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For prostate cancer patients who experience biochemical progression during androgen deprivation therapy (ADT), prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) has not been prospectively compared to planar bone scan plus CT. This was a single-arm, head-to-head, prospective phase II trial (NCT04928820) designed to enroll 102 men with prostate cancer who experienced biochemical progression (rising prostate-specific antigen [PSA] ≥ 1 ng/mL) during ADT. All patients received 68Ga-PSMA-11 PET/CT and 99mTc-MDP planar bone scans. Each scan was interpreted by three central independent readers. The primary endpoint was the per-patient bone metastasis detection rate of PSMA PET/CT versus planar bone scan and CT. Secondary endpoints compared the number of bone metastases detected per patient and the inter-reader agreement of each imaging modality. Twenty-two men were enrolled between July 2021 and June 2022. Due to slow accrual following approval of PSMA PET radiotracers in the U.S. and a lack of a statistical signal between the two imaging modalities on interim analysis, this trial was closed early on October 2022. Median PSA was 8.5 ng/mL (interquartile range: 1.6-77.6). There was 100% agreement between the two scans. Six patients (27%) had negative findings and 16 patients (73%) had positive findings on both scans. PSMA PET/CT and bone scan plus CT detected an equal number of bone lesions for 14 patients (64%), PSMA PET/CT detected more bone lesions for six patients (27%), and bone scan plus CT detected more bone lesions for two patients (9.1%) (p = 0.092). The inter-reader agreement rates of PSMA PET/CT and bone scan plus CT were 96% and 82%, respectively (p = 0.25). In men with biochemical progression during ADT, 68Ga-PSMA-11 PET/CT and 99mTc-MDP planar bone scan plus CT had identical bone metastasis detection rates. Bone scan plus CT can continue to serve as a cost-effective and readily accessible restaging modality in patients with biochemical progression. ClinicalTrials.gov NCT04928820. Registered 16/06/2021.

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide association study (GWAS) summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p 0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine-mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.

Nearly all men with metastatic hormone-sensitive prostate cancer treated with intermittent androgen deprivation therapy (ADT) experience recurrence within 6 mo of testosterone recovery. We conducted a single-arm phase 2 trial to evaluate whether addition of dual androgen receptor pathway inhibitors (ARPIs) and metastasis-directed stereotactic body radiotherapy (SBRT) to intermittent ADT improves recurrence rates for men with between one and five nonvisceral, extrapelvic metastases on prostate-specific membrane antigen positron emission tomography/computed tomography after prior radical prostatectomy. Patients received 6 mo of androgen annihilation therapy (AAT; leuprolide, abiraterone acetate plus prednisone, and apalutamide) and metastasis-directed SBRT. The primary endpoint was the percentage of patients with prostate-specific antigen (PSA)

BACKGROUND: Nearly one-third of patients with prostate cancer (PCa) experience biochemical recurrence (BCR) after primary definitive treatment. BCR increases the risk of distant metastasis and mortality in patients with prognostically unfavorable features. These patients are best managed with a tailored treatment strategy incorporating risk stratification using clinicopathological factors, next-generation imaging, and genomic testing. OBJECTIVE: This narrative review examines the utility of risk stratification for the management of patients with BCR in the context of clinical trial data, referencing the latest recommendations by European and US medical societies. METHODS: PubMed was searched for relevant studies published through May 21 2023 on treatment of patients with BCR after radical prostatectomy (RP) or external beam radiotherapy (EBRT). RESULTS: European and US guidelines support the risk-stratified management of BCR. Post-RP, salvage EBRT (with or without androgen deprivation therapy [ADT]) is an accepted treatment option for patients with BCR. Post-EBRT, local salvage therapies (RP, cryotherapy, high-intensity focused ultrasound, stereotactic body radiotherapy, and low-dose-rate and high-dose-rate brachytherapy) have demonstrated comparable relapse-free survival rates but differing adverse event profiles, short and long term. Local salvage therapies should be used for local-only relapses while ADT should be considered for regional or distant relapses. In practice, patients often receive ADT, with varying guidance for intermittent ADT vs. continuous ADT, due to consideration of quality-of-life effects. CONCLUSIONS: Despite a lack of consensus for BCR treatment among guideline associations and medical societies, risk stratification of patients is essential for personalized treatment approaches, as it allows for an informed selection of therapeutic strategies and estimation of adverse events. In lower-risk disease, observation is recommended while in higher-risk disease, after failed repeat local therapy, ADT and/or clinical trial enrollment may be appropriate. Results from ongoing clinical studies of patients with BCR should provide consensus for management.

