Lutetium-177 Prostate-specific Membrane Antigen Research Articles

Hematologic toxicity in 177lu-PSMA-617 treatment for mCRPC: Unraveling the impact of PSMA PET bone tumor volume (PSMA-bTTV).

5075 Background: Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA-617) is a life-prolonging treatment approved by the FDA in metastatic castration-resistant prostate cancer (mCRPC), at a very late stage when there frequently reduced bone marrow reserve. We aim to report the incidence of hematologic toxicity during treatment and potential risk factors in a single-center study. Methods: This retrospective single-institution case series included mCRPC patients who underwent at least one cycle of 177Lu-PSMA-617 treatment between June 2022 and January 2024. Hematological parameters were documented at baseline, 3 weeks after each treatment, and before each subsequent treatment administration. Then, we captured the nadir values for each parameter during treatment. Hematologic toxicities were assessed using the Common Terminology Criteria for Adverse Events v5.0, with Grades 3 and 4 considered significant. Multivariable logistic regression analyses were conducted to investigate the association between hematological adverse events and baseline characteristics including PSMA-bTTV, measured by semi-automatic contouring of the PSMA-expressing whole-body bone metastases on pre-treatment PSMA PET. Results: Our study included 138 mCRPC patients (median age: 73y, prior chemotherapy: 92%, prior radiation: 43.5%, bone involvement: 89.1%), who underwent a median of 3 cycles (IQR: 2-5) of 177Lu-PSMA-617 treatment. At baseline, 8 (5.8%) patients had grade 3 anemia, 2 (1.4%) patients had grade 3 leukopenia, and 1 (0.7%) patient had grade 3 thrombocytopenia. Nadir values during treatment indicated that 23 (16.7%) had grade 3 anemia, 5 (3.6%) had grade 3 leukopenia, and 11 (8%) had grade 3 and 4 thrombocytopenia. Multivariable analysis of predisposing factors for hematologic adverse events showed that the PSMA-bTTV was significantly associated with occurrence of any grade ≥3 hematologic toxicity, anemia, and thrombocytopenia after adjusting for other baseline clinical variables (Table). Conclusions: Over 1 in 5 patients with mCRPC experienced significant hematologic adverse events during treatment with 177Lu-PSMA-617. Bone tumor volume is a possible risk factor for developing significant hematologic toxicity. [Table: see text]

Does enzalutamide related PSMA upregulation affect outcomes of lutetium-177 PSMA radioligand therapy?

Enzalutamide is an antiandrogen drug used prior to lutetium-177 prostate specific membrane antigen (Lu-PSMA) radioligand therapy and has shown promising results for upregulating the PSMA expression on prostate cancer cells. In this study, we aim to compare prostate specific antigen (PSA) level changes in prostate cancer patients who received enzalutamide to those who did not. Prostate cancer patients who underwent Lu-PSMA between 2021 and 2023 were retrospectively included. Patients were grouped based on prior enzalutamide therapy: those who received enzalutamide (EZ+) for at least 14 days and those who did not (EZ-). PSA changes and F-18 DCFPyL SUV (Standardized Uptake Values) were compared. Thirty-seven patients were included, 18 EZ+ and 19 EZ-. The median age, Gleason score, and prior chemo/hormonal therapies were similar for EZ+ and EZ-, except for radium-223. Eleven patients (61%) in EZ+ and 13 patients (68%) in EZ- showed a decrease in PSA after the first cycle (p = 0.64). Four patients (22%) in EZ+ and seven patients (37%) in EZ- had more than 50% decrease in PSA after the first cycle (p = 0.33). The average percent decline at the end of the treatment was 23.3% in EZ+ and 50.4% in EZ- (p = 0.4). There was no difference in terms of lesion with highest SUVmax, mean SUV, total tumor volume or activity on pre-therapy PSMA imaging. Enzalutamide treatment prior to Lu-PSMA does not improve patient outcomes when applied remotely. Larger studies evaluating the combination therapies and the timing of enzalutamide are needed to assess its correlation with Lu-PSMA outcomes.

