Castration-resistant Prostate Carcinoma Research Articles

Incidental Detection of Second Primary Thyroid Malignancy in Patients of Metastatic Castration-Resistant Prostate Carcinoma: Documentation on 68 Ga-PSMA-11 and 64 CuCl 2 PET/CT.

Second primary tumors are being increasingly detected owing to and in proportion to the use of advanced imaging modalities including PET/CT. Patients suffering from prostate cancer have been reported to have increased second primary cancers of gastrointestinal tract, urinary bladder, and thyroid. We herein describe incidental detection of thyroid carcinoma, in 2 patients of mCRPC (metastatic castration-resistant prostate carcinoma) undergoing preradioligand therapy workup, on 68 Ga-prostate-specific membrane antigen PET/CT initially, subsequently also observed on multitracer PET/CT ( 64 CuCl 2 and 18 F-FDG). Thus, the potential of PET/CT for early in vivo second primary detection in mCRPC setting is illustrated in the aforementioned 2 patients.

A Comparison of 68Ga-PSMA PET/CT-Based Split Renal Function with 99mTc-MAG3 Renography in Patients with Metastatic Castration-Resistant Prostate Carcinoma Treated with 177Lu-PSMA.

Physiological PSMA expression in the cells of the proximal renal tubules and consecutive radiopharmaceutical binding and retention could potentially lead to radioligand-therapy-induced nephrotoxicity. Thus, patients with metastatic castration-resistant prostate cancer undergo 99mTc-Mercaptoacetyltriglycine (MAG3) renal scintigraphy to assess kidney function and to exclude renal obstruction as part of their workup for PSMA-targeted radioligand therapy (RLT). 99mTc-MAG-3 renal scintigraphy often requires an additional visit to the nuclear medicine department and patients spend 30-90 min in the department, which is inconvenient and takes up camera time. In addition, the patients are subjected to a baseline 68Ga-PSMA PET/CT to assess for PSMA-positive disease prior to targeted radioligand therapy. The aim of this retrospective cross-sectional study was to compare 99mTc-MAG-3-based split renal function (SRF) with 68Ga-PSMA-derived SRF. This retrospective cross-sectional study included 28 patients with histologically proven metastatic castration-resistant prostate cancer (mCRPC) who received 177Lu-PSMA617. A comparison between the split renal function using 68Ga-PSMA PET/CT and the 99mTc-MAG-3-derived split renal function was carried out in 56 kidneys (n = 56). The SRF on 68Ga-PSMA was calculated using the volume and the average standard uptake value (SUVmean) within each VOI calculated as previously described by Roser et al.: SRF = (VOLUMEright) ∗ SUVmeanright/(VOLUMEright ∗ SUVmeanright + VOLUMEleft ∗ SUVmeanleft). Paired tests and correlation coefficients were used to compare 68Ga-PSMA and 99mTc-MAG-3. A visual comparison of kidney morphology on both studies was also performed. The median SRF of the right kidney was 49.9% (range: 3-91%) using 68Ga-PSMA PET/CT and 50.5% (range: 0-94%) with 99mTc-MAG3 scintigraphy. Notably, there was a strong correlation between SRF measurements obtained from PSMA and 99mTcMAG3, with a Pearson correlation coefficient of 0.957 (p < 0.001). Both 99mTc-MAG3 and 68Ga-PSMA PET/CT studies identified morphological renal abnormalities; there were nine hydronephrotic kidneys, four shrunken kidneys and one obstructed kidney, and there was a strong positive correlation between 68Ga-PSMA kidney morphology and 99mTcMAG3 renal scintigraphy kidney morphology, with a correlation coefficient of 0.93. PSMA-derived split function demonstrated a high correlation with renal function assessed on diuretic 99mTc-MAG3 renograms. PET-derived split renal function may, therefore, be considered an alternative to diuretic renogram-based split function. Furthermore, both 99mTc-MAG3 and 68Ga-PSMA PET/CT studies identified morphological renal abnormalities such as hydronephrosis, shrunken and obstructed kidneys. This correlation underscores the potential utility of 68Ga-PSMA imaging as a valuable tool for assessing kidney morphology as an alternative to renogram split function in clinical practice.

Differentiation of Discordant Lesions on Dual-Tracer PET/CT (68Ga-PSMA-11 and 18F-FDG) in Prostate Carcinoma: Diagnosis of Second Primary Malignancies.

We present 2 cases of metastatic castration-resistant prostate carcinoma with discordant lesions on dual-tracer PET/CT (68Ga-PSMA-11 and 18F-FDG PET/CT), which on subsequent histopathologic evaluation revealed second primary malignancies of combined hepatocellular carcinoma and cholangiocarcinoma and poorly differentiated squamous cell carcinoma. These case illustrations emphasize the need to evaluate discordant lesions on dual-tracer PET/CT, which can lead to early diagnosis of second primary malignancies and thereby can provide better management in these patients.