BACKGROUND: Biochemical recurrence (BCR) following primary interventional treatment occurs in approximately one-third of patients with prostate cancer (PCa). Next-generation imaging (NGI) can identify local and metastatic recurrence with greater sensitivity than conventional imaging, potentially allowing for more effective interventions. This narrative review examines the current clinical evidence on the utility of NGI for patients with BCR. METHODS: A search of PubMed was conducted to identify relevant publications on NGI applied to BCR. Given other relevant recent reviews on the topic, this review focused on papers published between January 2018 to May 2023. RESULTS: NGI technologies, including positron emission tomography (PET) radiotracers and multiparametric magnetic resonance imaging, have demonstrated increased sensitivity and selectivity for diagnosing BCR at prostate-specific antigen (PSA) concentrations

We report our initial real-world experience with 177Lu-PSMA-617 radioligand therapy. Methods: We performed a retrospective review of patients treated with 177Lu-PSMA-617. Pretreatment PSMA PET, laboratory findings, overall survival, a fall in prostate-specific antigen by 50% (PSA50), and toxicities were evaluated. Results: Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%). Conclusion: At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from 177Lu-PSMA-617 radioligand therapy.

Opinion statementPSMA-PET has been a practice-changing imaging biomarker for the management of men with PCa. Research suggests improved accuracy over conventional imaging and other PET radiotracers in many contexts. With multiple approved PSMA-targeting radiotracers, PSMA PET will become even more available in clinical practice. Its increased use requires an understanding of the prospective data available and caution when extrapolating from prior trial data that utilized other imaging modalities. Future trials leveraging PSMA PET for treatment optimization and management decision-making will ultimately drive its clinical utility.

PURPOSE: To assess the diagnostic performance and utility of the ExoDx IntelliScore and an OPKO4K score to predict prostate cancer in men presenting with elevated PSA-both as independent predictors and in combination with clinical/MRI characteristics. METHODS: Patients with elevated PSA were retrospectively reviewed. Abnormal tests were defined as an OPKO4K score ≥ 7.5% and an ExoDx IntelliScore ≥ 15.6. Four regression models and ROC curves were generated based on: (1) age, PSA, and DRE, (2) model 1 + OPKO4K 4Kscore ≥ 7.5%, (3) model 2 + ExoDx IntelliScore ≥ 15.6, and (4) model 3 + MRI PIRADS 4-5. RESULTS: 359 men received an OPKO4K test, 307 had MRI and 113 had ExoDx tests. 163 men proceeded to prostate biopsy and 196 (55%) were saved from biopsy. Mean age was 65.0 ± 8.7 years and mean PSA was 7.1 ± 6.1 ng/mL. Positive biopsies were found in 84 (51.5%) men. The sensitivity and negative predictive value of an OPKO4K score were 86.7% and 72.3%; values for an ExoDx test were 76.5% and 77.1%, respectively. On regression analysis, clinical markers (Age, PSA, DRE) generated an AUC of 0.559. The addition of an OPKO4K score raised the AUC to 0.653. The stepwise addition of an ExoDx score raised the AUC to 0.766. The combined use of both biomarkers, patient characteristics, and MRI yielded an AUC of 0.825. CONCLUSION: This analysis demonstrates the high negative predictive value of both the OPKO4K score and ExoDX IntelliScore independently while demonstrating that the combination of an OPKO4K score, an ExoDX IntelliScore, and MRI increases predictive capability for biopsy confirmed prostate cancer.

Distinguishing indolent from clinically significant localized prostate cancer is a major clinical challenge and influences clinical decision-making between treatment and active surveillance. The development of novel predictive biomarkers will help with risk stratification, and clinical decision-making, leading to a decrease in over or under-treatment of patients with prostate cancer. Here, we report that Trop2 is a prognostic tissue biomarker for clinically significant prostate cancer by utilizing the Canary Prostate Cancer Tissue Microarray (CPCTA) cohort composed of over 1100 patients from a multi-institutional study. We demonstrate that elevated Trop2 expression is correlated with worse clinical features including Gleason score, age, and pre-operative PSA levels. More importantly, we demonstrate that elevated Trop2 expression at radical prostatectomy predicts worse overall survival in men undergoing radical prostatectomy. Additionally, we detect shed Trop2 in urine from men with clinically significant prostate cancer. Our study identifies Trop2 as a novel tissue prognostic biomarker and a candidate non-invasive marker for prostate cancer.