Radiopharmaceutical transport in solid tumors via a 3-dimensional image-based spatiotemporal model

Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA)-targeted radiopharmaceutical therapy is a clinically approved treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Even though common practice reluctantly follows “one size fits all” approach, medical community believes there is significant room for deeper understanding and personalization of radiopharmaceutical therapies. To pursue this aim, we present a 3-dimensional spatiotemporal radiopharmaceutical delivery model based on clinical imaging data to simulate pharmacokinetic of 177Lu-PSMA within the prostate tumors. The model includes interstitial flow, radiopharmaceutical transport in tissues, receptor cycles, association/dissociation with ligands, synthesis of PSMA receptors, receptor recycling, internalization of radiopharmaceuticals, and degradation of receptors and drugs. The model was studied for a range of values for injection amount (100–1000 nmol), receptor density (10–500 nmol•l–1), and recycling rate of receptors (10–4 to 10–1 min–1). Furthermore, injection type, different convection-diffusion-reaction mechanisms, characteristic time scales, and length scales are discussed. The study found that increasing receptor density, ligand amount, and labeled ligands improved radiopharmaceutical uptake in the tumor. A high receptor recycling rate (0.1 min–1) increased radiopharmaceutical concentration by promoting repeated binding to tumor cell receptors. Continuous infusion results in higher radiopharmaceutical concentrations within tumors compared to bolus administration. These insights are crucial for advancing targeted therapy for prostate cancer by understanding the mechanism of radiopharmaceutical distribution in tumors. Furthermore, measures of characteristic length and advection time scale were computed. The presented spatiotemporal tumor transport model can analyze different physiological parameters affecting 177Lu-PSMA delivery.

Advances in Radioligand Theranostics in Oncology.

Theranostics with radioligands (radiotheranostics) has played a pivotal role in oncology. Radiotheranostics explores the molecular targets expressed on tumor cells to target them for imaging and therapy. In this way, radiotheranostics entails non-invasive demonstration of the in vivo expression of a molecular target of interest through imaging followed by the administration of therapeutic radioligand targeting the tumor-expressed molecular target. Therefore, radiotheranostics ensures that only patients with a high likelihood of response are treated with a particular radiotheranostic agent, ensuring the delivery of personalized care to cancer patients. Within the last decades, a couple of radiotheranostics agents, including Lutetium-177 DOTATATE (177Lu-DOTATATE) and Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA), were shown to prolong the survival of cancer patients compared to the current standard of care leading to the regulatory approval of these agents for routine use in oncology care. This recent string of successful approvals has broadened the interest in the development of different radiotheranostic agents and their investigation for clinical translation. In this work, we present an updated appraisal of the literature, reviewing the recent advances in the use of established radiotheranostic agents such as radioiodine for differentiated thyroid carcinoma and Iodine-131-labeled meta-iodobenzylguanidine therapy of tumors of the sympathoadrenal axis as well as the recently approved 177Lu-DOTATATE and 177Lu-PSMA for differentiated neuroendocrine tumors and advanced prostate cancer, respectively. We also discuss the radiotheranostic agents that have been comprehensively characterized in preclinical studies and have shown some clinical evidence supporting their safety and efficacy, especially those targeting fibroblast activation protein (FAP) and chemokine receptor 4 (CXCR4) and those still being investigated in preclinical studies such as those targeting poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor 2.

Therapeutic efficacy and safety results of 177Lu-PSMA therapy in metastatic castration-resistant prostate cancer patients: first experience of a developing South Asian Country.

Metastatic castration resistant-prostate cancer (mCRPC) is deadly condition that remains incurable despite various therapies. Initial studies have shown promising results with Lutetium-177 prostate-specific membrane antigen ( 177 Lu-PSMA) therapy for advanced prostate cancer. However, most of the published efficacy and safety data is retrospective. The purpose of the study was to prospectively evaluate the therapeutic efficacy and safety results of 177 Lu-PSMA therapy in mCRPC patients after 2 cycles. Twenty-five patients of mCRPC, treated with standard care treatment were enrolled for 2 cycles of 177 Lu-PSMA therapy. Prostate-specific antigen (PSA), Eastern Cooperative Oncology Group (ECOG) performance status, Visual Analogue Score (VAS) and Analgesic Quantification Scale (AQS) for efficacy and hemoglobin, total leukocyte, platelets and serum creatinine for toxicity were recorded pre and post-therapy. Paired sample t-test was used for statistical analysis. Treated patients with mean PSA level of 157 ng/ml received mean dose of 6.84 GBq of 177 Lu-PSMA. For PSA, partial response (PR) was seen in 11/25 (44%), stable disease (SD) in 8/25 (32%) and progressive disease (PD) in 6/25 (24%) patients. Grade 1 and 2 hemoglobin toxicity was seen in 5/25 (20%) and 6/25 (24%) patients respectively. No patient developed grade 3 or 4 bone marrow toxicities. Grade 1 and 2 nephrotoxicity was seen in 1 patient each. Statistically significant difference was seen in ECOG, VAS and AQS scores ( P < 0.001). No significant nephrotoxicity was observed ( P = 0.558). Efficacy and safety of 177 Lu-PSMA therapy after 2 cycles have shown significant PSA response and pain palliation in heavily pretreated mCRPC patients.