ProSperA: Phase I study to evaluate safety, tolerability and preliminary efficacy of a bispecific PSMAxCD3 antibody in men with biochemical recurrence of prostate cancer.

TPS5114 Background: Bispecific antibodies (bsAbs), alike CAR T cells, are not yet successful in solid tumors. Recently we developed a PSMAxCD3 bsAb termed CC-1 in an IgG-based format mediating fully target cell-restricted T cell activation and potent antitumor activity (Zekri et al, EMBO Mol Med, 2020). In prostate cancer (PC), PSMA is not only expressed on the malignant cells themselves, but also on tumor vessels. Targeting the latter improves accessibility of the tumor site for immune effector cells, a critical prerequisite for success. CC-1 is under evaluation in a First in Human trial enrolling patients with castration resistant prostate carcinoma (NCT04104607) and, in combination with checkpoint inhibition, in a phase I trial enrolling patients with squamous cell carcinoma of the lung (NCT04104607). On the basis of the meanwhile available very favorable safety and preliminary efficacy data, CC-1 is now being evaluated as first line treatment in patients with biochemical recurrence (BCR) of PC (NCT05646550), where tumor burden is low and accordingly further reduced side effects and sustained efficacy are expected. Methods: This is an ongoing open label, single center phase I clinical trial evaluating CC-1 without androgen deprivation therapy as first line treatment in men with BCR of PC. Key eligibility criteria include low risk of disease progression (PSA-Doubling time &gt; 1 year after prostatectomy or interval to BCR &gt; 18 months after radiation; ISUP grade &lt; 4; PSA ≥ 0.2 ng/ml and &lt; 5 ng/ml) and no androgen deprivation therapy except in a neoadjuvant/adjuvant setting. The clinical trial consists of (i) a dose escalation part (24-42 patients) using a 3+3 design to determine overall safety, tolerability as well as maximum tolerated dose (MTD) and (ii) a dose expansion part, in which 14 patients are treated at the MTD. CC-1 is applied twice-weekly over 21 days as three-hour infusion in up to six 28-day cycles. In the first cycle, step dosing (day 1: 10µg, day 2: 28µg, day 3 and thereafter: target dose) is performed, and 7 patient cohorts receiving dose levels from 78µg to 600µg are evaluated. Premedication includes acetaminophen, dimetindene and cortisone to minimize the risk of infusion reactions and cytokine release syndrome (CRS). The primary objectives are definition of MTD and recommended phase II dose. Assessment of safety is based on the frequency of adverse events according to CTCAE v5.0. Dose limiting toxicities are defined as ≥ 3° adverse drug reactions (e.g. CRS) with predefined exceptions (e.g. temporary laboratory abnormalities). Efficacy is determined by serial PSA-measurements (PSA-response: ≥50% decrease compared to baseline). Furthermore, percentage of patients with no clinical relapse, no salvage and no subsequent antineoplastic therapy will be assessed. Clinical trial information: NCT05646550 .

Efficacy of PARP inhibitors in patients with metastatic castration resistant prostate carcinoma: A meta-analysis of phase III randomized controlled trials.

e17060 Background: PARP inhibitors effectively treat several solid tumors, regardless of the presence of BRCA mutations. Patients with castration-resistant metastatic prostate cancer become refractory to androgen deprivation therapy. PARP inhibitors were recently approved for use in prostate cancer, and have opened new avenues in prostate cancer treatment research. Methods: We systematically searched multiple databases using pre-specified search terms. We included only phase III RCTs comparing PARP inhibitors versus standard of care in patients with castration-resistant biopsy-proven metastatic prostate cancer. The outcomes studied were radiologically guided progression-free survival (PFS) and overall survival (OS). We used a random effects model via RevMan 5.4 software for statistical analysis. Results: 3 phase III RCTs met the inclusion criteria with a total of 1606 patients (PARP inhibitors = 867 patients, standard of care = 739 patients). Compared to the standard of care, PARP inhibitors showed significantly higher PFS [HR = 0.62( 95% CI, 0.49-0.78) P &lt; 0.0001]. There was no statistically significant difference in OS [HR = 0.85( 95% CI, 0.69-0.1.04) P = 0.11] between the two groups. Conclusions: The use of PARP inhibitors in patients with castration-resistant metastatic prostate cancer is associated with improved progression-free survival. No significant difference was observed in overall survival between the two groups. There is a need to study the cost-benefit analysis of using PARP inhibitors as they do not show any improvement in overall survival. [Table: see text]

Clinical development of the bispecific PSMAxCD3 antibody CC-1.

