Prostate-specific Membrane Antigen Radioligand Therapy Research Articles

PSMA Radiotheranostics in Prostate Cancer: Principles, Practice, and Future Prospects.

Prostate cancer is a leading cause of cancer-related mortality in men, with metastatic castration-resistant prostate cancer presenting a substantial treatment challenge. The authors focuse on prostate-specific membrane antigen (PSMA) radiotheranostics, particularly lutetium 177 (177Lu)-PSMA radioligand therapy, as an emerging treatment modality for metastatic castration-resistant prostate cancer. The U.S. Food and Drug Administration approval of 177Lu-PSMA-617 marked a substantial advancement in the treatment paradigm of metastatic castration-resistant prostate cancer, based on the VISION trial that showed improved overall survival and quality of life compared with those for standard care. PSMA expression, assessed via PSMA PET, is crucial for patient selection and assessment of treatment eligibility. The authors discuss current practices, including therapy administration, dosing, and side effects, with a particular focus on eligibility criteria and the added value of posttherapy imaging. Response assessment criteria using PSMA PET are discussed, although these require further validation. The discussion of future directions highlights ongoing trials investigating PSMA targeting agents, the extension of radioligand therapy to earlier stages of prostate cancer, and combination therapies. This review underscores the role of PSMA radioligand therapy in the evolving landscape of prostate cancer treatment and its promise for improving patient outcomes. ©RSNA, 2024 Supplemental material is available for this article.

Enhancing Effects of Olaparib by Alpha- and Beta-Emitting Radionuclides, X-Rays, and Ultraviolet A Light in Combination with Ortho-IodoHoechst in a Prostate Cancer Cell Model.

Background: New therapeutic strategies for metastatic castration-resistant prostate cancer (mCRPC) have been developed in the past to achieve the best response rates. Most recently, the use of combination therapies has been explored to optimize patient outcomes. Poly(ADP-ribose) polymerase inhibitors (PARPi) may help to treat mCRPC more effectively. Objectives: This study aimed to determine whether the combination of a PARPi with different radiation qualities results in different levels of radiosensitization of PC-3 cells. Methods: The radiosensitizing potential of Olaparib in combination with 177Lu, 223Ra, X-rays and photodynamic therapy (PDT) using the UVA light-activated photosensitizer ortho-iodoHoechst33258 (oIH) was evaluated by determining the clonogenic survival, DNA damage and cell cycle analysis. Results: Here, we show that this combination strategy differentially sensitized PC-3 cells to different radiation qualities. The combination of 177Lu with Olaparib increased the numbers of persistent double-strand breaks (DSBs) by a factor of 3.3 and cell death in PC-3 cells. Overall, the β-emitter 177Lu indicated a higher radiosensitization efficacy compared to 223Ra, with X-rays corresponding to dose modification factors (DMF) of 1.77, 1.17 and 1.16 respectively. Even in the case of the α-emitter 223Ra, the effects were much less pronounced than for 177Lu. PARPi also showed a slight potentiation of the cytotoxic effects both in co-treatment with X-rays and with PDT. Conclusions: The results of our study indicate a potential role for Olaparib in further optimizing the PSMA radioligand therapy (PRLT) outcomes. However, further evaluation of the combination of PARPi with PRLT is needed to gain more insights into improving the benefit to patients suffering from mCRPC.

Prostate-Specific Membrane Antigen Radioligand Therapy in Non-Prostate Cancers: Where Do We Stand?

