Administering [177Lu]Lu-PSMA-617 Prior to Radical Prostatectomy in Men with High-risk Localised Prostate Cancer (LuTectomy): A Single-centre, Single-arm, Phase 1/2 Study.

BACKGROUND: High-risk localised prostate cancer (HRCaP) has high rates of biochemical recurrence; [177Lu]Lu-PSMA-617 is effective in men with advanced prostate cancer. OBJECTIVE: To investigate the dosimetry, safety, and efficacy of upfront [177Lu]Lu-PSMA-617 in men with HRCaP prior to robotic radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS: In this single-arm, phase I/II trial, we recruited men with HRCaP (any of prostate-specific antigen [PSA] >20 ng/ml, International Society of Urological Pathology (ISUP) grade group [GG] 3-5, and ≥cT2c), with high tumour uptake on [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PSMA PET/CT), and scheduled for RP. INTERVENTION: Cohort A (n = 10) received one cycle and cohort B (n = 10) received two cycles of [177Lu]Lu-PSMA-617 (5 GBq) followed by surgery 6 weeks later. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was tumour radiation absorbed dose. Adverse events (AEs; Common Terminology Criteria for Adverse Events (CTCAE) version 5.0), surgical safety (Clavien-Dindo), imaging, and biochemical responses were evaluated (ClinicalTrials.gov: NCT04430192). RESULTS AND LIMITATIONS: Between May 29, 2020 and April 28, 2022, 20 patients were enrolled. The median PSA was 18 ng/ml (interquartile range [IQR] 11-35), Eighteen (90%) had GG ≥3, and six (30%) had N1 disease. The median (IQR) highest tumour radiation absorbed dose after cycle 1 for all lesions was 35.5 Gy (19.5-50.1), with 19.6 Gy (11.3-48.4) delivered to the prostate. Five patients received radiation to lymph nodes. Nine (45%) patients achieved >50% PSA decline. The most common AEs related to [177Lu]Lu-PSMA-617 were grade 1 fatigue in eight (40%), nausea in seven (35%), dry mouth in six (30%), and thrombocytopenia in four (20%) patients. No grade 3/4 toxicities or Clavien 3-5 complications occurred. Limitations include small a sample size. CONCLUSIONS: In men with HRCaP and high prostate-specific membrane antigen (PSMA) expression, [177Lu]Lu-PSMA-617 delivered high levels of targeted radiation doses with few toxicities and without compromising surgical safety. Further studies of [177Lu]Lu-PSMA-617 in this population are worthwhile to determine whether meaningful long-term oncological benefits can be demonstrated. PATIENT SUMMARY: In this study, we demonstrate that up to two cycles of [177Lu]Lu-PSMA-617 given prior to radical prostatectomy in patients with high-risk localised prostate cancer are safe and deliver targeted doses of radiation to tumour-affected tissues. It is tolerated well with minimal treatment-related adverse events, and surgery is safe with a low rate of complications. Activity measured through PSA reduction, repeat PSMA PET/CT, and histological response is promising.

A Novel Risk Calculator Incorporating Clinical Parameters, Multiparametric Magnetic Resonance Imaging, and Prostate-Specific Membrane Antigen Positron Emission Tomography for Prostate Cancer Risk Stratification Before Transperineal Prostate Biopsy.

Background: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect multiparametric magnetic resonance imaging (mpMRI)-invisible prostate tumours and improve the sensitivity of detection of prostate cancer (PCa) in comparison to mpMRI alone. Numerous risk calculators have been validated as tools for stratification of men at risk of being diagnosed with clinically significant (cs)PCa. Objective: To develop a novel risk calculator using clinical parameters and imaging parameters from mpMRI and PSMA PET/CT in a cohort of patients undergoing mpMRI and PSMA PET/CT before biopsy. Design setting and participants: A total of 291 men from the PRIMARY prospective trial underwent mpMRI and PSMA PET/CT before transperineal prostate biopsy with sampling of systematic and targeted cores. Outcome measurements and statistical analysis: Novel risk calculators were developed using multivariable logistic regression analysis to predict detection of overall PCa (International Society of Urological Pathology grade group [GG] ≥1) and csPCa (GG ≥2). The risk calculators were then compared with the European Randomised Study of Screening for Prostate Cancer risk calculator incorporating mpMRI (ERSPC-MRI). Resampling methods were used to evaluate the discrimination and calibration of the risk calculators and to perform decision curve analysis. Results and limitations: Age, prostate-specific antigen, prostate volume, and mpMRI Prostate Imaging-Reporting and Data System scores were included in the MRI risk calculator, resulting in area under the receiver operating characteristic curve (AUC) values of 0.791 for overall PCa (GG ≥1) and 0.812 for csPCa (GG ≥2). Addition of the maximum standardised uptake value (SUVmax) on PSMA PET/CT for the prostate lesion, and of SUVmax for the mpMRI lesions for the MRI-PSMA risk calculator resulted in AUCs of 0.831 for overall PCa and 0.876 for csPCa (≥ISUP2).The ERSPC-MRI risk calculator had AUCs of 0.758 (p = 0.02) for overall PCa and 0.805 (p = 0.001) for csPCa. Both the MRI and MRI-PSMA risk calculators were superior to the ERSPC-MRI for both overall PCa and csPCa. Conclusions: These novel risk calculators incorporate clinical and radiological parameters for stratification of men at risk of csPCa. The risk calculator including PSMA PET/CT data is superior to a calculator incorporating mpMRI data alone. Patient summary: We evaluated a new risk calculator that uses clinical information and results from two types of scan to predict the risk of clinically significant prostate cancer on prostate biopsy. This risk model can guide patients and clinicians in shared decision-making and may help in avoiding unnecessary prostate biopsies.

