA (HR, 4.26; P = 0.020) and PSA mRNA (HR, 3.52; P = 0.042) expressions showed significantly worse mCRPC-PFS rates than those with low expression. Increased PSA and PSMA mRNA expressions were significantly associated with shorter PSA-PFS and radiological PFS in mCPRC, indicating an association with drug resistance. PSMA and PSA mRNA expressions are associated with BCR in LPCa. In advanced prostate cancer, PSMA and PSA mRNA can also predict rapid progression from mHSPC to mCRPC and ARSI or taxane-based chemotherapy resistance.

To establish a novel quantitative method that automatically excludes the red bone marrow and accurately quantifies the tumor volume on whole-body magnetic resonance imaging using updated imaging software. To also evaluate the association between the quantified tumor volume and the prognosis of patients with metastatic prostate cancer. This prospective analysis included patients diagnosed with metastatic hormone-sensitive or metastatic castration-resistant prostate cancer between 2017 and 2022. We developed an imaging software (Attractive BD_Score) that analyzed whole-body diffusion-weighted and in-phase and opposed-phase T1-weighted images to automatically exclude the red bone marrow. The quantified tumor volume was compared with that quantified by traditional whole-body diffusion-weighted imaging without red bone marrow exclusion. Prostate-specific antigen progression-free survival, time-to-pain progression, and overall survival were evaluated to assess the prognostic value of the quantified tumor volume. The quantified tumor volume was significantly smaller than that quantified by the traditional method in metastatic hormone-sensitive (median: 81.0 ml vs. 149.4ml) and metastatic castration-resistant (median: 29.4 ml vs. 63.5ml) prostate cancer. A highly quantified tumor volume was associated with prostate-specific antigen progression-free survival (p= 0.030), time-to-pain progression (p=0.003), and overall survival (p= 0.005) in patients with metastatic hormone-sensitive prostate cancer and with poor prostate-specific antigen progression-free survival (p= 0.001) and time-to-pain progression (p= 0.005) in patients with metastatic castration-resistant prostate cancer. Our imaging method could accurately quantify the tumor volume in patients with metastatic prostate cancer. The quantified tumor volume can be clinically applied as a new prognostic biomarker for metastatic prostate cancer.