The term theragnostic refers to the combination of a predictive imaging biomarker with a therapeutic agent. The promising application of prostate-specific membrane antigen (PSMA)-based radiopharmaceuticals in the imaging and treatment of prostate cancer (PCa) patients opens the way to investigate a possible role of PSMA-based radiopharmaceuticals in cancers beyond the prostate. Therefore, the aim of this review was to evaluate the role of 177Lu-PSMA radioligand therapy (RLT) in malignancies other than prostate cancer by evaluating preclinical, clinical studies, and ongoing clinical trials. An extensive literature search was performed in three different databases using different combinations of the following terms: "Lu-PSMA", "177Lu-PSMA", "preclinical", "mouse", "salivary gland cancer", "breast cancer", "glioblastoma", "solid tumour", "renal cell carcinoma", "HCC", "thyroid", "salivary", "radioligand therapy", and "lutetium-177". The search had no beginning date limit and was updated to April 2024. Only articles written in English were included in this review. A total of four preclinical studies were selected (breast cancer model n = 3/4). PSMA-RLT significantly reduced cell viability and had anti-angiogenic effects, especially under hypoxic conditions, which increase PSMA binding and uptake. Considering the clinical studies (n = 8), the complexity of evaluating PSMA-RLT in cancers other than prostate cancer was clearly revealed, since in most of the presented cases a sufficient tumour radiation dose was not achieved. However, encouraging results can be found in some types of diseases, such as thyroid cancer. Some clinical trials are still ongoing, and results from prospective larger cohorts of patients are awaited. The need for larger patient cohorts and more RLT cycles administered underscores the need for further comprehensive studies. Given the very preliminary results of both preclinical and clinical studies, ongoing clinical trials in the near future may provide stronger evidence of both the safety and therapeutic efficacy of PSMA-RLT in malignancies other than prostate cancer.

Biological determinants of PSMA expression, regulation and heterogeneity in prostate cancer.

Prostate-specific membrane antigen (PSMA) is an important cell-surface imaging biomarker and therapeutic target in prostate cancer. The PSMA-targeted theranostic 177Lu-PSMA-617 was approved in 2022 for men with PSMA-PET-positive metastatic castration-resistant prostate cancer. However, not all patients respond to PSMA-radioligand therapy, in part owing to the heterogeneity of PSMA expression in the tumour. The PSMA regulatory network is composed of a PSMA transcription complex, an upstream enhancer that loops to the FOLH1 (PSMA) gene promoter, intergenic enhancers and differentially methylated regions. Our understanding of the PSMA regulatory network and the mechanisms underlying PSMA suppression is evolving. Clinically, molecular imaging provides a unique window into PSMA dynamics that occur on therapy and with disease progression, although challenges arise owing to the limited resolution of PET. PSMA regulation and heterogeneity - including intertumoural and inter-patient heterogeneity, temporal changes, lineage dynamics and the tumour microenvironment - affect PSMA theranostics. PSMA response and resistance to radioligand therapy are mediated by a number of potential mechanisms, and complementary biomarkers beyond PSMA are under development. Understanding the biological determinants of cell surface target regulation and heterogeneity can inform precision medicine approaches to PSMA theranostics as well as other emerging therapies.

Genetic analysis of metastatic castration resistant prostate cancer patients treated with Lu-177 PSMA radioligand therapy.

Genetic analysis of metastatic castration resistant prostate cancer patients treated with Lu-177 PSMA radioligand therapy.

From Despair to Hope: First Arabic Experience of 177Lu-PSMA and 161Tb-PSMA Therapy for Metastatic Castration-Resistant Prostate Cancer.

The objective of this retrospective study is to assess the effectiveness and safety of two beta-emitting prostate-specific membrane antigen (PSMA) radioligands, [177Lu]Lu and [161Tb]Tb, in heavily treated patients with metastatic castration-resistant prostate cancer (mCRPC). A total of 148 cycles of beta-emitting PSMA radioligand therapy were given to 53 patients at a specialized cancer care center in Amman, Jordan. This treatment was offered following the exhaustion of all prior treatment modalities. Approximately half of the cases (n = 26) demonstrated an initial partial response to PSMA radioligand therapy. Moreover, roughly one-fourth of the patients (n = 13) exhibited a sustained satisfactory biochemical response, which qualified them to receive a total of six PSMA radioligand therapy cycles and maintain continued follow-up for additional treatment cycles. This was reflected by an adequate prostate-specific antigen (PSA) decline and a concomitant partial response evident on [68Ga]Ga-PSMA positron emission tomography/computed tomography imaging. A minority of patients (n= 18; 34%) experienced side effects. Generally, these were low-grade and self-limiting toxicities. This study endorses previous research evidence about PSMA radioligand therapy's safety and efficacy. It also provides the first clinical insight from patients of Arab ethnicity. This should facilitate and promote further evidence, both regionally and internationally.

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.

Imaging and therapy in prostate cancer using prostate specific membrane antigen radioligands.