2534 Background: While being highly efficient in hematological malignancies, bispecific antibodies (bsAbs), alike CAR T cells, are yet not successful in solid tumors. Moreover, all available T cell-mobilizing strategies cause side effects that endanger patients and, in case of bsAbs, limit applicable doses and thus efficacy. We report on the clinical development of CC-1, a PSMAxCD3 bsAb, in an IgG-based format that induces fully target cell-restricted T cell activity (Zekri et al, EMBO Mol Med, 2020). Targeting PSMA, which is expressed on malignant cells and on the neovasculature, improves accessibility of the tumor site for immune effector cells as critical prerequisite for success in solid tumors. Notably, CC-1 binds a unique PSMA epitope which is expressed on malignant cells both of prostate carcinoma (PC) and 50% of patients with squamous cell carcinoma (SCC) of the lung. Methods: A FIH trial evaluating CC-1 with pre-emptive Tocilizumab included patients with metastatic castration resistant prostate carcinoma (mCRPC) (NCT04104607) and consisted of two parts. Dose escalation (n=10-66) using a novel intra-individual dose escalation design to rapidly reach the target dose of 826µg to determine safety, tolerability and maximum tolerated dose (MTD) (Labrenz et al, Pharm Stat, 2022). The dose expansion cohort exposed patients to CC-1 at MTD and explored efficacy to define RP2D (n=14). Our second phase I trial enrolls patients with SCC of the lung (NCT04496674) to receive CC-1 in combination with checkpoint inhibition. Based on the meanwhile available very favorable safety and preliminary efficacy data, a third phase I trial was initiated where CC-1 is evaluated as first line treatment in patients with hormone sensitive biochemical recurrence (BCR) of PC (NCT05646550), where tumor burden is low and accordingly lower side effects and long-lasting efficacy are expected. Results: Recruitment in the dose escalation part of the trial in mCRPC has been completed and the target dose was reached and MTD defined without DLT upon treatment of the 9th and 14th patient, respectively. 24 patients completed treatment, with the most frequently observed toxicity being cytokine release syndrome (CRS, max. 2°) (88%). Besides grade 1 to 2 hypertension (46%) and xerostomia (8%), no further CC-1 related toxicities were observed. A rapid and profound decline of elevated PSA levels was observed in all but one patient, with up to 60% reduction compared to baseline. So far 5 patients received multiple treatment cycles at MTD-level. One patient with SCC of the lung has been treated and CC-1 was escalated up to 153µg without occurrence of CRS. In the phase I trial in BCR of PC, the first three patients were enrolled in February 2023. Conclusions: CC-1 is a promising compound with a favourable toxicity profile and promising clinical activity. Details on study designs and updated data from the 3 clinical trials will be presented at the meeting. Clinical trial information: NCT04104607 , NCT04496674 , NCT05646550 .

Abstract 3383: Liquid biopsy for PDL-1 status by analysis of cfRNA: Clinical data from a large community practice

Abstract PD-L1 testing via immunochemistry has become a widely used tool to predict response to immune checkpoint inhibitor (ICI) therapy in many tumor types. However this marker can be expressed heterogeneously, and can vary with time, treatment effects, and local factors including cytokine expression. Gene expression profiles of immunologically active genes are currently being studied to more accurately predict response to ICI treatment. To evaluate a potentially more straightforward way to accomplish this, we utilized an assay of cfRNA in plasma for PD-L1, utilizing a real-time PCR based assay (Circulogene, Inc, Birmingham, AL). The demonstrated limit of detection for PD-L1 RNA was 1 copy/ul. Results were reported as either not detected, or low at over 1%, or high at over 50%. We used the PCR 30th percentile Ct value corresponding to a tissue IHC PD-L1 of&amp;gt;50%, and the 66th percentile Ct value corresponding to a tissue PD-L1 expression of &amp;gt;1%. We then collected data on over 400 patients over a two year period at a large community oncology practice and at a university clinic (Florida Cancer Specialists and Atrium Health/Wake Forest-Baptist Comprehensive Cancer Center) who had a clinical necessity for molecular testing in a commercially available setting with a CLIA certified lab. In some cases the corresponding tissue PD-L1 testing was also available, and may have been either positive or negative.To date 41 patients have been found to have high levels of cfRNA for PD-L1. Their clinical course has been analyzed using the electronic medical record. Some patients have received standard of care therapy, and some have been given CPI therapy with or without chemotherapy, if the attending oncologist felt this to be the best palliative option. These include tumors such as CRPC, metastatic low grade neuroendocrine carcinoma and HR+ metastatic breast carcinoma, that have rarely been treated successfully with CPI therapy. Tumor types - all are stage IV solid tumor patients: 19 NSCLC, 7 breast carcinoma, 3 colorectal cancer, 3 castrate resistant prostate carcinoma, 9 other tumor types.Data collection for tumor response or clinical benefit on the 41 patients is ongoing and will be presented at the meeting, and compared to published CPI response data using standard tissue IHC testing. Citation Format: Lowell L. Hart, Magali Van den Bergh. Liquid biopsy for PDL-1 status by analysis of cfRNA: Clinical data from a large community practice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3383.

