Acute exercise induces distinct quantitative and phenotypical T cell profiles in men with prostate cancer.

Background: Reduced testosterone levels can influence immune system function, particularly T cells. Exercise during cancer reduces treatment-related side effects and provide a stimulus to mobilize and redistribute immune cells. However, it is unclear how conventional and unconventional T cells (UTC) respond to acute exercise in prostate cancer survivors compared to healthy controls. Methods: Age-matched prostate cancer survivors on androgen deprivation therapy (ADT) and those without ADT (PCa) along with non-cancer controls (CON) completed ∼45 min of intermittent cycling with 3 min at 60% of peak power interspersed by 1.5 min of rest. Fresh, unstimulated immune cell populations and intracellular perforin were assessed before (baseline), immediately following (0 h), 2 h, and 24 h post-exercise. Results: At 0 h, conventional T cell counts increased by 45%-64% with no differences between groups. T cell frequency decreased by -3.5% for CD3+ and -4.5% for CD4+ cells relative to base at 0 h with CD8+ cells experiencing a delayed decrease of -4.5% at 2 h with no group differences. Compared to CON, the frequency of CD8+CD57+ cells was -18.1% lower in ADT. Despite a potential decrease in maturity, ADT increased CD8+perforin+ GMFI. CD3+Vα7.2+CD161+ counts, but not frequencies, increased by 69% post-exercise while CD3+CD56+ cell counts increased by 127% and were preferentially mobilized (+1.7%) immediately following the acute cycling bout. There were no UTC group differences. Cell counts and frequencies returned to baseline by 24 h. Conclusion: Following acute exercise, prostate cancer survivors demonstrate normal T cell and UTC responses that were comparable to CON. Independent of exercise, ADT is associated with lower CD8+ cell maturity (CD57) and perforin frequency that suggests a less mature phenotype. However, higher perforin GMFI may attenuate these changes, with the functional implications of this yet to be determined.

[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial.

BACKGROUND: Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers ß radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer. METHODS: We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0-2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428. FINDINGS: Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16-42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9-37]; p=0·0016). Grade 3-4 adverse events occurred in 32 (33%) of 98 men in the [177Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [177Lu]Lu-PSMA-617. INTERPRETATION: [177Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [177Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel. FUNDING: Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.

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.

Natural killer cell mobilization and egress following acute exercise in men with prostate cancer.

NEW FINDINGS: What is the central question of this study? What are the characteristics of the NK cell response following acute moderate-intensity aerobic exercise in prostate cancer survivors and is there a relationship between stress hormones and NK cell mobilization? What is the main finding and its importance? NK cell numbers and proportions changed similarly between prostate cancer survivors and controls following acute exercise. Consecutive training sessions can likely be used without adverse effects on the immune system during prostate cancer treatment. ABSTRACT: Prostate cancer treatment affects multiple physiological systems, although the immune response during exercise has been minimally investigated. The objective was to characterize the natural killer (NK) cell response following acute exercise in prostate cancer survivors. Prostate cancer survivors on androgen deprivation therapy (ADT) and those without (PCa) along with non-cancer controls (CON) completed a moderate intensity cycling bout. NK cells were phenotyped before and 0, 2 and 24 h after acute exercise using flow cytometry. CD56 total NK cell frequency increased by 6.2% at 0 h (P < 0.001) and decreased by 2.5% at 2 h (P < 0.01) with similar findings in CD56dim cells. NK cell counts also exhibited a biphasic response. Independent of exercise, ADT had intracellular interferon γ (IFNγ) expression that was nearly twofold higher than CON (P < 0.01). PCa perforin expression was reduced by 11.4% (P < 0.05), suggesting these cells may be more prone to degranulation. CD57- NK cells demonstrated increased perforin and IFNγ frequencies after exercise with no change within the CD57+ populations. All NK and leukocyte populations returned to baseline by 24 h. NK cell mobilization and egress with acute exercise appear normal, as cell counts and frequencies in prostate cancer survivors change similarly to CON. However, lower perforin proportions (PCa) and higher IFNγ expression (ADT) may alter NK cytotoxicity and require further investigation. The return of NK cell proportions to resting levels overnight suggests that consecutive training sessions can be used without adverse effects on the immune system during prostate cancer treatment.