Prostate specific membrane antigen (PSMA) directed PET imaging has rapidly transformed prostate cancer workup over the past decade and paved the way for a theranostic approach using 177Lu-labelled PSMA radioligand therapy (RLT). This review gives an overview of the underlying principles behind PSMA as a target; the current use of PSMA PET in prostate cancer imaging and benefits compared to conventional imaging; and therapeutic applications including optimisation of patient selection. It also explores the evidence base of PSMA PET for other indications not in routine clinical use and the future of PSMA-directed RLT.

Radiation levels outside a patient undergoing 177Lu-PSMA radioligand therapy

Understanding the spatial distribution of radiation levels outside of a patient undergoing 177Lu radioligand therapy is not only helpful for conducting correct tests for patient release, but also useful for estimation of its potential exposure to healthcare workers, caregivers, family members, and the general public. In this study, by mimicking the 177Lu-labeled prostate-specific membrane antigen radioligand therapy for prostate cancers in an adult male, the spatial distribution of radiation levels outside of the phantom was simulated based on the Monte Carlo software of Particle and Heavy Ion Transport System, and verified by a series of measurements. Moreover, the normalized dose rates were further formulized on the three transverse planes representing the heights of pelvis, abdomen and chest. The results showed that the distributions of radiation levels were quite complex. Multi-directional and multi-height measurements are needed to ensure the external dose rate to meet the release criteria. In general, the radiation level was higher at the horizontal plane where the source was located, and the levels in front and behind of the body were higher than those of the left and right sides at the same height. The ratio of simulated dose rates to measured ones ranged from 0.82 to 1.19 within 1 m away from the body surface in all directions. Based on the established functions, the relative root mean square deviation between the calculated and simulated values were 0.21, 0.25 and 0.23 within a radius of 1 m on the pelvis, abdomen and chest transverse planes, respectively. It is expected that the results of this study would be helpful for guiding the test of extracorporeal radiation to determine the patient’s release, and of benefit to estimate the radiation exposure to others.

Abstract 6023: 225Ac-FL-020 is a novel PSMA-targeting radionuclide drug conjugate (RDC) with superior in vivo anti-tumor activity

Abstract Despite significant developments over the last few decades, metastatic castration-resistant prostate cancer (mCRPC) remains incurable. Prostate specific membrane antigen (PSMA), a prostate cancer-specific membrane marker which directly correlates with androgen independence, metastasis, and disease progression, has been well-established as a radioligand target for the diagnosis and treatment of mCRPC. Lutetium-177 (177Lu)-PSMA-617 (PLUVICTOTM) was approved in 2022 for the treatment of progressive PSMA-positive mCRPC. However, only 30% of patients showed a radiological response in the registrational trial. Meanwhile, recent clinical experience has shown very limited efficacy in low PSMA expressing patients. These data collectively request for further improvement in the clinical benefit of PSMA-targeted radiotherapy. Actinium-225 (225Ac), an alpha emitter, is significantly more potent on cancer cell killing and has a shorter range in tissue penetration when compared to the beta emitter 177Lu. Such a profile supports the development of 225Ac based radiotherapies. Using our proprietary Clear-XTM technology platform, we developed 225Ac-FL-020, a novel 225Ac-based PSMA radioligand therapy candidate which has demonstrated prominent pre-clinical properties. We have assessed the binding affinity against PSMA of the non-labeled vector FL-020 in vitro. The in vivo biodistribution profile of FL-020 was characterized by SPECT/CT imaging and biodistribution using Indium-111 (111In)-FL-020 in PSMA high LNCaP tumor-bearing nude mice. In addition, anti-tumor activities of 225Ac-FL-020 were evaluated in the LNCaP xenograft model and directly compared to 225Ac-PSMA-617. FL-020 was found bound to LNCaP cells with an IC50 value of 51.55 nM. Meanwhile, the off-target screening showed that less than 50% inhibition of binding or activity was observed by FL-020 at 10 µM against 85 targets including receptors, ion channels, enzymes, and transporters, indicating the high selectivity of FL-020. Moreover, 111In-FL-020 displayed a very promising in vivo distribution profile with high and sustained tumor uptake and fast systemic clearance. Furthermore, 225Ac-FL-020 exhibited superior anti-tumor activity compared to 225Ac-PSMA-617 at the same dose level (10 KBq/mouse) in the LNCaP xenograft model with a favorable safety profile as indicated by body weight and hematological parameters. A mechanistic study was also conducted in 225Ac-FL-020-treated LNCaP tumor samples where DNA double-strand breaks and tumor cell apoptosis were observed, confirming the MOA of alpha emitters. Taken together, these results collectively demonstrate that 225Ac-FL-020 is a potent and selective PSMA-targeting radioligand therapy candidate with superior anti-tumor activity and a favorable safety profile warranting further clinical development. Citation Format: Fa Liu, Jiangwei Zhang, Junyu Yang, Kirstine T. Thrane, Mathias W. Hallund, Rikke V. Grønlund, Nicholas C. Wong. 225Ac-FL-020 is a novel PSMA-targeting radionuclide drug conjugate (RDC) with superior in vivo anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6023.