Evolution of the views on the role of testosterone in prostate cancer. Literature review

Background. Prostate cancer is one of the most common cancers in men. The views on the role of the main male hormone, testosterone, in the genesis of prostate carcinoma has changed dramatically over the last two centuries. Aim. To study the evolution of views on the relationship between testosterone and prostate cancer and to assess their impact on the organization of medical care. Materials and methods. Publications were searched in the National Library of Medicine of the United States and the Central Scientific Medical Library of the Russian Federation using the keywords: prostate cancer, testosterone. Only original publications and meta-analyses were considered. As a result, 59 publications were selected and their descriptive analysis was performed. Results. The information aboutthe doubtfulness ofthe negative role oftestosterone in genesis of prostate cancer is presented, taking into account the small number of observations and numerous methodological defects of the studies. The evidence for the theory of androgenic saturation in prostate carcinoma is outlined, which is based on publications with a sufficient number of publications. Studies confirming the absence of a carcinogenic effect of androgen replacement therapy in healthy individuals and progression of the tumor process on testosterone administration after treatment of the cancer process are described. Moreover, there is information on the use of this hormone in the treatment of castration-resistant prostate carcinoma. Conclusion. Over time, there is increasing evidence for the protective role of testosterone in the development and even treatment of prostate cancer. This raises the prospect of a global transformation in the organization of medical care in the management of patients with prostatic carcinoma, as well as older men in general. There is a clear need for new and better research on this issue.

Suppression of prostate cancer and amelioration of the immunosuppressive tumor microenvironment through selective immunoproteasome inhibition

ABSTRACT New treatment options to battle hormone-refractory prostate carcinoma (PC) are a pressing medical need. Chronic inflammation has been implicated in PC etiology. The pro-inflammatory cytokines IL-6, IL-23 and IL-17 are key mediators to promote growth of PC. Here, we evaluate the potential of immunoproteasome inhibition for anti-inflammatory and direct anti-tumorigenic therapy of PC. The anti-tumor effect of immunoproteasome inhibitor ONX 0914 was tested in mouse and human PC cells and the in vivo therapeutic efficacy of immunoproteasome inhibition was analyzed in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice in preventive and therapeutic settings and in castration-resistant (CR)PC after castration. Inhibition of the immunoproteasome subunit LMP7 induced apoptotic cell death in PC cell lines. In TRAMP mice, ONX 0914-treatment resulted in significant inhibition of PC growth with a decreased frequency of malignant prostatic lesions and inhibition of metastasis formation. The number of immunosuppressive myeloid cells in PC was greatly reduced in response to ONX 0914. Thus, immunoproteasome inhibition shows remarkable efficacy against PC progression in vivo and impedes tumor recurrence in CRPC-TRAMP mice by blocking the immunosuppressive inflammatory response in the tumor microenvironment. In conclusion, we show that the immunoproteasome is a promising drug target for the treatment of PC.

Lean Body Mass and Total Body Weight Versus Body Surface Area as a Determinant of Docetaxel Pharmacokinetics and Toxicity.

This study examined whether anthropometric and body composition parameters such as body surface area (BSA), lean body mass (LBM), and total body weight (TBW) are correlated with docetaxel clearance and exposure by analyzing area under the curve. In addition, LBM, TBW, and a fixed dose were compared with BSA as dosing parameters for dose individualization of docetaxel. Thirty-six patients receiving docetaxel chemotherapy for breast or metastatic castration-resistant prostate carcinoma were included. Before treatment, LBM was measured using a dual-energy X-ray absorptiometry scanner. Blood samples were collected up to 180 minutes after dosing to analyze docetaxel concentrations and determine individual pharmacokinetic parameters. No significant correlations were found between docetaxel clearance and the anthropometric and body composition variables (BSA, LBM, and TBW). The area under the curve was significantly but poorly correlated with BSA [r = 0.452 ( P = 0.016)] and TBW [r = 0.476 ( P = 0.011)]. The mean absolute percentage error and mean error of simulated dosing based on LBM and fixed dosing were not significantly different from those of BSA. For TBW, only mean absolute percentage error was significantly higher compared with dosing based on BSA (24.1 versus 17.1, P = 0.001). There was no clinically relevant correlation between docetaxel pharmacokinetics and the anthropometric and body composition variables BSA, LBM, and TBW. Therefore, dose individualization of docetaxel based on LBM, TBW, or fixed dosing cannot be recommended over BSA-based dosing.

Abstract CT141: CC-1, a bispecific PSMAxCD3 antibody for treatment of prostate carcinoma: Results of the ongoing phase I dose escalation trial