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

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

Radiation Dosimetry in 177Lu-PSMA-617 Therapy Using a Single Posttreatment SPECT/CT Scan: A Novel Methodology to Generate Time- and Tissue-Specific Dose Factors.

Calculation of radiation dosimetry in targeted nuclear medicine therapies is traditionally resource-intensive, requiring multiple posttherapy SPECT acquisitions. An alternative approach is to take advantage of existing pharmacokinetic data from these smaller cohorts to enable dose computation from a single posttreatment scan in a manner that may be applied to a much broader patient population. Methods: In this work, a technical description of simplified dose estimation is presented and applied to the assessment of 177Lu-prostate-specific membrane antigen (PSMA)-617 therapy for metastatic prostate cancer. By normalizing existing time-activity curves to a single measurement time, it is possible to calculate a mean and range of time-integrated activity values that relate to absorbed radiation dose. To assist with accurate pharmacokinetic modeling of the training cohort, a method for contour-guided image registration was developed. Results: Tissue-specific dose conversion factors for common posttreatment imaging times are reported along with a characterization of added uncertainty in comparison to a traditional serial imaging protocol. Single-time-point dose factors for tumor were determined to be 11.0, 12.1, 13.6, and 15.2 Gy per MBq/mL at image times of 24, 48, 72, and 96 h, respectively. For normal tissues, parotid gland factors were 6.7, 9.4, 13.3, and 19.3 Gy per MBq/mL at those times, and kidneys were 7.1, 10.3, 15.0, and 22.0 Gy per MBq/mL. Tumor dose estimates were most accurate using delayed scanning at times beyond 72 h. Dose to healthy tissues is best characterized by scanning patients in the first 2 d of treatment because of the larger degree of tracer clearance in this early phase. Conclusion: This work demonstrates a means for efficient dose estimation in 177Lu-PSMA-617 therapy. By providing methods to simplify and potentially automate radiation dosimetry, we hope to accelerate the understanding of radiobiology and development of dose-response models in this unique therapeutic context.

Lutetium-177 prostate-specific membrane antigen (PSMA) theranostics: practical nuances and intricacies.

Theranostic principles utilize a molecular biomarker specific for a tumor target, initially for imaging to assess target expression and, if deemed suitable, for targeted therapy. This presents an exciting opportunity for a highly personalized treatment strategy in the era of precision medicine. Prostate-specific membrane antigen (PSMA) theranostics has attracted increasing attention as a promising targeted treatment in metastatic prostate cancer (PC). 177Lu-DOTA-PSMA-617 (177Lu-PSMA-617) is a PSMA-targeted small molecule with favorable properties and is the most extensively investigated PSMA radioligand for radionuclide therapy (RNT) in PC. Since 2014 multiple retrospective studies and more recently a phase II prospective study demonstrated safety and impressive efficacy of 177Lu-PSMA RNT. The evidence generated by these trials led to two currently underway randomized trials in metastatic castrate-resistant PC: TheraP (NCT03392428) and VISION (NCT03511664). While we wait for these pivotal trials to read out, nuclear medicine physicians, medical oncologists, radiation oncologists, and urologists are facing a steep learning curve to master the intricacies and nuances of this novel therapeutic strategy. This review article aims to share and discuss the evolving experience in practical aspects of PSMA theranostics.

Long-Term Follow-up and Outcomes of Retreatment in an Expanded 50-Patient Single-Center Phase II Prospective Trial of 177Lu-PSMA-617 Theranostics in Metastatic Castration-Resistant Prostate Cancer.