The use of Lutetium-177 PSMA radioligand therapy with high dose rate brachytherapy for locally recurrent prostate cancer after previous definitive radiation therapy: a randomized, single-institution, phase I/II study (ROADSTER).

BackgroundIsolated local failure (ILF) can occur in patients who initially receive definitive radiation therapy for prostate cancer. Salvage therapy for ILF includes high dose rate (HDR) brachytherapy. Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) can accurately detect ILF and can exclude extraprostatic disease. Lutetium-177 PSMA Radioligand Therapy (RLT) is a novel treatment for prostate cancer that can target prostate cancer accurately, while sparing radiation dose to normal tissues.MethodsROADSTER is a phase I/II randomized, single-institution study. Patients with an ILF of prostate cancer after definitive initial radiation therapy are eligible. The ILF will be confirmed with biopsy, magnetic resonance imaging (MRI) and PSMA PET. Patients will be randomized between HDR brachytherapy in two fractions (a standard of care salvage treatment at our institution) (cohort 1) or one treatment of intravenous Lutetium-177 PSMA RLT, followed by one fraction of HDR brachytherapy (cohort 2). The primary endpoints for the phase I portion of the study (n = 12) will be feasibility, defined as 10 or more patients completing the study protocol within 24 months of study activation; and safety, defined as zero or one patients in cohort 2 experiencing grade 3 or higher toxicity in the first 6 months post-treatment. If feasibility and safety are achieved, the study will expand to a phase II study (n = 30 total) where preliminary efficacy data will be evaluated. Secondary endpoints include changes in prostate specific antigen levels, acute toxicity, changes in quality of life, and changes in translational biomarkers. Translational endpoints will include interrogation of blood, urine, and tissue for markers of DNA damage and immune activation with each treatment.DiscussionROADSTER explores a novel salvage therapy for ILF after primary radiotherapy with combined Lutetium-177 PSMA RLT and HDR brachytherapy. The randomized phase I/II design will provide a contemporaneous patient population treated with HDR alone to facilitate assessment of feasibility, tolerability, and biologic effects of this novel therapy.Trial registrationNCT05230251 (ClinicalTrials.gov).

Time interval between radium-223 (223Ra) therapy and Lutetium-177–prostate-specific membrane antigen (177Lu-PSMA) treatment and outcomes in the RALU study.

73 Background: 223Ra and 177Lu-PSMA-617 both prolong overall survival (OS) in different mCRPC settings. The observational, retrospective study, RALU, investigated safety and clinical outcomes of sequential 223Ra/177Lu-PSMA therapy in patients (pts) with mCRPC. This analysis evaluated the association of time interval between 223Ra and 177Lu-PSMA treatments and safety and OS outcomes of 177Lu-PSMA. Methods: Retrospective data were collected from 2021–22 in German nuclear medicine centers for all pts receiving 177Lu-PSMA with prior history of 223Ra therapy. Time intervals were &lt;6 months (mo) (Group [Grp]1) or ≥6 mo (Grp 2) from last 223Ra dose to first 177Lu-PSMA dose. Results: 42 pts received 177Lu-PSMA within 6 mo after 223Ra (Grp 1) and 90 pts received 223Ra ≥6 mo prior to 177Lu-PSMA (Grp 2). Baseline characteristics prior to 177Lu-PSMA therapy were, respectively: median ages 72 and 74 years; 57% and 63% with Eastern Cooperative Oncology Group performance status (ECOG PS) 1, 43% and 37% with ECOG PS 2; median prostate-specific antigen (PSA) values were 366 and 268 ng/ml, and median alkaline phosphatase (ALP) values were 133 and 149 U/L; 40% and 64% received ≥4 life prolonging therapies before starting 177Lu-PSMA. All pts had prior 223Ra; 57% and 77% received 6 223Ra injections; other prior therapies were abiraterone (60%, 77%), enzalutamide (50%, 78%), docetaxel (71%, 76%) and cabazitaxel (17%, 26%). Prior to 177Lu-PSMA, 24% and 29% of pts had visceral metastases. 45% and 52% of pts received ≥4 177Lu-PSMA cycles. From 177Lu-PSMA start to ≤30 days post last dose, 71% and 82% of pts had treatment-emergent adverse events (TEAEs) of any grade; most common were fatigue (12%, 7%), nausea (12%, 8%) and dry mouth (7%, 18%); 36% and 24% of pts had grade 3–4 TEAEs; excluding laboratory abnormalities, osteonecrosis of the jaw was the most frequent grade 3–4 TEAE (5%, 2%). Grade 3–4 laboratory abnormalities (177Lu-PSMA start to ≤90 days post last dose) are shown; treatment-related deaths were reported for 2% and 4% of pts. AEs led to treatment delays in 10% and 9% of pts. Median OS from start of 177Lu-PSMA was 12.0 mo (95% CI, 8.8–19.9) in Grp 1 and 13.2 mo (95% CI, 10.0–15.9) in Grp 2. During 177Lu-PSMA therapy, PSA response ≥50% occurred in 53% and 39% and ALP response ≥30% in 28% and 14% of pts, respectively. Conclusions: In this real-world setting, treating pts with 177Lu-PSMA within 6 mo of completing 223Ra was clinically feasible and well tolerated: no safety signals or concerns were seen. OS outcomes were similar in pts receiving 177Lu-PSMA &lt;6 mo vs. pts receiving it ≥6 mo after completing 223Ra. [Table: see text]