Prostate cancer is the second leading cause of cancer-related deaths in men in the United States. Imaging techniques such as CT, MRI, and bone scans have traditionally been used for diagnosis and staging. Molecular imaging modalities targeting the prostate-specific membrane antigen (PSMA) have recently gained attention due to their high affinity and accuracy. PSMA PET has been combined with other modalities such as multiparametric MRI for better diagnostic and prognostic performance. PSMA imaging has been studied at different clinical settings with a wide range of disease aggressiveness. In this review we will explore the role of PSMA PET in high-risk prostate cancer staging, biochemical recurrence, and castration-resistant prostate cancer. The primary focus of this review article is to examine the latest developments in the use of PSMA imaging and emphasize the clinical situations where its effectiveness has been demonstrated to significantly impact the treatment of prostate cancer. In addition, we will touch upon the potential future advancements of PSMA PET imaging and its evolving significance in the management of prostate cancer.

INTRODUCTION: Men with a detectable PSA after radical prostatectomy (RP) are often offered salvage therapy while those with an undetectable PSA are monitored. We aim to better characterize the natural history of men with an initially undetectable PSA who subsequently developed a detectable PSA > 6 months after RP. METHODS: Retrospective analysis of men who underwent RP for clinically localized prostate cancer at the University of California, San Francisco from 2000 to 2022. The primary outcome was biochemical recurrence, defined as 2 consecutive PSA > = 0.03 ng/mL starting 6 months after surgery. Secondary outcomes were salvage treatment, post-salvage treatment, metastasis free survival (MFS), prostate cancer specific mortality (PCSM), and all-cause mortality (ACM). This cohort was compared to a previously described cohort who had an immediately detectable post-operative PSA. RESULTS: From our cohort of 3348 patients, we identified 2868 men who had an undetectable post-op PSA. Subsequently, 642 men had a delayed detectable PSA at a median of 25 months (IQR 15, 43) with median follow-up of 72 months after RP. PSA at time of failure was  6 months post-operatively may have excellent long-term outcomes, even in the absence of salvage therapy.

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendalls tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendalls tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.

BACKGROUND: Grade Group 1 (GG1) prostate cancer should be managed with active surveillance (AS). Global uptake of AS remains disappointingly slow and heterogeneous. Removal of cancer labels has been proposed to reduce GG1 overtreatment. We sought to determine the impact of GG1 disease terminology on individuals perceptions and decision making. METHODS: Discrete choice experiments were conducted on 3 cohorts: healthy men, canonical partners (partners), and patients with GG1 (patients). Participants reported preferences in a series of vignettes with 2 scenarios each, permuting key opinion leader-endorsed descriptors: biopsy (adenocarcinoma, acinar neoplasm, prostatic acinar neoplasm of low malignant potential [PAN-LMP], prostatic acinar neoplasm of uncertain malignant potential), disease (cancer, neoplasm, tumor, growth), management decision (treatment, AS), and recurrence risk (6%, 3%, 1%,

BACKGROUND: The Cancer Epitope Database and Analysis Resource (CEDAR) is a newly developed repository of cancer epitope data from peer-reviewed publications, which includes epitope-specific T cell, antibody, and MHC ligand assays. Here we focus on prostate cancer as our first cancer category to demonstrate the capabilities of CEDAR, and to shed light on the advances of epitope-related prostate cancer research. RESULTS: The meta-analysis focused on a subset of data describing epitopes from 8 prostate-specific (PS) antigens. A total of 460 epitopes were associated with these proteins, 187 T cell, 109B cell, and 271 MHC ligand epitopes. The number of epitopes was not correlated with the length of the protein; however, we found a significant positive correlation between the number of references per specific PS antigen and the number of reported epitopes. Forty-four different class I and 27 class II restrictions were found, with the most epitopes described for HLA-A*02:01 and HLA-DRB1*01:01. Cytokine assays were mostly limited to IFNg assays and a very limited number of tetramer assays were performed. Monoclonal and polyclonal B cell responses were balanced, with the highest number of epitopes studied in ELISA/Western blot assays. Additionally, epitopes were generically described as associated with prostate cancer, with little granularity specifying diseases state. We found that in vivo and tumor recognition assays were sparse, and the number of epitopes with annotated B/T cell receptor information were limited. Potential immunodominant regions were identified by the use of the ImmunomeBrowser tool. CONCLUSION: CEDAR provides a comprehensive repository of epitopes related to prostate-specific antigens. This inventory of epitope data with its wealth of searchable T cell, B cell and MHC ligand information provides a useful tool for the scientific community. At the same time, we identify significant knowledge gaps that could be addressed by experimental analysis.