177Lu-PSMA-617 is a radioligand with high affinity for prostate-specific membrane antigen (PSMA), enabling targeted ß-irradiation of prostate cancer. We have previously reported favorable activity with low toxicity in a prospective phase II trial involving 30 men with metastatic castration-resistant prostate cancer. We now report their longer-term outcomes, including a 20-patient extension cohort and outcomes of subsequent systemic treatments after completion of trial therapy. Methods: Fifty patients with PSMA-avid metastatic castration-resistant prostate cancer who had progressed after standard therapies received up to 4 cycles of 177Lu-PSMA every 6 wk. Endpoints included prostate-specific antigen (PSA) response (Prostate Cancer Working Group 2), toxicity (Common Terminology Criteria for Adverse Events, version 4.03), imaging response, patient-reported health-related quality of life, progression-free survival, and overall survival. We also describe, as a novel finding, outcomes of men who subsequently progressed and had further systemic therapies, including 177Lu-PSMA. Results: Seventy-five men were screened to identify 50 patients eligible for treatment. Adverse prognostic features of the cohort included short median PSA doubling time (2.3 mo) and extensive prior treatment, including prior docetaxel (84%), cabazitaxel (48%), and abiraterone or enzalutamide (92%). The mean administered radioactivity was 7.5 GBq/cycle. A PSA decline of at least 50% was achieved in 32 of 50 patients (64%; 95% confidence interval [CI], 50%-77%), including 22 patients (44%; 95% CI, 30%-59%) with at least an 80% decrease. Of 27 patients with measurable soft-tissue disease, 15 (56%) achieved an objective response by RECIST 1.1. The most common toxicities attributed to 177Lu-PSMA were self-limiting G1-G2 dry mouth (66%), transient G1-G2 nausea (48%), G3-G4 thrombocytopenia (10%), and G3 anemia (10%). Brief Pain Inventory severity and interference scores decreased at all time points, including at the 3-mo follow-up, with a decrease of -1.2 (95% CI, -0.5 to -1.9; P = 0.001) and -1.0 (95% CI, -0.2 to -0.18; P = 0.013), respectively. At a median follow-up of 31.4 mo, median overall survival was 13.3 mo (95% CI, 10.5-18.7 mo), with a significantly longer survival of 18.4 mo (95% CI, 13.8-23.8 mo) in patients achieving a PSA decline of at least 50%. At progression after prior response, further 177Lu-PSMA was administered to 15 (30%) patients (median of 2 cycles commencing 359 d from enrollment), with a PSA decline of at least 50% in 11 patients (73%). Four of 21 patients (19%) receiving other systemic therapies on progression experienced a PSA decline of at least 50%. There were no unexpected adverse events with 177Lu-PSMA retreatment. Conclusion: This expanded 50-patient cohort of men with extensive prior therapy confirms our earlier report of high response rates, low toxicity, and improved quality of life with 177Lu-PSMA radioligand therapy. On progression, rechallenge 177Lu-PSMA demonstrated higher response rates than other systemic therapies.

TheraP: a randomized phase 2 trial of 177 Lu-PSMA-617 theranostic treatment vs cabazitaxel in progressive metastatic castration-resistant prostate cancer (Clinical Trial Protocol ANZUP 1603).

OBJECTIVE: To assess the activity and safety of cabazitaxel chemotherapy vs that of treatment with 177 Lu-PSMA-617, a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), in men with metastatic castration-resistant prostate cancer (mCRPC) who have received prior docetaxel treatment. PATIENTS AND METHODS: The TheraP trial (ANZUP 1603) is an open-label, randomized, stratified, two-arm multicentre phase 2 trial comparing the activity and safety of cabazitaxel chemotherapy vs 177 Lu-PSMA-617 therapy in the treatment of men with mCRPC. Key eligibility criteria include prior docetaxel chemotherapy, rising prostate-specific antigen (PSA) level, sufficient PSMA avidity, as defined by centrally reviewed 68 Ga-PSMA-11 and fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) with no discordant FDG-avid PSMA-negative sites of disease. Patients in the control group receive standard treatment with cabazitaxel (20 mg/m2 ) i.v. every 3 weeks with prednisolone 10 mg daily orally, for a maximum of 10 cycles. Patients in the experimental group receive 177 Lu-PSMA-617 (8.5 GBq decreasing by 0.5 GBq per cycle) i.v. every 6 weeks, for up to a maximum of six cycles. In the event of an exceptional response as defined on centrally reviewed post-therapy single-photon emission CT imaging, treatment will be suspended but can recommence on progression. The trial aims to include 200 patients who will be centrally randomized to one of the two treatment groups, in a 1:1 ratio. The primary endpoint is PSA response. Secondary endpoints are overall survival, progression-free survival (PFS), radiographic PFS, PSA PFS, objective tumour response, pain response, pain PFS, health-related quality of life, and frequency and severity of adverse events. The treatment and outcomes of patients excluded on the basis of low PSMA avidity or discordant FDG-avid disease on screening 68 Ga-PSMA-11 and Fluorine-18 (18 F)-FDG-PET/CT scan will also be assessed. Enrolment in the study commenced on 29 January 2018. RESULTS AND CONCLUSIONS: 177 Lu-PSMA-617 offers a potential additional life-prolonging treatment option for men with mCRPC. The results of this trial will determine, for the first time in a randomized design, the activity and safety of 177 Lu-PSMA-617, as compared with cabazitaxel chemotherapy in men with progressive mCRPC.