Erratum: PSMA Radioligand Therapy in Prostate Cancer: Where Are We and Where Are We Heading?

Erratum: PSMA Radioligand Therapy in Prostate Cancer: Where Are We and Where Are We Heading?

Clinical outcomes with systemic therapy given after progression on prostate specific membrane antigen radioligand therapy (PSMA-RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC).

78 Background: PSMA-RLT is a novel therapeutic modality that improves overall survival in mCRPC. However, outcomes for systemic therapy given after progression on PSMA-RLT are not well described. We investigated treatment choices and outcomes in patients (pts) with mCRPC who experienced disease progression after PSMA-RLT. Methods: We performed a single center retrospective cohort study of pts with mCRPC, who received PSMA-RLT at the Jewish General Hospital between 2020 and 2023. Clinical characteristics, PSA50, further lines of therapy post PSMA-RLT and survival were abstracted from chart review. A log-rank test was used to assess overall survival (OS). Post-PSMA-RLT specific OS (Post-RLT-OS) was defined from the date of first systemic treatment after PSMA-RLT failure to death or last follow up. Results: We identified 42 pts who received PSMA-RLT for mCRPC. The median age was 63 years (47-89) and the majority (56.1%) of pts received PSMA-RLT as a 3rd or later line of therapy in mCRPC setting. Amongst these pts, 15/42 (35.7%) achieved a PSA50 response to PSMA-RLT; 36 pts experienced disease progression, and 25/36 with disease progression (69.4%) received subsequent active systemic therapy. Post-PSMA-RLT systemic therapy included chemotherapy (n=17), PARP inhibitors (PARPi) (n=3), bipolar androgen therapy (BAT) followed by androgen receptor-axis targeted agent (ARAT) (BAT+ARAT) (n=2), Radium (n=2), BAT (n=1), and different PSMA-RLT agent (n=1). Amongst the pts who received post-PSMA-RLT therapy, 5/25 (20%) achieved a PSA50 response. PSA50 responses were observed in pts who received chemotherapy (n=2), BAT+ARAT (n=2) and PARPi (n=1). After a median follow-up of 10 months, the median Post-RLT-OS in the entire cohort was 11.7 months. Post-RLT-OS was significantly associated with PSA levels at the time of post-PSMA-RLT systemic therapy. The median Post-RLT-OS for pts with PSA < 100 (n=11), 100 ≤ PSA < 1000 (n=5) PSA ≥ 1000 (n=5) was 15, 15.7, and 8.6 months respectively (P = 0.014). Conclusions: Some pts derive benefit from post-PSMA-RLT systemic therapy; however, the overall response rate is low and therapeutic options are limited. More research is needed to define mechanisms of resistance to PSMA-RLT, and to identify novel therapeutic opportunities in this patient population.

Prognostic value of FDG, PSMA, and DOTATATE uptake on PET imaging in metastatic castration-resistant prostate cancer (mCRPC).