Logistical, technical, and radiation safety aspects of establishing a radiopharmaceutical therapy program: A case in Lutetium-177 prostate-specific membrane antigen (PSMA) therapy.

Prostate-specific membrane antigen (PSMA) is a cell surface protein highly expressed in nearly all prostate cancers, with restricted expression in some normal tissues. The differential expression of PSMA from tumor to non-tumor tissue has resulted in the investigation of numerous targeting strategies for therapy of patients with metastatic prostate cancer. In March of 2022, the FDA granted approval for the use of lutetium-177 PSMA-617 (Lu-177-PSMA-617) for patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. Therefore, the use of Lu-177-PSMA-617 is expected to increase and become more widespread. Herein, we describe logistical, technical, and radiation safety considerations for implementing a radiopharmaceutical therapy program, with particular focus on the development of operating procedures for therapeutic administrations. Major steps for a center in the U.S. to implement a new radiopharmaceutical therapy (RPT) program are listed below, and then demonstrated in greater detail via examples for Lu-177-PSMA-617 therapy.

Neoadjuvant 177Lu-PSMA-I&T Radionuclide Treatment in Patients with High-risk Prostate Cancer Before Radical Prostatectomy: A Single-arm Phase 1 Trial

BackgroundHigh-risk localized prostate cancer (HRLPC) has a substantial risk of disease progression despite local treatment. Neoadjuvant systemic therapy before definitive local therapy may improve oncological outcomes by targeting the primary tumor and micrometastatic disease. ObjectiveTo evaluate whether a lutetium-177 prostate-specific membrane antigen radioligand (LuPSMA) can be safely administered to patients with HRLPC before robot-assisted radical prostatectomy (RARP) and to describe immediate oncological outcomes. Design, setting, and participantsThis was an open-label, single-arm clinical trial. Patients with HRLPC and elevated radioligand uptake on PSMA positron emission tomography/computed tomography were enrolled. Two or three LuPSMA radioligand doses (7.4 GBq) were given at 2-wk intervals. RARP with lymph node dissection was performed 4 wk after the last LuPSMA dose. Outcome measurements and statistical analysisThe rate of surgical complications, operative parameters, changes in functional and quality-of-life measures, and immediate oncological outcomes (histological findings and biochemical response) were measured. Data were analyzed descriptively. Results and limitationsFourteen patients participated (median age 67 yr). Prostate-specific antigen decreased by 17% (interquartile range [IQR] 9–50%) after two LuPSMA doses and 34% (IQR 11–60%) after three doses. Thirteen patients underwent RARP with no identifiable anatomical changes or intraoperative complications. Four patients (30%) had postoperative complications (pneumonia, pulmonary embolism, urinary leak with urinary tract infection). At 3 mo postoperatively, 12 patients (92%) required one pad or less. Final whole-mount pathology showed positive surgical margins (PSMs) in seven patients (53%) and downgrading to International Society of Urological Pathology grade group 3 in three patients (23%). Treatment-related effects included a clear vacuolated cytoplasm and pyknotic nuclei. ConclusionsLuPSMA followed by RARP appears to be surgically safe. While oncological outcomes are pending, continence recovery seems to be unaffected by LuPSMA treatment. Patient summaryWe evaluated outcomes for patients with aggressive localized prostate cancer who received treatment with a radioactive agent before surgical removal of their prostate. This approach appears to be safe and feasible, but its therapeutic efficacy is still unknown.