Poor Outcomes for Patients with Metastatic Castration-resistant Prostate Cancer with Low Prostate-specific Membrane Antigen (PSMA) Expression Deemed Ineligible for 177Lu-labelled PSMA Radioligand Therapy.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is overexpressed in metastatic castration-resistant prostate cancer (mCRPC) and represents a target for imaging and therapy. We undertook a prospective trial of 177Lu-PSMA-617 radioligand therapy in men with high PSMA expression who progressed after standard therapies. OBJECTIVE: To determine outcomes for men screened for the trial but not treated because of low PSMA expression. DESIGN, SETTING, AND PARTICIPANTS: Patients screened with 68Ga-PSMA-11 and 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography in a prospective trial. Patients ineligible for enrolment with low PSMA expression or FDG-positive PSMA-negative (discordant FDG-avid) disease were assessed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Subsequent treatments received were recorded. Kaplan-Meier analysis was used to determine overall survival from date of screening. RESULTS AND LIMITATIONS: Sixteen patients (24%) had low PSMA expression (n=8) or discordant FDG-avid disease (n=8). The median prostate-specific antigen doubling-time was 2.1mo. Eleven patients had Gleason ≥8 disease. All patients had previously progressed after docetaxel, 44% after cabazitaxel, and 94% after abiraterone and/or enzalutamide. Nine patients had subsequent systemic antitumour treatment. Fifteen patients died, with median OS of 2.5mo (95% confidence interval 1.7-5.0). Study limitations include uncertainty for imaging thresholds that define low PSMA expression. It is also possible that theranostic therapy could have improved survival in this cohort. CONCLUSIONS: Low PSMA expression or discordant FDG-avid disease in patients with mCRPC who progress after conventional therapies identifies a group with poor prognosis and short survival. PATIENT SUMMARY: The 177Lu-PSMA-617 radioligand may be an effective therapy for patients with advanced prostate cancer who progress after standard therapies. In this report we looked at outcomes for patients who were not eligible for this novel therapy on the basis of low prostate-specific membrane antigen uptake on screening positron emission tomography scans. We found that their outcomes were poor, with short survival.

Dosimetry of 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer: Correlations Between Pretherapeutic Imaging and Whole-Body Tumor Dosimetry with Treatment Outcomes.

177Lu-prostate-specific membrane antigen (PSMA)-617 enables targeted delivery of ß-particle radiation to prostate cancer. We determined its radiation dosimetry and relationships to pretherapeutic imaging and outcomes. Methods: Thirty patients with prostate cancer receiving 177Lu-PSMA-617 within a prospective clinical trial (ACTRN12615000912583) were studied. Screening 68Ga-PSMA-11 PET/CT demonstrated high PSMA expression in all patients. After therapy, patients underwent quantitative SPECT/CT at 4, 24, and 96 h. Pharmacokinetic uptake and clearance at a voxel level were calculated and translated into absorbed dose using voxel S values. Volumes of interest were drawn on normal tissues and tumor to assess radiation dose, and a whole-body tumor dose was defined. Correlations between PSMA PET/CT parameters, dosimetry, and biochemical and therapeutic response were analyzed to identify relationships between absorbed dose, tumor burden, and patient physiology. Results: Mean absorbed dose to kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.39, 0.44, 0.58, 0.1, 0.06, and 0.11 Gy/MBq, respectively. Median whole-body tumor-absorbed dose was 11.55 Gy and correlated with prostate-specific antigen (PSA) response at 12 wk. A median dose of 14.1 Gy was observed in patients achieving a PSA decline of at least 50%, versus 9.6 Gy for those achieving a PSA decline of less than 50% (P < 0.01). Of 11 patients receiving a tumor dose of less than 10 Gy, only one achieved a PSA response of at least 50%. On screening PSMA PET, whole-body tumor SUVmean correlated with mean absorbed dose (r = 0.62), and SUVmax of the parotids correlated with absorbed dose (r = 0.67). There was an inverse correlation between tumor volume and mean dose to the parotids (r = -0.41) and kidneys (r = -0.43). The mean parotid dose was also reduced with increasing body mass (r = -0.41) and body surface area (r = -0.37). Conclusion:177Lu-PSMA-617 delivers high absorbed doses to tumor, with a significant correlation between whole-body tumor dose and PSA response. Patients receiving less than 10 Gy were unlikely to achieve a fall in PSA of at least 50%. Significant correlations between aspects of screening 68Ga-PET/CT and tumor and normal tissue dose were observed, providing a rationale for patient-specific dosing. Reduced salivary and kidney doses were observed in patients with a higher tumor burden. The parotid dose also reduced with increasing body mass and body surface area.