The PRIMARY Score: Using Intraprostatic 68Ga-PSMA PET/CT Patterns to Optimize Prostate Cancer Diagnosis.

Multiparametric MRI (mpMRI) is validated for the diagnosis of clinically significant prostate cancer (csPCa). 68Ga-PSMA-11 PET/CT (68Ga-PSMA PET/CT) combined with mpMRI has improved negative predictive value over mpMRI alone for csPCa. The aim of this post hoc analysis of the PRIMARY study was to evaluate the clinical significance of patterns of intraprostatic PSMA activity, proposing a 5-point PRIMARY score to optimize the accuracy of 68Ga-PSMA PET/CT for csPCa in a low-prevalence population. Methods: The PRIMARY trial was a prospective multicenter phase II imaging trial that enrolled men with suspected PCa, no prior biopsy, and a recent mpMRI examination (6 mo) and for whom prostate biopsy was planned. In total, 291 men underwent mpMRI, 68Ga-PSMA PET/CT, and systematic biopsy with or without targeted biopsy. The mpMRI was read separately using the Prostate Imaging Reporting and Data System (PI-RADS) (version 2). 68Ga-PSMA PET/CT (pelvis only) was acquired a minimum of 60 min after injection. 68Ga-PSMA PET/CT was centrally read for pattern (diffuse transition zone [TZ], symmetric central zone [CZ], focal TZ, or focal peripheral zone [PZ]) and intensity (SUVmax). In this post hoc analysis, a 5-level PRIMARY score was assigned on the basis of analysis of the central read: no pattern (score of 1), diffuse TZ or CZ (not focal) (score of 2), focal TZ (score of 3), focal PZ (score of 4), or an SUVmax of at least 12 (score of 5). Two further readers independently assigned a PRIMARY score to 118 scans to determine interrater agreement. Associations between PRIMARY score and csPCa (International Society of Urological Pathology grade group ≥ 2) were evaluated. Results: Of the 291 men enrolled, 162 (56%) had csPCa. A PRIMARY score of 1 was present in 16% (47); a score of 2, in 19% (55); a score of 3, in 10% (29); a score of 4 in 40% (117); and a score of 5, in 15% (43). The proportion of patients with csPCa and a PRIMARY score of 1, 2, 3, 4, and 5 was 8.5% (4/47), 27% (15/55), 38% (11/29), 76% (89/117), and 100% (43/43), respectively. Sensitivity, specificity, positive predictive value, and negative predictive value for a PRIMARY score of 1 or 2 (low-risk patterns) versus a PRIMARY score of 3-5 (high-risk patterns) were 88%, 64%, 76%, and 81%, respectively, compared with 83%, 53%, 69%, and 72%, respectively, for a PI-RADS score of 2 versus 3-5 on mpMRI. The Cohen κ for a PRIMARY score of 1 of 2 versus a PRIMARY score of 3-5 was 0.76 (95% CI, 0.64-0.88) for reader 1 and 0.64 (95% CI, 0.49-0.78) for reader 2. Conclusion: A PRIMARY score incorporating intraprostatic pattern and intensity on 68Ga-PSMA PET/CT shows potential, with high diagnostic accuracy for csPCa. Further validation is warranted before implementation.

The Additive Diagnostic Value of Prostate-specific Membrane Antigen Positron Emission Tomography Computed Tomography to Multiparametric Magnetic Resonance Imaging Triage in the Diagnosis of Prostate Cancer (PRIMARY): A Prospective Multicentre Study.