Abstract While highly efficient in hematological malignancies, bispecific antibodies (bsAbs), alike the closely related CAR T cells, are as of yet not successful in solid tumors. Moreover, all presently available T cell-mobilizing strategies cause substantial side effects that endanger patients and limit applicable doses and thus efficacy. Here we report on the development of CC-1, a PSMAxCD3 bsAb that is constructed in a novel IgG-based format (IgGsc) and contains a proprietary PSMA binder with extended reactivity. CC-1 displays a prolonged serum half-life, especially when compared to the BiTE bsAb format. Extensive in vitro and in vivo characterization demonstrated the potency of CC-1 to induce T cell activity in a highly target cell-restricted manner, resulting in profound antitumor activity, which among others allowed for elimination of large established tumors in humanized mice (Zekri et al, EMBO 2020). Exclusively funded by public resources, we conducted GMP production of CC-1 and in November 2019 initiated a first in human trial enrolling castration resistant prostate carcinoma patients (NCT04104607). The trial consists of two parts: a dose escalation phase with intra-individual dose escalation until the target dose of 826µg to determine overall safety, tolerability as well as the maximum tolerated dose (MTD), and a dose expansion phase, where patients are treated on the MTD level to detect possible efficacy. In August 2021, recruitment in the dose escalation phase was completed and the target dose was reached without DLT upon treatment of the 9th patient. A total of 14 patients were treated, with the most frequently observed toxicity being cytokine release syndrome (CRS) in 79% of patients. CRS did not exceed grade 2 according to the Lee et al. grading system (Lee et al., 2014) and resolved in most cases without additional application of tocilizumab. Besides hypertension (observed in 50% of patients), no further CC-1 related toxicities (i.e., Xerostomia, or anaphylactic reaction) were observed. As expected, after prophylactic tocilizumab application decreased neutrophile counts and elevated liver enzymes were observed in 86% and 43% of patients, respectively. In terms of efficacy, a rapid and profound decline of elevated PSA levels was observed in all the heavily pre-treated patients, with up to 60% reduction compared to baseline. Three patients of the dose escalation phase received multiple treatment cycles at the highest dose level, based on clinical tolerability, documented induction of potent T cell activation as well as rapid and profound decline of elevated PSA levels. Taken together, CC-1 is a promising compound with a favorable toxicity profile and promising clinical activity. Recruitment in the dose expansion phase is ongoing with the respective data to be presented at the meeting. Citation Format: Jonas S. Heitmann, Juliane S. Walz, Martin Pflügler, Maddalena Marconato, Christian M. Tegeler, Julia Reusch, Jannik Labrenz, Richard Schlenk, Gundram Jung, Helmut Salih. CC-1, a bispecific PSMAxCD3 antibody for treatment of prostate carcinoma: Results of the ongoing phase I dose escalation trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT141.

High eEF1A1 Protein Levels Mark Aggressive Prostate Cancers and the In Vitro Targeting of eEF1A1 Reveals the eEF1A1-actin Complex as a New Potential Target for Therapy.

Although the eukaryotic elongation factor eEF1A1 plays a role in various tumours, there is little information on its prognosis/therapeutic value in prostate carcinoma. In high-grade and castration-resistant prostate carcinoma (CRPC), the identification of novel therapeutic markers/targets remains a priority. The expression of eEF1A1 protein was determined in formalin-fixed, paraffin-embedded prostate cancer and hyperplasia tissue by IHC. The role of eEF1A1 was investigated in a cellular model using a DNA aptamer (GT75) we previously developed. We used the aggressive CRPC cancer PC-3 and non-tumourigenic PZHPV-7 lines. Cytotoxicity was measured by the MTS assay and eEF1A1 protein levels by in-cell Western assays. The mRNA levels of eEF1A1 were measured by qPCR and ddPCR. Higher expression of eEF1A1 was found in Gleason 7–8 compared with 4–6 tissues (Gleason ≥ 7, 87% versus Gleason ≤ 6, 54%; p = 0.033). Patients with a high expression of eEF1A1 had a worse clinical outcome. In PC-3, but not in PZHPV-7, GT75 decreased cell viability and increased autophagy and cell detachment. In PC-3 cells, but not in PZHPV-7, GT75 mainly co-localised with the fraction of eEF1A1 bound to actin. Overexpression of the eEF1A1 protein can identify aggressive forms of prostate cancer. The targeting of eEF1A1 by GT75 impaired cell viability in PC-3 cancer cells but not in PZHPV-7 non-tumourigenic cells, indicating a specific role for the protein in cancer survival. The eEF1A1–actin complexes appear to be critical for the viability of PC-3 cancer cells, suggesting that eEF1A1 may be an attractive target for therapeutic strategies in advanced forms of prostate cancer.

Current Trends in Advanced Prostate Cancer Medical Setting

Abstract Treatment of advanced and metastatic prostate carcinoma (PCa) is still challenging and changing in the era of personalised medicine. Combination therapies with docetaxel and new anti-hormonal substances lead to improved OS (overall survival) in a broad group of patients with metastatic hormone sensitive prostate carcinoma (mHSPCa). Addition of docetaxel or an androgen receptor targeting agent (ARTA) with abiraterone plus prednisolone, with apalutamide or with enzalutamide leads to a significant improvement in OS and an increase in the time to transition to castration resistance. The choice of therapy sequence in advanced PCa should be based, among other things, on the side-effect profiles of the substances and patient’s preferences. Within metastatic castration resistant prostate carcinoma (mCRPCa) setting, the therapy with abiraterone, enzalutamide, docetaxel, cabazitaxel and radium-223 is approved and indicated in Europe. Respectively, five substances are available, each of which has led to a significant increase in survival time in phase III studies. The optimal therapy sequence in the mCRPCa stage is still unclear. The current trend in personalised medicine in the next decade in therapy, regarding prostate carcinoma, are poly(ADP)-ribose polymerase (PARP) inhibitors, which are and will be available as an effective therapy option for patients with mutations in DNA repair genes. The most important question is when and how patients should be tested for mutations in DNA repair genes and to which line of therapy will PARP inhibitors belong.