Stereotactic Abative Body Radiotherapy (SABR) for Oligometastatic Prostate Cancer: A Prospective Clinical Trial.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is an emerging treatment option for oligometastatic prostate cancer. However, limited prospective evidence is available. OBJECTIVE: To determine the safety and feasibility of single fraction SABR for patients with oligometastatic prostate cancer. Secondary endpoints were local and distant progression-free survival (LPFS and DPFS), toxicity, quality of life (QoL), and prostate-specific antigen response. DESIGN, SETTING, AND PARTICIPANTS: In a prospective clinical trial, patients were screened with computed tomography, bone scan, and sodium fluoride positron emission tomography scan and had one to three oligometastases. Kaplan-Meier methods were used to determine LPFS and DPFS. Toxicity was graded using Common Terminology Criteria for Adverse Event version 4.0. QoL was assessed using European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-BM22 at 1, 3,12, and 24 mo. INTERVENTION: A single fraction of 20-Gy SABR to each lesion. RESULTS AND LIMITATIONS: Between 2013 and 2014, 33 consecutive patients received SABR to a total of 50 oligometastases and were followed for 2 yr. The median age was 70 yr. The Gleason score was ≥8 in 15 patients (45%). Twenty patients had bone only, 12 had node only, and one had mixed disease. SABR was feasible and delivered as planned in 97% of cases. There was one grade 3 adverse event (3.0%, vertebral fracture). No patient died. The 1 and 2-yr LPFS was 97% (95% confidence interval [CI]: 91-100) and 93% (95% CI: 84-100), and DPFS was 58% (95% CI: 43-77) and 39% (95% CI: 25-60), respectively. In those not on androgen deprivation therapy (ADT; n=22), the 2-yr freedom from ADT was 48%. There was no significant difference from baseline QoL observed. Limitations include small sample size, limited duration of follow-up, and lack of a control arm. CONCLUSIONS: A single SABR session was feasible and associated with low morbidity in this cohort. Over one-third of patients did not progress and were free from ADT at 2-yr. QoL measures were maintained with this treatment strategy. PATIENT SUMMARY: This clinical trial investigated single treatment stereotactic radiotherapy for low volume advanced prostate cancer. The approach was found to be safe with avoidance of hormone therapy in almost half of the participants at 2 yr.

[177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study.