1414P Treatment efficacy and safety of 177Lu-PSMA radioligand therapy in octogenarians with metastatic castration-resistant prostate cancer

Lutetium-177 prostate-specific membrane antigen radioligand therapy (177Lu-PSMA-RLT) is an option for treatment of metastatic castration-resistant prostate cancer (mCRPC). It is increasingly used in old or comorbid patients. Purpose was to evaluate the safety and efficacy in patients ≥80 years of age.

Lutetium-177 Prostate-Specific Membrane Antigen Therapy: A Practical Review

Prostate-specific membrane antigen is a transmembrane protein found predominately on prostate epithelium and is expressed at high levels in prostate cancer. In this review, we discuss the background, clinical data, patient selection, side effects, and necessary resources to deliver lutetium-177 prostate-specific membrane antigen in the research setting, or as standard of care if approved by the United States Food and Drug Administration. Targeted radionuclide therapeutics require understanding of fundamental principles of radiobiology and physics, and radiation oncologists and medical physicists are well-suited to play an integral role in their delivery and treatment response monitoring as key components of a multidisciplinary care team.

Safety and survival outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with lutetium-177–prostate-specific membrane antigen (177Lu-PSMA) after radium-223 (223Ra): Interim analysis of the RALU study.

5040 Background: 223Ra and 177Lu-PSMA both prolong overall survival (OS) in different mCRPC settings. Previous data from the observational REASSURE (Sartor O, et al. 2021) and WARMTH (Ahmadzadehfar H, et al. 2021) studies suggested the feasibility of sequencing 223Ra and 177Lu-PSMA therapies. Here we used data from the observational, retrospective RALU study to further examine the safety and clinical outcomes of sequential 223Ra/177Lu-PSMA therapy in pts with mCRPC. Methods: This interim analysis investigated the baseline characteristics, safety (primary endpoint) and OS (secondary endpoint) in pts who received 177Lu-PSMA after 223Ra using retrospective data collected in German centers. Results: Data from 49 pts were available for this interim analysis. At baseline, before the start of 177Lu-PSMA, 73% of pts were Eastern Cooperative Oncology Group performance status (ECOG PS) 1 and 27% ECOG PS 2. Visceral metastases were present in 31% of pts. Median prostate-specific antigen (PSA) and alkaline phosphatase (ALP) were 287 ng/ml and 142 U/L, respectively (Table). 70% of pts received ≥4 life-prolonging therapies prior to 177Lu-PSMA, with abiraterone acetate (80%), enzalutamide (67%) and docetaxel (92%) being the most frequently used. 74% of pts received ≥5 223Ra injections. Pts received either PSMA-617 (67%) or PSMA I&amp;T (33%): 65% of pts received 1–4 cycles and 33% received 5–6 cycles. Median duration of 177Lu-PSMA therapy was 4.9 months (m) (0–57.1). Median time from the last 223Ra dose to first 177Lu-PSMA dose was 9.3 m (0.9–41.9). Any grade treatment-emergent adverse events (TEAEs) from the start of 177Lu-PSMA therapy to 30 days of follow-up occurred in 91.8% of pts, and serious TEAEs in 20% of pts. Grade 3-4 hematologic laboratory abnormalities up to 90 days post-177Lu-PSMA occurred in 34.7% of pts for anemia, 12.8% for thrombocytopenia and 2.0% for neutropenia. No grade 5 toxicities occurred. 39% of pts had ≥30% decline in PSA during 177Lu-PSMA treatment. Median OS was 12.6 m (95% CI 8.8–16.1) from the start of 177Lu-PSMA therapy. Conclusions: In this real-world retrospective analysis of selected pts with advanced mCRPC, the 223Ra/177Lu-PSMA treatment sequence was clinically feasible and well tolerated. [Table: see text]

Superscan Appearance of 68Ga PSMA PET/CT in a Patient with Refractory Prostate Cancer.