MCRPC Patients Receiving 225Ac-PSMA-617 Therapy in the Post-Androgen Deprivation Therapy Setting: Response to Treatment and Survival Analysis.

225Ac-PSMA-617, targeting the prostate-specific membrane antigen (PSMA), which is overexpressed on prostate cancer cells, has shown a remarkable therapeutic efficacy in heavily pretreated patients with metastatic castration-resistant prostate carcinoma (mCRPC). Here, we report on treatment outcome and survival using this novel treatment modality in a series of 53 patients with mCRPC directly after their androgen deprivation treatment (ADT). Methods: 225Ac-PSMA-617 was administered to 53 such patients. 68Ga-PSMA PET/CT was obtained at baseline, before every treatment cycle, and on follow-up to select patients for treatment, determine the activity to be administered, and assess their response. Serial prostate-specific antigen (PSA) measurements were obtained for response assessment. Results: The median age of the patients was 63.4 y (range, 45-83 y). In total, 167 cycles were administered (median, 3; range, 1-7). Forty-eight patients (91%) had a PSA decline of at least 50%, and 51 patients (96%) had any decline in PSA. 68Ga-PSMA PET findings became negative in 30 patients. In the multivariate analysis, a PSA decline of at least 50% proved predictive of both progression-free survival (PFS) and overall survival (OS), and platelet count also proved predictive for PFS. The median estimated OS was 9 mo for patients with a PSA decline of less than 50% but was not yet reached at the latest follow-up (55 mo) for patients with a PSA decline of 50% or more. The estimated median PFS was 22 mo for patients with a PSA decline of at least 50% and 4 mo for patients with a PSA decline of less than 50%. No severe hematotoxicity was noted, and only 3 patients had grade III-IV nephrotoxicity. The commonest toxicity seen was grade I-II xerostomia, observed in 81% of patients. Conclusion: In 91% of 53 patients with mCRPC, treatment with 225Ac-PSMA-617 immediately after ADT resulted in at least a 50% decrease in PSA level. Furthermore, a PSA decline of at least 50% proved the single most important factor predicting PFS and OS after 225Ac-PSMA-617 treatment. Of interest, median OS in patients with a PSA decline of at least 50% was not yet reached at the latest follow-up (55 mo). These favorable results suggest that it would be of major clinical relevance to perform a prospective randomized study comparing 225Ac-PSMA-617 with current standard-of-care treatment options such as enzalutamide, abiraterone acetate, and docetaxel after ADT.

Preparation of 177Lu-PSMA-617 in Hospital Radiopharmacy: Convenient Formulation of a Clinical Dose Using a Single-Vial Freeze-Dried PSMA-617 Kit Developed In-House.

Objective In the recent time, endoradionuclide therapy for metastatic castration-resistant prostate carcinoma employing 177Lu-PSMA-617 has yielded encouraging results and several clinical trials with the agent are currently ongoing. Routine preparation of 177Lu-PSMA-617 patient doses can be made simpler and convenient, if the ingredients essential for radiolabeling are made available in a ready-to-use lyophilized form. Methods PSMA-617 freeze-dried kit was formulated and used for the preparation of 177Lu-PSMA-617 clinical dose with high radiochemical purity using low/medium specific activity 177Lu. Detailed radiochemical studies were performed to determine the maximum activity and volume of 177LuCl3, which can be added in the kit for the formulation of 177Lu-PSMA-617. Studies were also performed to determine the shelf life of the kit to ensure its long-term usage. Studies were performed in buffer as well as human serum medium to determine the stability of the 177Lu-PSMA-617 complex after storing in respective media up to 7 days postpreparation. About ten patient doses of 177Lu-PSMA-617 were administered, and posttherapy scans were acquired. Results The formulated freeze-dried kit of PSMA-617 could be radiolabeled with an average percentage radiochemical purity > 98.53 ± 0.38. The freeze-dried kit was found suitable for tolerating up to 0.5 mL of 177LuCl3 (in 0.01 N HCl) and specific activity of 555 MBq/μg (15 mCi/μg) for the preparation of the patient dose of 177Lu-PSMA-617. The 177Lu-PSMA-617 complex prepared using the freeze-dried kit of PSMA-617 was observed to maintain % radiochemical purity (RCP) of 96.74 ± 0.87 and 94.81 ± 2.66, respectively, even after storing up to 7 days in buffer and human serum, respectively. 177Lu-PSMA-617 prepared using the in-house formulated freeze-dried kit of PSMA-617 exhibited accumulation in metastatic lesions picked up in a pretherapy PET scan. Reduction in number as well as size of lesions was observed in posttherapy scans acquired after two months of administering the first therapeutic dose of 177Lu-PSMA-617. Conclusions The freeze-dried kit of PSMA-617 could be used for the preparation of 177Lu-PSMA-617 with high radiochemical purity (>98%) in a reproducible manner. 177Lu-PSMA-617 prepared using the developed kit was successfully evaluated in patients suffering from metastatic prostate cancer.