BACKGROUND: Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. METHODS: We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. FINDINGS: Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2-21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35-76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. INTERPRETATION: A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. FUNDING: Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck.

Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) is a promising option for metastatic castration-resistant prostate cancer. Clinical experience using 177Lu or 225Ac has demonstrated encouraging treatment responses; however, responses are not durable. Dual-isotope combinations, or tandem approaches, may improve tolerability while retaining a high tumor dose. In this study, we directly compared α- versus β-particle treatment, as well as a combination thereof, at different stages of disease in a murine model of disseminated prostate cancer. Methods: First, to determine comparable injected activities from 177Lu- and 225Ac-PSMA-617, ex vivo biodistribution studies were performed at 5 time points after treatment of C4-2 subcutaneous tumor-bearing NSG mice. To establish a more representative model of metastatic prostate cancer, NSG mice were inoculated with luciferase-expressing C4-2 cells in the left ventricle, leading to disseminated visceral and bone lesions. At either 3 or 5 wk after inoculation, the mice were treated with equivalent tumor dose-depositing activities of 177Lu- or 225Ac-PSMA-617 alone or in combination (35 MBq of 177Lu, 40 kBq of 225Ac, or 17 MBq of 177Lu + 20 kBq 225Ac; 10/group). Disease burden was assessed by weekly bioluminescence imaging. Treatment efficacy was evaluated using whole-body tumor burden and overall survival. Results: The ex vivo biodistribution studies revealed that 35 MBq of 177Lu and 40 kBq of 225Ac yield equivalent absorbed tumor doses in a subcutaneous C4-2 model. The disease burden of mice treated at 3 wk after inoculation (microscopic disease) with 177Lu was not significantly different from that of untreated mice. However, 225Ac-PSMA-617 both as a single agent and in combination with 177Lu (17 MBq of 177Lu + 20 kBq of 225Ac) were associated with significant whole-body tumor growth retardation and survival benefit (overall survival, 8.3 wk for nontreatment, 9.4 wk for 177Lu, 15.3 wk for 225Ac alone, and 14.1 wk for tandem therapy). When treated at 5 wk after inoculation (macroscopic disease), all treatment groups showed retarded tumor growth and improved survival, with no significant differences between 225Ac alone and administration of half the 225Ac activity in tandem with 177Lu (overall survival, 7.9 wk for nontreatment, 10.3 wk for 177Lu, 14.6 wk for 225Ac alone, and 13.2 wk for tandem therapy). Conclusion: Treatment of a disseminated model of prostate cancer with simultaneous 225Ac- and 177Lu-PSMA-617 results in significantly decreased tumor growth compared with 177Lu, which was ineffective as a single agent against microscopic lesions. Mice treated later in the disease progression and bearing macroscopic, millimeter-sized lesions experienced significant tumor growth retardation and survival benefit in both monoisotopic and tandem regimens of 177Lu and 225Ac. Although the greatest benefits were observed with the single agent 225Ac, the tandem arm experienced no significant difference in disease burden or survival benefit, suggesting that the reduced activity of 225Ac was adequately compensated in the tandem arm. The superior therapeutic efficacy of 225Ac in this model suggests a preference for α-emitters alone, or possibly in combination, in the microscopic disease setting.