A 64-year-old male patient with metastatic prostate carcinoma diagnosis received lutetium-177 prostate-specific membrane antigen (PSMA) treatment; however, his disease progressed. Herein, presented the final images of the patient that demonstrated a superscan appearance in the Gallium-68 PSMA positron emission tomography/computed tomography, which is a rare phenomenon.

Efficacy and safety of therapies for advanced prostate cancer in Asia: Evidence from a systematic literature review.

Several therapies are available for the treatment of advanced/metastatic prostate cancer (PC). However, the systematic assessment of evidence pertaining to the use of these therapies in Asian patients is lacking. A systematic literature review (SLR) was conducted using PubMed/Medline search in May 2021 to identify the randomized/nonrandomized controlled trials (RCTs/non-RCTs) and real-world observational studies (prospective/retrospective). Only studies published as full manuscripts in English were included if reporting the efficacy, effectiveness, and/or safety of treatments in Asian patients with advanced/metastatic PC. Of the 1,898 retrieved publications, 24 studies were included. These studies had patients with nonmetastatic castration-resistant PC (n = 2), metastatic castration-sensitive PC (n = 4), and metastatic castration-resistant PC (n = 18). Study designs included RCTs (n = 7), non-RCTs (n = 2), and real-world studies (n = 15). Treatments used in included studies were abiraterone acetate plus prednisone (AAP; n = 6), enzalutamide, lutetium-177 prostate-specific membrane antigen (177Lu-PSMA; n = 4 each), docetaxel (n = 3), apalutamide, radium-223 (n = 2 each), darolutamide, cabazitaxel, and pembrolizumab (n = 1 each). The evidence from RCTs (i.e., ARAMIS, SPARTAN, ARCHES, TITAN, LATITUDE, PREVAIL) demonstrated the clinical benefits of apalutamide, darolutamide, enzalutamide, and AAP in terms of overall, disease-free, and metastasis-free survival in Asian patients. These treatments were reported to be well tolerated, with no new safety signals identified in Asian population. The efficacy and safety profiles in Asian patients were consistent with the overall trial population. Data from real-world studies supported the effectiveness and tolerability of AAP, enzalutamide, radium-223, docetaxel, cabazitaxel, 177Lu-PSMA, and pembrolizumab in patients with advanced/metastatic PC. This SLR of the Asian data on therapies for advanced PC from the pivotal and real-world studies confirms similar efficacy and safety outcomes, consistent with the results from the pivotal clinical trials. These findings will help clinicians make better treatment decisions in clinical practice for patients with advanced/metastatic PC.

Expression of Prostate-specific Membrane Antigen (PSMA) in Papillary Renal Cell Carcinoma - Overview and Report on a Large Multicenter Cohort.

Prostate specific membrane antigen (PSMA) is an emerging diagnostic and therapeutic target in prostate cancer. 68Ga-PSMA-labeled hybrid imaging is used for the detection of prostate primary tumors and metastases. Therapeutic applications such as Lutetium-177 PSMA radionuclide therapy or bispecific antibodies that target PSMA are currently under investigation within clinical trials. The expression of PSMA, however, is not specific to prostate-tissue. It has been described in the neovascular endothelium of different types of cancer such as breast cancer, and clear cell renal cell carcinoma (ccRCC). The aim of this study was to analyze PSMA expression in papillary RCC (pRCC) type 1 and type 2, the most common non-ccRCC subtypes, and to evaluate the potential of PSMA-targeted imaging and treatment in pRCC. Formalin-fixed, paraffin-embedded tissue samples of primary tumors were analyzed for PSMA expression by immunohistochemistry. Out of n=374 pRCC specimens from the multicenter PANZAR consortium, n=197 pRCC type 1 and n=110 type 2 specimens were eligible for analysis and correlated with clinical data. In pRCC type 1 PSMA staining was positive in 4 of 197 (2.0%) samples whereas none (0/110) of the pRCC type 2 samples were positive for PSMA in this large cohort of pRCC patients. No significant PSMA expression was detected in pRCC. Reflecting current clinical evaluation of PMSA expression in RCC do not encourage further analysis in papillary subtypes.

Update on radioligand therapy with 177Lu-PSMA for metastatic castration-resistant prostate cancer: clinical aspects and survival effects.