BACKGROUND: Multiparametric magnetic resonance imaging (MRI) is validated for the detection of clinically significant prostate cancer (csPCa), although patients with negative/equivocal MRI undergo biopsy for false negative concerns. In addition, 68Ga-PSMA-11 positron emission tomography/computed tomography (prostate-specific membrane antigen [PSMA]) may also identify csPCa accurately. OBJECTIVE: This trial aimed to determine whether the combination of PSMA + MRI was superior to MRI in diagnostic performance for detecting csPCa. DESIGN, SETTING, AND PARTICIPANTS: A prospective multicentre phase II imaging trial was conducted. A total of 296 men were enrolled with suspected prostate cancer, with no prior biopsy or MRI, recent MRI (6 mo), and planned transperineal biopsy based on clinical risk and MRI. In all, 291 men underwent MRI, pelvic-only PSMA, and systematic ± targeted biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Sensitivity, specificity, and predictive values (negative predictive value [NPV] and positive predictive value) for csPCa were determined for MRI, PSMA, and PSMA + MRI. PSMA + MRI was defined as negative for PSMA negative Prostate Imaging Reporting and Data System (PI-RADS) 2/3 and positive for either MRI PI-RADS 4/5 or PSMA positive PI-RADS 2/3; csPCa was any International Society of Urological Pathology (ISUP) grade group ≥2 malignancy. RESULTS AND LIMITATIONS: Of the patients, 56% (n = 162) had csPCa; 67% had PI-RADS 3-5, 73% were PSMA positive, and 81% were combined PSMA + MRI positive. Combined PSMA + MRI improved NPV compared with MRI alone (91% vs 72%, test ratio = 1.27 [1.11-1.39], p < 0.001). Sensitivity also improved (97% vs 83%, p < 0.001); however, specificity was reduced (40% vs 53%, p = 0.011). Five csPCa cases were missed with PSMA + MRI (four ISUP 2 and one ISUP 3). Of all men, 19% (56/291) were PSMA + MRI negative (38% of PI-RADS 2/3) and could potentially have avoided biopsy, risking delayed csPCa detection in 3.1% men with csPCa (5/162) or 1.7% (5/291) overall. CONCLUSIONS: PSMA + MRI improved NPV and sensitivity for csPCa in an MRI triaged population. Further randomised studies will determine whether biopsy can safely be omitted in men with a high clinical suspicion of csPCa but negative combined imaging. PATIENT SUMMARY: The combination of magnetic resonance imaging (MRI) + prostate-specific membrane antigen positron emission tomography reduces false negatives for clinically significant prostate cancer (csPCa) compared with MRI, potentially allowing a reduction in the number of prostate biopsies required to diagnose csPCa.

The application of theranostics in different stages of prostate cancer.

Despite the remarkable achievements in treating metastatic prostate cancer over the last two decades, castrate-resistant status is still considered the lethal stage of the disease. Theranostics combines a targeting compound (ligand) with a therapeutic radioisotope (radioactive particle) injected into the blood to target the cancer cells. The most studied radioligand is 177Lu-PSMA-617, which targets PSMA, a protein found in prostate cancer cells. This new approach has shown promising results in treating metastatic castration-resistant prostate cancer. Currently, many trials are using PSMA-targeting radioligands in combination with conventional therapies in advanced prostate cancer or even in the earlier stages of the disease. Other preclinical trials are exploring the possibility of using newer ligands or radioisotopes to treat prostate cancer to increase the specificity and efficacy of this treatment.

Is the Toxicity of Salvage Prostatectomy Related to the Primary Prostate Cancer Therapy Received?