PURPOSE: Intermediate-risk prostate cancer is a heterogeneous disease state with diverse treatment options. The 22-gene Decipher genomic classifier (GC) retrospectively has shown to improve risk stratification in these patients. We assessed the performance of the GC in men with intermediate-risk disease enrolled in NRG Oncology/RTOG 01-26 with updated follow-up. METHODS AND MATERIALS: After National Cancer Institute approval, biopsy slides were collected from NRG Oncology/RTOG 01-26, a randomized phase 3 trial of men with intermediate-risk prostate cancer randomized to 70.2 Gy versus 79.2 Gy of radiation therapy without androgen deprivation therapy. RNA was extracted from the highest-grade tumor foci to generate the locked 22-gene GC model. The primary endpoint for this ancillary project was disease progression (composite of biochemical failure, local failure, distant metastasis, prostate cancer-specific mortality, and use of salvage therapy). Individual endpoints were also assessed. Fine-Gray or cause-specific Cox multivariable models were constructed adjusting for randomization arm and trial stratification factors. RESULTS: Two-hundred fifteen patient samples passed quality control for analysis. The median follow-up was 12.8 years (range, 2.4-17.7). On multivariable analysis, the 22-gene GC (per 0.1 unit) was independently prognostic for disease progression (subdistribution hazard ratio [sHR], 1.12; 95% confidence interval [CI], 1.00-1.26; P = .04), biochemical failure (sHR, 1.22; 95% CI, 1.10-1.37; P < .001), distant metastasis (sHR, 1.28; 95% CI, 1.06-1.55; P = .01), and prostate cancer-specific mortality (sHR, 1.45; 95% CI, 1.20-1.76; P < .001). Ten-year distant metastasis in GC low-risk patients was 4% compared with 16% for GC high-risk patients. In patients with lower GC scores, the 10-year difference in metastasis-free survival rate between arms was -7%, compared with 21% for higher GC patients (P-interaction = .04). CONCLUSIONS: This study represents the first validation of a biopsy-based gene expression classifier, assessing both its prognostic and predictive value, using data from a randomized phase 3 trial of intermediate-risk prostate cancer. Decipher improves risk stratification and can aid in treatment decision-making in men with intermediate-risk disease.

Purpose/objective(s)Radiographic MRI response following prostate radiotherapy, particularly stereotactic body radiotherapy (SBRT), remains poorly understood. Our objective was to describe radiographic changes to the prostate gland and prostate tumor following SBRT of men treated on a prospective, randomized trial.Materials/methodsMIRAGE (NCT04384770) is a single center, randomized phase III trial of patients receiving either CT or MRI guided SBRT for localized prostate cancer. Patients underwent pre-treatment and annual post-treatment MRIs, in addition to routine PSA surveillance. Outcomes reported include percent gland shrinkage, percent PSA response at one year, and presence of residual tumor based on radiographic interpretation. Patient characteristics were compared via two-sample t-test or Fischer's exact test. Both univariate and multivariable logistical analysis were employed to identify potential clinical predictors of residual tumor on 1-year follow up MRI.ResultsThis study cohort included 94 eligible patients with baseline characteristics in Table 1. Residual lesions were seen in 13 patients (14%), 5/27 (18.5%) treated without ADT and 8/67 (12%) with ADT. PSA ablation was deep, with a 79% median decrease without ADT and 98% median decrease with ADT. Patients receiving ADT showed more gland shrinkage (17% vs. 34% shrinkage, p = 0.0001), while radiographic non-responders and responders experienced similar gland shrinkage (median 21% vs 29% shrinkage, p > 0.05). No significant clinical predictors of residual tumor were identified on univariate and multivariate analysis. No patient had any clinical or biochemical evidence of failure.ConclusionA total of 14% of patients were found to have residual tumor detected on MRI one year after SBRT. These data highlight the protracted nature of radiographic tumor response to radiation therapy, even with ablative radiation techniques. The analysis is limited by the lack of biopsy data to quantify whether visualized residual tumor harbor active cancer.

BACKGROUND: Early endpoints in clinical trials of high-risk localized prostate cancer (HRLPC) that resemble those monitored in real-world practice could expedite clinical development. OBJECTIVE: To assess the association of prostate-specific antigen (PSA) recurrence (PSA-R)-based early endpoints with metastasis-free survival (MFS), overall survival (OS), and prostate cancer (PC)-specific survival (PCSS), and to identify clinically undetectable disease. DESIGN, SETTING, AND PARTICIPANTS: A post hoc analysis of patients with HRLPC from Radiation Therapy Oncology Group studies 9202, 9902, and 0521 was performed. INTERVENTION: Long-term adjuvant androgen-deprivation therapy (ADT) and post-primary definitive radiotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Event-free survival (EFS; PSA-R, locoregional recurrence [LRR], distant metastasis [DM], or death), biochemical failure (PSA-R), general clinical failure (PSA-R, LRR, DM, ADT initiation, or death), and no evidence of disease (NED; alive patients without PSA-R, LRR, DM, and subsequent PC therapy, and with testosterone recovery) were assessed for association with MFS, OS, and PCSS using correlation and landmark analyses, Kaplan-Meier method, and Cox proportional-hazard model. PSA-R was defined as PSA nadir + 2 ng/ml; PSA nadir + 2 ng/ml and rising; PSA >5, 10, and 25 ng/ml; or PSA doubling time (PSADT) 5 ng/ml was associated with MFS, OS, and PCSS. No development of EFS with PSADT 5 ng/ml, or PSADT