BACKGROUND: Progressive metastatic castration-resistant prostate cancer is a highly lethal disorder and new effective therapeutic agents that improve patient outcomes are urgently needed. Lutetium-177 [177Lu]-PSMA-617, a radiolabelled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA) enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer. We aimed to investigate the safety, efficacy, and effect on quality of life of [177Lu]-PSMA-617 in men with metastatic castration-resistant prostate cancer who progressed after standard treatments. METHODS: In this single-arm, single-centre, phase 2 trial, we recruited men (aged 18 years and older) with metastatic castration-resistant prostate cancer and progressive disease after standard treatments, including taxane-based chemotherapy and second-generation anti-androgens, from the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Patients underwent a screening PSMA and FDG-PET/CT to confirm high PSMA-expression. Eligible patients had progressive disease defined by imaging (according to Response Evaluation Criteria In Solid Tumours [RECIST] or bone scan) or new pain in an area of radiographically evident disease, and were required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or lower. Eligible patients received up to four cycles of intravenous [177Lu]-PSMA-617, at six weekly intervals. The primary endpoint was PSA response according to Prostate Cancer Clinical Trial Working Group criteria defined as a greater than 50% PSA decline from baseline and toxicity according to CTCAE. Additional primary endpoints were imaging responses (as measured by bone scan, CT, PSMA, and FDG PET/CT) and quality of life (assessed with the EORTC-Q30 and Brief Pain Inventory-Short Form questionnaires), all measured up to 3 months post completion of treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number 12615000912583. FINDINGS: Between Aug 26, 2015, and Dec 8, 2016, 43 men were screened to identify 30 patients eligible for treatment. 26 (87%) had received at least one line of previous chemotherapy (80% docetaxel and 47% cabazitaxel) and 25 (83%) received prior abiraterone acetate, enzalutamide, or both. The mean administered radioactivity was 7·5 GBq per cycle. 17 (57%) of 30 patients (95% CI 37-75) achieved a PSA decline of 50% or more. There were no treatment-related deaths. The most common toxic effects related to [177Lu]-PSMA-617 were grade 1 dry mouth recorded in 26 (87%) patients, grade 1 and 2 transient nausea in 15 (50%), and G1-2 fatigue in 15 (50%). Grade 3 or 4 thrombocytopenia possibly attributed to [177Lu]-PSMA-617 occurred in four (13%) patients. Objective response in nodal or visceral disease was reported in 14 (82%) of 17 patients with measurable disease. Clinically meaningful improvements in pain severity and interference scores were recorded at all timepoints. 11 (37%) patients experienced a ten point or more improvement in global health score by the second cycle of treatment. INTERPRETATION: Our findings show that radionuclide treatment with [177Lu]-PSMA-617 has high response rates, low toxic effects, and reduction of pain in men with metastatic castration-resistant prostate cancer who have progressed after conventional treatments. This evidence supports the need for randomised controlled trials to further assess efficacy compared with current standards of care. FUNDING: None.

Prostate-specific membrane antigen theranostics: therapy with lutetium-177.

PURPOSE OF REVIEW: Prostate-specific membrane antigen (PSMA) theranostics offers a new approach for a personalized and targeted treatment for metastatic prostate cancer. Lutetium-177-labelled PSMA-ligands (Lu-PSMA) is a radionuclide therapy that is directed to PSMA expressing prostate cancer. Clinical experience with Lu-PSMA in men with advanced prostate cancer is growing. The purpose of this review is to outline the mechanism of action of this therapy, summarize recent efficacy and toxicity data and highlight future direction and challenges in establishing Lu-PSMA treatment as part of routine clinical practice. RECENT FINDINGS: The first reports on safety and efficacy of Lu-PSMA have been retrospective series of men with advanced prostate cancer who previously failed conventional therapies and received Lu-PSMA on compassionate basis. These studies highlight promising efficacy, favourable toxicity profile and quality of life improvements. Limitation stem from the retroospective nature of these data with short follow-up. SUMMARY: Several studies suggest that radionuclide therapy with Lu-PSMA has high activity and is well tolerated. Crucial to establishing this treatment in routine clinical management will be the generation of high-level evidence from prospective trials that can confirm the encouraging patient outcomes reported to date.

Effect of androgen deprivation therapy on the contractile properties of type I and type II skeletal muscle fibres in men with non-metastatic prostate cancer.

The contractile properties of vastus lateralis muscle fibres were examined in prostate cancer (PrCa) patients undergoing androgen deprivation therapy (ADT) and in age- and activity-matched healthy male subjects (Control). Mechanically-skinned muscle fibres were exposed to a sequence of heavily Ca2+ -buffered solutions at progressively higher free [Ca2+ ] to determine their force-Ca2+ relationship. Ca2+ -sensitivity was decreased in both type I and type II muscle fibres of ADT subjects relative to Controls (by -0.05 and -0.04 pCa units, respectively, P < .02), and specific force was around 13% lower in type I fibres of ADT subjects than in Controls (P = .02), whereas there was no significant difference in type II fibres. Treatment with the reducing agent dithiothreitol slightly increased specific force in type I and type II fibres of ADT subjects (by ~2%-3%, P < .05) but not in Controls. Pure type IIx fibres were found frequently in muscle from ADT subjects but not in Controls, and the overall percentage of myosin heavy chain IIx in muscle samples was 2.5 times higher in ADT subjects (P < .01). The findings suggest that testosterone suppression can negatively impact the contractile properties by (i) reducing Ca2+ -sensitivity in both type I and type II fibres and (ii) reducing maximum specific force in type I fibres.