31 Background: In mCRPC, fluorodeoxyglucose (FDG) and prostate-specific membrane antigen (PSMA) PET/CT are often used in combination for selecting patients for PSMA-radioligand therapy (PSMA-RLT). Few studies have specifically assessed the prognostic value of FDG+/PSMA- lesions, which exclude patients from PSMA-RLT. Also, little is known about the significance of somatostatin receptor expression, a potential biomarker of neuroendocrine differentiation of mCRPC, which can be assessed with DOTATATE-PET/CT. 3TMPO is a prospective study in progressing mCRPC patients who were imaged with up to 3 PET tracers. Here, we report on patient’s overall survival (OS), with respect to the presence of FDG+/PSMA- and DOTATATE+ lesions. Methods: In 3TMPO (NCT04000776, protocol in PMID 34674367), all patients had 68Ga-PSMA-617 and 18F-FDG PET/CT scans. A 68Ga-DOTATATE scan was ordered if an FDG+/PSMA- lesion was found. For all tracers, positivity was defined as lesion SUVpeak being 1.5x higher than liver SUVmean. Kaplan-Meier with log-rank test was used to assess the difference in OS between groups. Cox regression model was used to quantify the effect of factors predictive of OS. Results: The median [95% CI] OS of the 98 enrolled patients was 10.2 [8.5-11.8] mo. At least one FDG+/PSMA- lesion was found in 45 (45.9%) patients and their OS was shorter than that of the others: 5.6 [4.3-6.9] vs. not reached (p=0.0001). Six (16.2%) of 37 patients who underwent 68Ga-DOTATATE-PET had ≥1 DOTATATE+ lesion and their OS was shorter than that of patients without a DOTATATE+ lesion: 3.0 [2.2-3.7] vs. 6.4 [1.6-11.1] mo. (p=0.0004). Characteristics significantly associated with worse OS were ECOG, ISUP grade, number of metastases, number of lines of therapy, presence of visceral metastases, FDG and PSMA molecular tumor volumes (MTV) (p<0.05). In a multivariate analysis adjusted for the number of metastases and of treatment lines, the presence of an FDG+/PSMA- lesion increased the risk of death (HR [95% CI]=2.4 [1.4-4.3], p=0.002), and this was also significant after adjusting for both PSMA and FDG-MTV (HR [95% CI]=2.9 [1.4-5.8], p=0.003). Conclusions: mCRPC patients harboring FDG+/PSMA- lesion(s) had a shorter OS than those who did not, and their prognosis was even poorer if they also had DOTATATE+ lesion(s). Upfront FDG/PSMA-PET followed by DOTATATE-PET might help clinicians to guide patient towards palliative care vs. further systemic therapy, including PSMA-RLT. Clinical trial information: NCT04000776 .

Change of glucometabolic activity per PSMA expression predicts survival in mCRPC patients non-responding to PSMA radioligand therapy: introducing a novel dual imaging biomarker.

The value of [18F]fluorodeoxyglucose ([18F]FDG) PET/CT in monitoring prostate-specific membrane antigen (PSMA) targeted radioligand therapy (RLT) is still unclear. The aim of this study was to identify appropriate prognostic dynamic parameters derived from baseline and follow-up [18F]FDG and dual [18F]FDG/[68Ga]Ga-PSMA-11 PET/CT for monitoring early non-responding mCRPC patients undergoing PSMA-RLT. Twenty-three mCRPC patients of a prospective registry (NCT04833517), who were treated with [177Lu]Lu-PSMA-617 RLT and classified as early non-responders were included in this study. All patients received dual PET/CT imaging with [18F]FDG and [68Ga]Ga-PSMA-11 at baseline and after median two cycles of RLT. We tested potential biomarkers representing the "change of glucometabolic activity (cGA)" and "change of glucometabolic activity in relation to PSMA expression (cGAP)" composed of established parameters on [18F]FDG PET/CT as SUVmax, cumulative SUV of five lesions (SUV5), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) and its corresponding parameters on [68Ga]Ga-PSMA-11 PET/CT, respectively, for association with overall survival (OS). Kaplan-Meier analyses showed no significant association with OS for each tested cGA (cGASUVmaxp = 0.904, cGASUV5, p = 0.747 cGAMTVp = 0.682 and cGATLGp = 0.700), likewise the dual imaging biomarkers cGAPSUVmax (p = 0.136), cGAPSUV5 (p = 0.097), and cGAPTV (p = 0.113) failed significance. In contrast, cGAPTL, which is based on TLG and total lesion PSMA (TLP) showed a significant association with OS (p = 0.004). Low cGAPTL (cut-off 0.7) was associated with significant longer survival (17.6 vs. 12.9 months). The novel biomarker cGAPTL, which represents the temporal change of whole-body TLG normalized by TLP, predicts overall survival in the challenging cohort of patients non-responding to PSMA-RLT.

Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicentre, retrospective study

Actinium-225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC). We aimed to report the safety and antitumour activity of 225Ac-PSMA RLT of mCRPC in a large cohort of patients treated at multiple centres across the world. This retrospective study included patients treated at seven centres in Australia, India, Germany, and South Africa. We pooled data of consecutive patients of any age and Eastern Cooperative Oncology Group performance status with histopathologically confirmed adenocarcinoma of the prostate who were treated with one or more cycles of 8 MBq 225Ac-PSMA RLT administered intravenously for mCRPC. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium-177 (177Lu) PSMA RLT, and radium-223 dichloride. The primary outcomes were overall survival and progression-free survival. Between Jan 1, 2016, and May 31, 2023, 488 men with mCRPC received 1174 cycles of 225Ac-PSMA RLT (median two cycles, IQR 2-4). The mean age of the patients was 68·1 years (SD 8·8), and the median baseline prostate-specific antigen was 169·5 ng/mL (IQR 34·6-519·8). Previous lines of treatment were docetaxel in 324 (66%) patients, cabazitaxel in 103 (21%) patients, abiraterone in 191 (39%) patients, enzalutamide in 188 (39%) patients, 177Lu-PSMA RLT in 154 (32%) patients, and radium-223 dichloride in 18 (4%) patients. The median follow-up duration was 9·0 months (IQR 5·0-17·5). The median overall survival was 15·5 months (95% CI 13·4-18·3) and median progression-free survival was 7·9 months (6·8-8·9). In 347 (71%) of 488 patients, information regarding treatment-induced xerostomia was available, and 236 (68%) of the 347 patients reported xerostomia after the first cycle of 225Ac-PSMA RLT. All patients who received more than seven cycles of 225Ac-PSMA RLT reported xerostomia. Grade 3 or higher anaemia occurred in 64 (13%) of 488 patients, leukopenia in 19 (4%), thrombocytopenia in 32 (7%), and renal toxicity in 22 (5%). No serious adverse events or treatment-related deaths were recorded. 225Ac-PSMA RLT shows a substantial antitumour effect in mCRPC and represents a viable therapy option in patients treated with previous lines of approved agents. Xerostomia is a common side-effect. Severe bone marrow and renal toxicity are less common adverse events. None.

Comparison of 18F-DCFPyL and 68Ga-PSMA-11 for 177Lu-PSMA-617 therapy patient selection.

68Ga-PSMA-11 is recommended for the selection of patients for treatment in the package insert for 177Lu-PSMA-617. We aimed to compare imaging properties and post-treatment outcomes from radioligand therapy (RLT) of patients selected with 68Ga-PSMA-11 and 18F-DCFPyL. We retrospectively evaluated 80 patients undergoing PSMA RLT, who had pretreatment imaging using either 68Ga-PSMA-11 or 18F-DCFPyL. For both groups, we compared the biodistribution and lesion uptake and the PSA response to treatment. Both agents had comparable biodistribution. Patients initially imaged with 18F-DCFPyL had a higher PSA response (66% vs. 42%), and more patients had a PSA50 response (72% vs. 43%) compared to patients imaged with 68Ga-PSMA-11. 18F-DCFPyL and 68Ga-PSMA-11 had comparable biodistribution and lesion uptake. Patients imaged with 18F-DCFPyL demonstrated clinical benefit to PSMA RLT comparable to those imaged with 68Ga-PSMA-11, and either agent can be used for screening patients.

PSMA-PET follow-up to assess response in patients not receiving PSMA therapy: Is there value beyond localization of disease?