Renal Safety of [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Compromised Baseline Kidney Function.

Simple SummaryRadioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is an effective antitumor-treatment in metastatic castration-resistant prostate carcinoma (mCRPC). Concerns of potential nephrotoxicity are based on renal tubular PSMA expression and the resulting radiopharmaceutical retention during RLT, but data confirming clinically significant renal toxicity are still lacking. In this study, n = 22 patients treated within a prospective patient registry (REALITY Study) with significantly impaired baseline kidney function were investigated for treatment-associated nephrotoxicity and the potential relationship with administered activities of [177Lu]Lu-PSMA-617. As opposed to prevailing concerns, glomerular filtration rate (GFR) improved significantly in our cohort of patients and no significant correlation between change in GFR and administered activities were found. As pre-treatment chronic kidney failure did not lead to detectable RLT-induced deterioration of renal function in our study, the nephrotoxic potential of [177Lu]Lu-PSMA-617 RLT may be overestimated. We suggest not to categorically exclude patients from enrolment to PSMA-RLT due to renal impairment.Background: Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is an effective antitumor-treatment in metastatic castration-resistant prostate carcinoma (mCRPC). Concerns of potential nephrotoxicity are based on renal tubular PSMA expression and the resulting radiopharmaceutical retention during RLT, but data confirming clinically significant renal toxicity are still lacking. In this study, patients with significantly impaired baseline kidney function before initiation of therapy were investigated for treatment-associated nephrotoxicity and the potential relationship with administered activities of [177Lu]Lu-PSMA-617. Methods: Twenty-two mCRPC patients with impaired renal function (glomerular filtration rate (GFR) ≤ 60 mL/min) who received more than two cycles of [177Lu]Lu-PSMA-617 RLT (median 5 cycles and median 6-week time interval between consecutive cycles) were analyzed in this study. Patients were treated within a prospective patient registry (REALITY Study, NCT04833517). Cumulative administered activities ranged from 17.1 to 85.6 GBq with a median activity of 6.5 GBq per cycle. Renal function was closely monitored during and after PSMA-RLT. Results: Mean pre-treatment GFR was 45.0 ± 10.7 mL/min. After two (22/22 patients), four (20/22 patients), and six cycles (10/22 patients) of RLT, a significant increase of GFR was noted (each p < 0.05). End-of-treatment GFR (54.1 ± 16.7 mL/min) was significantly higher than baseline GFR (p = 0.016). Only one patient experienced deterioration of renal function (change of CTCAE grade 2 to 3). The remaining patients showed no significant reduction of GFR, including follow-up assessments (6, 9, and 12 months), and even showed improved (10/22 patients) or unchanged (11/22 patients) CTCAE-based renal impairment grades during and after the end of PSMA-RLT. No significant correlation between the change in GFR and per-cycle (p = 0.605) or cumulative (p = 0.132) administered activities were found. Conclusions: As pre-treatment chronic kidney failure did not lead to detectable RLT-induced deterioration of renal function in our study, the nephrotoxic potential of [177Lu]Lu-PSMA-617 RLT may be overestimated and not of clinical priority in the setting of palliative treatment in mCRPC. We suggest not to categorically exclude patients from enrolment to PSMA-RLT due to renal impairment.

Efficacy and Safety of [225Ac]Ac-PSMA-617 Augmented [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Highly Advanced mCRPC with Poor Prognosis.

The use of 225Ac in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), either as monotherapy or in combination with 177Lu, is a promising therapy approach in patients with metastatic castration-resistant prostate carcinoma (mCRPC). In this study, we report the efficacy and safety of [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 RLT in 177Lu-naive mCRPC patients (n = 15) with poor prognosis (presence of visceral metastases, high total tumor burden with diffuse bone metastases or a short PSA doubling time of <2 months). Biochemical (by PSA serum value) and molecular imaging response (by [68Ga]Ga-PSMA-11 PET/CT) was assessed after two cycles of [177Lu]Lu-PSMA-617 RLT, with at least one [225Ac]Ac-PSMA-617 augmentation. In addition, PSA-based progression-free survival (PSA-PFS), overall survival (OS) and toxicity (according to CTCAE) were analyzed. We observed a biochemical- and molecular imaging-based partial remission in 53.3% (8/15) and 66.7% (10/15) of patients, respectively. The median PSA-PFS and OS was 9.1 and 14.8 months, respectively. No serious acute adverse events were recorded. Two out of fifteen patients experienced grade 3 anemia. No other grade 3/4 toxicities were observed. RLT-related xerostomia (grade 1/2) was recorded in 2/15 patients. Our data showed a high clinical efficacy with a favorable side effects profile of [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 RLT in this highly challenging patient cohort.