PURPOSE: To compare the toxicity profile and oncological outcome of salvage radical prostatectomy following focal therapy versus salvage radical prostatectomy after radiation therapies (external beam radiation therapy or brachytherapy). MATERIALS AND METHODS: Data concerning all men undergoing salvage radical prostatectomy for recurrent prostate cancer after either focal therapy, external beam radiation therapy or brachytherapy were retrospectively collected from 4 high volume surgical centers. The primary outcome measure of the study was toxicity of salvage radical prostatectomy characterized by any 30-day postoperative Clavien-Dindo complication rate, 12-month continence rate and 12-month potency rate. The secondary outcome was oncological outcome after salvage radical prostatectomy including positive margin rate and 12-month biochemical recurrence rate. Biochemical recurrence was estimated using Kaplan-Meier methods and significant differences were calculated using a log rank test. Median followup was 29.5 months. RESULTS: Between April 2007 and September 2018, 185 patients underwent salvage radical prostatectomy of whom 95 had salvage radical prostatectomy after focal therapy and 90 had salvage radical prostatectomy after radiation therapy (external beam radiation therapy or brachytherapy). Salvage radical prostatectomy after radiation therapy was associated with a significantly higher 30-day Clavien-Dindo I-IV complication rate (34% vs 5%, p <0.001). At 12 months following surgery, patients undergoing salvage radical prostatectomy after focal therapy had significantly better continence (83% pad-free vs 49%) while potency outcomes were similar (14% vs 11%). Men undergoing salvage radical prostatectomy after radiation therapy had a significantly higher stage and grade of disease together with a higher positive surgical margin rate (37% vs 13%, p=0.001). The 3-year biochemical recurrence after focal therapy was 35% compared to 32% after radiation therapy (p=0.76). In multivariable analysis, men undergoing salvage radical prostatectomy after focal therapy experienced a higher risk of biochemical recurrence (HR 0.36, 95% CI 0.16-0.82, p=0.02). CONCLUSIONS: This multicenter study demonstrates the toxicity of salvage radical prostatectomy in terms of perioperative complications and long-term urinary continence recovery is dependent on initial primary prostate cancer therapy received with men undergoing salvage radical prostatectomy after focal therapy experiencing lower postoperative complication rates and better urinary continence outcomes.

Clinical Trial Protocol for LuTectomy: A Single-arm Study of the Dosimetry, Safety, and Potential Benefit of 177Lu-PSMA-617 Prior to Prostatectomy.

LuTectomy is an open-label phase 1/2 nonrandomised clinical trial evaluating the dosimetry, efficacy, and toxicity of the lutetium-177-radiolabelled small molecule PSMA-617 in men with high-risk localised/locoregional advanced prostate cancer with high prostate-specific membrane antigen expression who are undergoing radical prostatectomy and pelvic lymph node dissection.

Indirect Comparisons of Efficacy between Combination Approaches in Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review and Network Meta-analysis.

CONTEXT: There have been substantial changes in the management of men with metastatic hormone-sensitive prostate cancer (mHSPC) over the past 5 yr, with upfront combination therapies replacing androgen-deprivation therapy (ADT) alone. A range of therapies have entered the space with no clear answer regarding their comparative efficacy. OBJECTIVE: To perform a systematic review and network meta-analysis to characterise the comparative efficacy of combination approaches in men with mHSPC. EVIDENCE ACQUISITION: We searched multiple databases and abstracts of major meetings up to June 2019 for randomised trials of patients receiving first-line therapy for metastatic disease, a combination of ADT and one (or more) of taxane-based chemotherapy, and androgen receptor-targeted therapies. The primary endpoint was overall survival (OS) and we evaluated progression-free survival as a secondary outcome. We performed subgroup analysis based on the volume of disease. EVIDENCE SYNTHESIS: We found seven trials that met our eligibility criteria using either docetaxel, abiraterone acetate, enzalutamide, or apalutamide in combination with ADT. All agents in combination with ADT were shown to be superior to ADT alone; enzalutamide + ADT had the lowest absolute hazard ratio compared with ADT only (hazards ratio 0.53, 95% confidence interval 0.37-0.75), and an estimated 76.9% probability that it is the preferred treatment to prolong OS compared with other combination treatments, or with ADT alone. Enzalutamide appeared to have better OS compared with docetaxel in men with low-volume disease, but there was no difference in other comparisons. CONCLUSIONS: Combination therapy with any of docetaxel, abiraterone acetate, enzalutamide, or apalutamide provides a significant OS benefit when compared with ADT alone. We did not identify significant differences in OS between different combination therapies. Subtle differences between these options provide clinicians considerable flexibility when selecting options for individual patients. PATIENT SUMMARY: Many men with metastatic, hormone-sensitive prostate cancer should be managed with upfront combination therapy instead of androgen-deprivation therapy alone. Clinicians may consider many factors during the decision-making process, and thus management should be tailored for patients individually.

The Role of Local Therapy for Oligometastatic Prostate Cancer: Should We Expect a Cure?

The role of local treatment in oligometastatic prostate cancer remains contentious. Treatment of the prostate in metastatic disease may confer benefit, but prospective data are lacking. With improvements in treatments, aggressive strategies directed at metastases have increasingly become of clinical interest. Current evidence suggests good local control can be achieved; however, further data are required to determine overall cancer outcomes. This article evaluates the evidence available and consider whether local treatment of oligometastatic disease is a feasible, safe, and a positive strategy in this disease cohort. Cure should not be expected, although prolonged disease and treatment-free survival may be observed.