Introduction: Prostate Specific Membrane Antigen Positron Emission Tomography (PSMA-PET) is routinely used for the staging of patients with prostate cancer, but data on response assessment are sparse and primarily stem from metastatic castration-resistant prostate cancer (mCRPC) patients treated with PSMA radioligand therapy. Still, follow-up PSMA-PET is employed in earlier disease stages in case of clinical suspicion of disease persistence, recurrence or progression to decide if localized or systemic treatment is indicated. Therefore, the prognostic value of PSMA-PET derived tumor volumes in earlier disease stages (i.e., hormone-sensitive prostate cancer (HSPC) and non-[177Lu]Lu-PSMA-617 (LuPSMA) therapy castration resistant prostate cancer (CRPC)) are evaluated in this manuscript. Methods: A total number of 73 patients (6 primary staging, 42 HSPC, 25 CRPC) underwent two (i.e., baseline and follow-up, median interval: 379 days) whole-body [68Ga]Ga-PSMA-11 PET/CT scans between Nov 2014 and Dec 2018. Analysis was restricted to non-LuPSMA therapy patients. PSMA-PETs were retrospectively analyzed and primary tumor, lymph node-, visceral-, and bone metastases were segmented. Body weight-adjusted organ-specific and total tumor volumes (PSMAvol: sum of PET volumes of all lesions) were measured for baseline and follow-up. PSMAvol response was calculated as the absolute difference of whole-body tumor volumes. High metastatic burden (>5 metastases), RECIP 1.0 and PSMA-PET Progression Criteria (PPP) were determined. Survival data were sourced from the cancer registry. Results: The average number of tumor lesions per patient on the initial PET examination was 10.3 (SD 28.4). At baseline, PSMAvol was strongly associated with OS (HR 3.92, p <0.001; n = 73). Likewise, response in PSMAvol was significantly associated with OS (HR 10.48, p < 0.005; n = 73). PPP achieved significance as well (HR 2.19, p <0.05, n = 73). Patients with hormone sensitive disease and poor PSMAvol response (upper quartile of PSMAvol change) in follow-up had shorter outcome (p < 0.05; n = 42). PSMAvol in bones was the most relevant parameter for OS prognostication at baseline and for response assessment (HR 31.11 p < 0.001; HR 32.27, p < 0.001; n = 73). Conclusion: PPP and response in PSMAvol were significantly associated with OS in the present heterogeneous cohort. Bone tumor volume was the relevant miTNM region for OS prognostication. Future prospective evaluation of the performance of organ specific PSMAvol in more homogeneous cohorts seems warranted.

Impact of TP53 loss-of-function alterations on the response to PSMA radioligand therapy in metastatic castration-resistant prostate cancer patients.

Rationale: PSMA-targeting radioligand therapy (PSMA-RLT) has shown promise in metastatic castration-resistant prostate cancer (mCRPC), particularly in PSMA-avid tumours. However, predicting response remains challenging. Preclinical data suggests aberrant p53-signalling as a predictor of poor response. Methods: The patient population of this pre-planned retrospective cohort study consists of 96 patients with mCRPC who underwent treatment with PSMA-RLT and were molecularly profiled by whole-genome sequencing and or targeted next-generation sequencing. Response to PSMA-RLT was assessed per molecular subtype, including TP53-mutational status. Results: Patients with TP53 loss-of-function alterations had a shorter median progression-free survival (3.7 versus 6.2 months, P<0.001), a lower median PSA change (-55% vs. -75%, P=0.012) and shorter overall survival from initiation of PMSA-RLT (7.6 vs. 13.9 months, P=0.003) compared to TP53-wildtype patients. Pathogenic alterations in AR, MYC, BRCA1, or BRCA2 as well as in genes linked to the PI3K or MAPK pathways or genes involved in homologous recombination repair, were not associated with response. Only lactate dehydrogenase was, alongside TP53-status, significantly associated with response. Transcriptome analysis of 21 patients, identified six p53 signalling genes whose low expression was associated to a shorter progression-free survival (P<0.05). Conclusion: TP53 loss-of-function may serve as a prognostic factor for PSMA-RLT outcomes in patients with mCRPC.

La radiothérapie interne vectorisée au 177Lu-PSMA

Lutetium-177-labeled PSMA radio-ligand therapy is becoming more and more widespread in nuclear medicine departments, in France and around the world. Practitioners must master specificities of this treatment in order to develop this type of therapeutic care in the best conditions. This summary article presents the methods of carrying out treatment with 177Lu-PSMA in nuclear medicine departments as well as the various current clinical research subjects concerning this theme.

Sequential and Combination Therapies of 223RaCl2 and Prostate-Specific Membrane Antigen Radioligand Therapy.

Sequential and Combination Therapies of 223RaCl2 and Prostate-Specific Membrane Antigen Radioligand Therapy.