Apalutamide in patients with high-risk M0CRPC: data from the pivotal SPARTAN study and initial experience from a compassionate use program

Non-metastatic castration-resistant prostate carcinoma (M0CRPC) is associated with an increased risk of progression and mortality, especially if the prostate-specific antigen doubling time is short (PSADT ≤ 10 months). The risk of progression and mortality increases even further if the disease progresses to the metastatic stage (mCRPC). The androgen receptor inhibitors apalutamide, darolutamide and enzalutamide, each in combination with androgen deprivation therapy (ADT), are available for the treatment of patients with high-risk M0CRPC.Data from the pivotal SPARTAN study showed that apalutamide + ADT delayed metastasis-free survival (MFS) and thus also the development of mCRPC in these patients. Prior to the approval of apalutamide in the European Union, the active substance was available in Germany as part of an international compassionate use program. A total of 109 patients from 50 centres participated in Germany: 45 patients were treated for more than 3 months and 13 patients for more than 6 months. The compassionate use program continues in some countries; 556 patients have been enrolled worldwide.In our experience, this real-world population showed a good PSA response, which was also shown for this exploratory endpoint in the SPARTAN study. We were also unable to identify any significant differences from the pivotal trial with regards to the tolerability profile.Apalutamide in combination with ADT was also effective in this real-world population and led to a rapid decrease in PSA. The tolerability profile did not differ from that in the SPARTAN trial.

Concept proposal for a six-tier integrated dual tracer PET-CT (68Ga-PSMA and FDG) image scoring system ('Pro-PET' score) and examining its potential implications in metastatic castration-resistant prostate carcinoma theranostics and prognosis.

To develop and examine a scoring system in metastatic castration-resistant prostate carcinoma (mCRPC) that integrates findings of both 68Ga-prostate-specific membrane antigen (PSMA) and flurodeoxyglucose (FDG) PET-CT imaging in a single combined parameter and referred to as the 'Pro-PET' score. A six-tier integrated dual tracer PET-CT (68Ga-PSMA and FDG) Image Scoring System ('Pro-PET' score) was conceptualized, based on the findings of both 68Ga-PSMA-11 and FDG PET-CT in patients of mCRPC. This proposed integrated scoring was examined in a retrospective analytical study assessing mCRPC patients (n = 47) referred for 177Lu-PSMA-617 peptide receptor radioligand therapy (PRLT) and had both FDG and 68Ga-PSMA PET-CT undertaken within 15 days of each other without any interim treatment intervention. The 'Pro-PET' score grades and subgrades were assigned and compared with clinical data, such as histopathology, Gleason score, serum prostate-specific antigen (PSA), treatment response (symptomatic, biochemical, metabolic and anatomical) and survival [overall survival (OS) and progression-free survival (PFS)]. The Pro-PET score significantly correlated with symptomatic (P = 0.05), biochemical (P = 0.05), metabolic (P = 0.001) and anatomical (P = 0.012) responses, PFS (P = 0.03) and OS (P = 0.027). On multivariate analysis, histopathology, Gleason score and PSA as individual parameters were not significantly associated with OS and PFS, whereas the Pro-PET score was found to have a significant association (P = 0.001 for PFS and 0.011 for OS). The 'Pro-PET' scoring system integrating dual tracer PET-CT imaging findings in a single parameter appeared as a potentially promising prognostic marker that has the potential to enhance the objectivity and scientific basis of prostate carcinoma theranostics and prognostication.

In-House Preparation and Quality Control of Ac-225 Prostate-Specific Membrane Antigen-617 for the Targeted Alpha Therapy of Castration-Resistant Prostate Carcinoma.

Purpose:Ac-225 labeled with prostate-specific membrane antigen (PSMA-617), a transmembrane glycoprotein which is highly expressed in prostate carcinoma cells, is presently being considered a promising agent of targeted alpha therapy for the treatment of patients suffering from metastatic castration-resistant prostate cancer. In the present study, we report an optimized protocol for the preparation of therapeutic dose of Ac-225 PSMA-617 with high yield and radiochemical purity (RCP).Methods:Ac-225 PSMA-617 was prepared by adding the peptidic precursor-PSMA-617 (molar ratios, Ac-225: PSMA-617 = 30:1) in 1 ml ascorbate buffer to Ac-225 and heating the reaction mixture at 90°C for 25 min to obtain the radiopeptide with high RCP and yield. The radiolabeled peptide was administered in patients who met the eligibility criteria and posttherapy assessment was done.Results:Ten batches of Ac-225 PSMA-617 were prepared following this protocol. The radiopeptide was obtained with an adequate yield of 85%–87% and RCP of 97%–99%.Conclusion:The current protocol allows single-step, successful, routine inhouse radiolabeling of Ac-225 with PSMA-617 with high yield and RCP.