BACKGROUND: The prognosis of diabetic men with advanced prostate cancer is poorly understood and understudied. Hence, we studied associations between diabetes and progression to metastases, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). METHODS: Data from men diagnosed with nmCRPC between 2000 and 2017 at 8 Veterans Affairs Health Care Centers were analyzed using Cox regression to determine HRs and 95% confidence intervals (CI) for associations between diabetes and outcomes. Men with diabetes were classified according to: (i) ICD-9/10 codes only, (ii) two HbA1c values > 6.4% (missing ICD-9/10 codes), and (iii) all diabetic men [(i) and (ii) combined]. RESULTS: Of 976 men (median age: 76 years), 304 (31%) had diabetes at nmCRPC diagnosis, of whom 51% had ICD-9/10 codes. During a median follow-up of 6.5 years, 613 men were diagnosed with metastases, and 482 PCSM and 741 ACM events occurred. In multivariable-adjusted models, ICD-9/10 code-identified diabetes was inversely associated with PCSM (HR, 0.67; 95% CI, 0.48-0.92) while diabetes identified by high HbA1c values (no ICD-9/10 codes) was associated with an increase in ACM (HR, 1.41; 95% CI, 1.16-1.72). Duration of diabetes, prior to CRPC diagnosis was inversely associated with PCSM among men identified by ICD-9/10 codes and/or HbA1c values (HR, 0.93; 95% CI, 0.88-0.98). CONCLUSIONS: In men with late-stage prostate cancer, ICD-9/10 code-identified diabetes is associated with better overall survival than undiagnosed diabetes identified by high HbA1c values only. IMPACT: Our data suggest that better diabetes detection and management may improve survival in late-stage prostate cancer.

BACKGROUND: Management of localized or recurrent prostate cancer since the 1990s has been based on risk stratification using clinicopathological variables, including Gleason score, T stage (based on digital rectal exam), and prostate-specific antigen (PSA). In this study a novel prognostic test, the Decipher Prostate Genomic Classifier (GC), was used to stratify risk of prostate cancer progression in a US national database of men with prostate cancer. METHODS: Records of prostate cancer cases from participating SEER (Surveillance, Epidemiology, and End Results) program registries, diagnosed during the period from 2010 through 2018, were linked to records of testing with the GC prognostic test. Multivariable analysis was used to quantify the association between GC scores or risk groups and use of definitive local therapy after diagnosis in the GC biopsy-tested cohort and postoperative radiotherapy in the GC-tested cohort as well as adverse pathological findings after prostatectomy. RESULTS: A total of 572 545 patients were included in the analysis, of whom 8927 patients underwent GC testing. GC biopsy-tested patients were more likely to undergo active active surveillance or watchful waiting than untested patients (odds ratio [OR] =2.21, 95% confidence interval [CI] = 2.04 to 2.38, P

BACKGROUND: Androgen deprivation therapy (ADT) with radiotherapy can benefit patients with localized prostate cancer. However, ADT can negatively impact quality of life, and there remain no validated predictive models to guide its use. METHODS: We used digital pathology images from pretreatment prostate tissue and clinical data from 5727 patients enrolled in five phase 3 randomized trials, in which treatment was radiotherapy with or without ADT, as our data source to develop and validate an artificial intelligence (AI)–derived predictive patient-specific model that would determine which patients would develop the primary end point of distant metastasis. The model used baseline data to provide a binary output that a given patient will likely benefit from ADT or not. After the model was locked, validation was performed using data from NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9408 (n=1594), a trial that randomly assigned men to radiotherapy plus or minus 4 months of ADT. Fine–Gray regression and restricted mean survival times were used to assess the interaction between treatment and the predictive model and within predictive model–positive, i.e., benefited from ADT, and –negative subgroup treatment effects. RESULTS: Overall, in the NRG/RTOG 9408 validation cohort (14.9 years of median follow-up), ADT significantly improved time to distant metastasis. Of these enrolled patients, 543 (34%) were model positive, and ADT significantly reduced the risk of distant metastasis compared with radiotherapy alone. Of 1051 patients who were model negative, ADT did not provide benefit. CONCLUSIONS: Our AI-based predictive model was able to identify patients with a predominantly intermediate risk for prostate cancer likely to benefit from short-term ADT. (Supported by a grant [U10CA180822] from NRG Oncology Statistical and Data Management Center, a grant [UG1CA189867] from NCI Community Oncology Research Program, a grant [U10CA180868] from NRG Oncology Operations, and a grant [U24CA196067] from NRG Specimen Bank from the National Cancer Institute and by Artera, Inc. ClinicalTrials.gov numbers NCT00767286, NCT00002597, NCT00769548, NCT00005044, and NCT00033631.)