To give an updated overview on clinical aspects and survival effects of lutetium-177-prostate-specific membrane antigen (PSMA) (177Lu-PSMA) radioligand therapy (RLT), a novel treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). PubMed/MEDLINE database was searched for relevant articles published up to March 2021. The search was restricted to English-language articles. Current evidence from the literature consistently demonstrated the efficacy, safety, and survival benefit of 177Lu-PSMA RLT in mCRPC. However, current data rely predominantly on retrospective analyses, showing heterogeneity of patient population and treatment protocols. More recently, results from the first randomized phase II study (TheraP) demonstrated that 177Lu-PMSA therapy significantly improved prostate-specific antigen response rate (66% vs 37%) and had fewer grade 3/4 adverse events when compared to cabazitaxel in patients with docetaxel-pretreated, progressive mCRPC. This review is intended to provide an updated overview of treatment protocols and responses, toxicity profile, and survival effects of 177Lu-PSMA RLT. 177Lu-PSMA RLT has emerged as a promising targeted treatment in mCRPC. It is currently applied in compassionate use programs and following exhaustion of approved therapies. Crucial for establishing this treatment in routine clinical management will be the results of the phase III VISION trial, which may confirm the encouraging patient outcomes reported to date.

Real-World Data Analysis of Efficacy and Survival After Lutetium-177 Labelled PSMA Ligand Therapy in Metastatic Castration-Resistant Prostate Cancer.

Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA) radioligand therapy is emerging as a promising treatment for metastatic castration-resistant prostate cancer refractory to established therapies. While there is an increasing body of survival and other data from retrospective analyses and prospective trials, there is no clear understanding of how best to predict therapy response and survival outcomes. In this retrospective cohort analysis, we aimed to identify features that are associated with response to radioligand therapy and greater survival based on analysis of real-world data. 191 patients aged 70 ± 8 years with metastatic castration-resistant prostate cancer treated with radioligand therapy from November 2015 to February 2019 were included for analysis. Eligible patients had PSMA-expressing metastatic castration-resistant prostate cancer (confirmed by a 68Ga-PSMA-ligand positron emission tomography(PET)/computed tomography (CT)scan), an Eastern Cooperative Oncology Group performance status score ≤ 2 and no significant kidney, liver or bone marrow dysfunction (as characterised by kidney and liver function tests and a full blood count). Patients received one to five cycles of intravenous 177Lu-PSMA-ligand therapy. Endpoints included biochemical [prostate-specific antigen (PSA)] and radiologic (PSMA PET/CT) response, progression-free survival and overall survival, defined according to the Prostate Cancer Working Group 3 guidelines. Survival analysis was conducted by Kaplan-Meier estimation. Most individuals (89.5%) previously underwent first- and second-line systematic therapy. Of the 191 men treated with 452 cycles with mean injected activity of 6.1 ± 1.0 GBq per cycle, 159 patients were assessed for a biochemical response defined as a PSA decline ≥ 50% from baseline. A ≥ 50% PSA decline was observed in 89 (56%) patients, while any PSA decline occurred in 120 (75%) men. For the entire cohort, median values (interquartile range) of overall survival [n = 191], PSA progression-free survival [n = 132] and PET/CTprogression-free survival were 12 (5-18), 4 (3-8) and 6 (3-10) months, respectively. Survival analysis confirmed better outcomes in individuals who had demonstrated therapy response. Predominantly lymph node metastatic disease and chemotherapy-naïve status were significant pre-therapy factors associated with longer survival. Baseline PSA was significantly linked to survival outcomes: lower levels predicted a lower risk of death and disease progression. Treatment-related adverse events included grade 3 or 4 haematological (12%), grade 1 or 2 renal (4.5%), and grade 3 or 4 clinical events (5.7%). Our findings suggest that 177Lu-PSMA radioligand therapy provides a significant response rate with a low toxicity profile. The evidence promotes greater efficacy of radioligand therapy in predominantly lymph node metastatic castration-resistant prostate cancer, and in individuals with chemotherapy-naïve status and lower levels of baseline PSA.

Lutetium-177-PSMA therapy for prostate cancer patients—a brief overview of the literature

AbstractRadioligand therapy with lutetium-177 prostate specific membrane antigen ([177Lu]Lu-PSMA) represents a promising treatment for metastatic castration-resistant prostate cancer patients. In this paper, we aim to summarize the current knowledge derived from the literature as well as the authors’ experiences on [177Lu]Lu-PSMA therapy. Various systematic reviews, mostly including small retrospective studies, summarized efficacy and oncological outcomes of [177Lu]Lu-PSMA therapy. Any therapy-related prostate-specific antigen (PSA) response was reported in the majority of the patients (68–75%); &gt;50% PSA decline was demonstrated in 34.5–51% of the patients. Incidence of side effects was low and in most patients, hematological toxicity remained limited to Common Terminology Criteria for Adverse Events (CTCAE) grade 1–2. Also, favorable efficacy was shown with regard to tumor response on imaging, pain symptoms and quality of life. In the near future, results of the awaited pivotal prospective studies (NCT03511664, NCT03392428) will define efficacy of [177Lu]Lu-PSMA therapy and its oncological value for metastatic castration-resistant prostate cancer patients.

A Retrospective Analysis of the Safety and Activity of Lutetium-177-Prostate-Specific Membrane Antigen Radionuclide Treatment in Older Patients with Metastatic Castration-Resistant Prostate Cancer.

Prostate cancer is a common malignancy of the elderly, and with the aging of the population, the need is growing for therapies suitable for this age group. Lutetium-177-prostate-specific membrane antigen (Lu-PSMA), a radiolabeled small molecule, binds with high affinity to prostate-specific membrane antigen, enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer (mCRPC). In a recent single-arm phase II trial and a subsequent expansion cohort, a prostate-specific antigen (PSA) decline of ≥50% was observed in approximately 60% of patients receiving Lu-PSMA. Taking into account the specific challenges and potential toxicities of Lu-PSMA administration in elderly men, we sought to retrospectively analyze the safety and activity of Lu-PSMA in men aged older than 75 years with mCRPC. The electronic medical records of 24 patients aged older than 75 years treated with Lu-PSMA "off-trial" were reviewed, and clinical data were extracted. Clinical endpoints were toxicity and activity, defined as a PSA decline ≥50%. Descriptive statistics were performed using Excel. The median age at treatment start was 81.7 years (range 75.1-91.9). The median number of previous treatment lines was four. The number of treatment cycles ranged from one to four; the mean administered radioactivity was 6 GBq per cycle. Treatment was generally tolerable; side effects included fatigue (n = 8, 33%), anemia (n = 7, 29%), thrombocytopenia (n = 5, 21%), and anorexia/nausea (n = 3, 13%). Clinical benefit was observed in 12 of 22 patients (54%); PSA decline above 50% was observed in 11 patients (48%) and was associated with significantly longer overall survival. Our results indicate that Lu-PSMA is safe and active in elderly patients with mCRPC. Lutetium-177-prostate-specific membrane antigen (Lu-PSMA), a radiolabeled small molecule, binds with high affinity to prostate-specific membrane antigen, enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer (mCRPC). The recently published single-arm phase II trial with Lu-PSMA, describing its safety and activity, did not include patients aged older than 75 years. In this study, Lu-PSMA activity was retrospectively analyzed in patients aged older than 75 years and results indicate that treatment was tolerable and similarly active in this age group, with no new emerging safety signals. Despite the small cohort size, this analysis suggests that Lu-PSMA can serve as an advanced palliative treatment line in mCRPC in elderly patients.

Prognostic biomarkers in men with metastatic castration-resistant prostate cancer receiving [177Lu]-PSMA-617.

We analysed quantitative biomarkers derived from both baseline whole-body imaging and blood serum to identify prognostic markers in patients treated within the lutetium-177 prostate-specific membrane antigen (LuPSMA) phase 2 trial. PET image analysis was carried out using whole-body segmentation quantifying molecular tumour volume (SUV > 3 threshold for PSMA, SUV > liver+2sd for fluorodeoxyglucose (FDG) including SUVmax and SUVmean. For baseline bone scans, EXINI bone scan index (BSI) was used to calculate the percentage of involved bone. Baseline alkaline phosphatase (ALP), lactate dehydrogenase (LDH), prostate specific antigen (PSA) and PSA doubling time were also used in this analysis. We used univariate cox regression analysis and log-rank comparison with optimised cut-offs to find suitable biomarkers prognostic of overall survival from time of enrolment. This analysis identified FDG-positive tumour volume (FDGvol; HR 2.6; 95% CI, 1.4-4.8), mean intensity of PSMA-avid tumour uptake (PSMAmean; HR 0.89; 95% CI, 0.8-0.98), bone scan index (BSI; HR 2.3; 95% CI, 1.2-4.4), ALP (HR 1.1; 95% CI, 1-1.2) and LDH (HR 1.2; 95% CI, 1-1.5) as biomarkers prognostic of overall survival. In addition to established biomarkers, both FDG and PSMA PET/CT parameters have prognostic significance for survival in men undergoing LuPSMA therapy.