BACKGROUND: De novo neuroendocrine prostate cancer (NEPC) and treatment-emergent neuroendocrine prostate cancer (T-NEPC) are rare diseases with a poor prognosis. After first-line platinum chemotherapy, there is no consensus on second-line treatments. PATIENTS AND METHODS: Patients with a pathologic diagnosis of de novo NEPC or T-NEPC between 2000 and 2020 who received first-line platinum and any second-line systemic therapy were selected and standardized clinical data was collected via the electronic health record at each institution. The primary endpoint was overall survival (OS) based on second-line therapy. Secondary endpoints included objective response rate (ORR) to second-line therapy, PSA response, and time on treatment. RESULTS: Fifty-eight patients (32 de novo NEPC, 26 T-NEPC) from 8 institutions were included. At de novo NEPC or T-NEPC diagnosis, the overall cohort had a median age of 65.0 years (IQR 59.2-70.3) and median PSA of 3.0 ng/dL (IQR 0.6-17.9). Following first-line platinum chemotherapy, 21 patients (36.2%) received platinum chemotherapy, 10 (17.2%) taxane monotherapy, 11 (19.0%) immunotherapy, 10 (17.2%) other chemotherapy, and 6 (16.2%) other systemic therapy. Among 41 evaluable patients, the ORR was 23.5%. The mOS after start of second-line therapy was 7.4 months (95% CI 6.1-11.9). CONCLUSIONS: In this retrospective study, patients with de novo NEPC or T-NEPC who received second-line therapy were treated with wide variety of treatment regimens, reflecting the lack of consensus in this setting. Most patients received chemotherapy-based treatments. Overall prognosis was poor and ORR was low in the second line regardless of treatment choice.

Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [177Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that 177Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from 177Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [177Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis.

Lu-PSMA was approved in the USA for patients with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer already treated with androgen receptor pathway inhibition and taxane-based chemotherapy on the basis of results from VISION. Three limitations affected the control arm in VISION: choice of the standard of care was limited, some patients initially deemed ineligible for taxane later received it, and there was a high attrition rate. VISION is an example of the many challenges in modern oncology trials. The direct and indirect costs of Lu-PSMA also mean that this therapy is likely to be out of reach for many nations, deepening global inequities in health care access.

The aim of this study was to analyze the patterns of prostate bed (PB) recurrence in prostate cancer patients experiencing prostate-specific antigen (PSA) persistence (BCP) or biochemical recurrence (BCR) after radical prostatectomy using 68Ga-PSMA-11 PET/CT (68Ga-PSMA PET) in relation to the Radiation Therapy Oncology Group (RTOG) clinical target volumes (CTVs). Methods: This single-center, retrospective analysis included patients with BCP or BCR after radical prostatectomy and PB recurrence on 68Ga-PSMA PET. The PB recurrences were delineated by nuclear medicine physicians, the CTVs by radiation oncologists contouring guidelines on the 68Ga-PSMA PET, respectively, masked from each other. The coverage of the 68Ga-PSMA PET recurrence was categorized as PSMA recurrence completely covered, partially covered, or not covered by the RTOG-based CTV. Further, we evaluated the differences in PSMA recurrence patterns among patients with different 68Ga-PSMA PET staging (miTNM). Mann-Whitney U tests, the chi-square test, and Spearman (ρ) correlation analysis were used to investigate associations between CTV coverage and 68Ga-PSMA PET-based tumor volume, serum PSA levels, miTNM, and rectal/bladder involvement. Results: A total of 226 patients were included in the analysis; 127 patients had PSMA recurrence limited to the PB (miTrN0M0), 30 had pelvic nodal disease (miTrN1M0), 32 had extrapelvic disease (miTrN0M1), and 37 had both pelvic nodal disease and extrapelvic disease (miTrN1M1). In the miTrN0M0 cohort, the recurrence involved the rectal and bladder walls in 12 of 127 (9%) and 4 of 127 (3%), respectively. The PSMA-positive PB recurrences were completely covered by the CTV in 68 of 127 patients (53%), partially covered in 43 of 127 (34%), and not covered in 16 of 127 (13%). Full coverage was associated with a smaller tumor volume (P = 0.043), a lack of rectal/bladder wall involvement (P = 0.03), and lower miTNM staging (P = 0.035) but not with lower serum PSA levels (P = 0.979). Conclusion: Our study suggests that 68Ga-PSMA PET can be a valuable tool for guiding salvage radiation therapy (SRT) planning directed to the PB in the setting of postoperative BCR or BCP. These data should be incorporated into the redefinition of PB contouring guidelines.

Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P

BackgroundCurrently, follow-up protocols are applied equally to men on active surveillance (AS) for prostate cancer (PCa) regardless of findings at their initial follow-up biopsy. To determine whether less intensive follow-up is suitable following negative biopsy findings, we assessed the risk of converting to active treatment, any subsequent upgrading, volume progression (>33% positive cores), and serious upgrading (grade group >2) for negative compared with positive findings on initial follow-up biopsy.Methods13,161 men from 24 centres participating in the Global Action Plan Active Surveillance Prostate Cancer [GAP3] consortium database, with baseline grade group ≤2, PSA ≤ 20 ng/mL, cT-stage 1-2, diagnosed after 1995, and ≥1 follow-up biopsy, were included in this study. Risk of converting to treatment was assessed using multivariable mixed-effects survival regression. Odds of volume progression, any upgrading and serious upgrading were assessed using mix-effects binary logistic regression for men with ≥2 surveillance biopsies.Results27% of the cohort (n = 3590) had no evidence of PCa at their initial biopsy. Over 50% of subsequent biopsies in this group were also negative. A negative initial biopsy was associated with lower risk of conversion (adjusted hazard ratio: 0.45; 95% confidence interval [CI]: 0.42-0.49), subsequent upgrading (adjusted odds ratio [OR]: 0.52; 95%CI: 0.45-0.62) and serious upgrading (OR: 0.74; 95%CI: 0.59-92). Radiological progression was not assessed due to limited imaging data.ConclusionDespite heterogeneity in follow-up schedules, findings from this global study indicated reduced risk of converting to treatment, volume progression, any upgrading and serious upgrading among men whose initial biopsy findings were negative compared with positive. Given the low risk of progression and high likelihood of further negative biopsy findings, consideration should be given to decreasing follow-up intensity for this group to reduce unnecessary invasive biopsies.

Higher diagnostic accuracy, even if desirable, is not automatically associated with better outcomes. If used in settings validated with less sensitive imaging modalities, it is of paramount importance to prospectively ascertain that the higher sensitivity of prostate-specific antigen membrane-based imaging will benefit patients, and will probably not do harm.

BACKGROUND: There is an unmet clinical need for interventions to prevent disease progression in patients with localized prostate cancer on active surveillance (AS). OBJECTIVE: To determine the immunologic response to the PROSTVAC vaccine and the clinical indicators of disease progression in patients with localized prostate cancer on AS. DESIGN, SETTING, AND PARTICIPANTS: This was a phase 2, double-blind, randomized controlled trial in 154 men with low- or intermediate-risk prostate cancer on AS. INTERVENTION: Participants were randomized (2:1) to receive seven doses of subcutaneous PROSTVAC, a vaccinia/fowlpox viral vector-based immunotherapy containing a prostate-specific antigen (PSA) transgene and three T-cell co-stimulatory molecules, or an empty fowlpox vector (EV) over 140 d. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the change from baseline in CD4 and CD8 T-cell infiltration in biopsy tumor tissue. Key secondary outcomes were safety and changes in prostate biopsy tumor pathology, peripheral antigen-specific T cells, and serum PSA. Continuous variables were compared using nonparametric tests. Categorical variables were compared using Fishers exact test. RESULTS AND LIMITATIONS: The PROSTVAC/EV vaccination was well tolerated. All except one participant completed the vaccination series. Changes in CD4 or CD8 density in biopsy tumor tissue did not differ between the PROSTVAC and EV arms. The proportions of patients with Gleason upgrading to grade group 3 after treatment was similar between the arms. There were no differences in postvaccination peripheral T-cell responses or the PSA change from baseline to 6-mo post-treatment follow-up between the groups. CONCLUSIONS: In this first-of-kind trial of immunotherapy in patients on AS for prostate cancer, PROSTVAC did not elicit more favorable prostate tissue or peripheral T-cell responses than the EV. There was no difference between the arms in clinicopathologic effects. Despite the null findings, this is the first study reporting the feasibility and acceptability of an immunotherapy intervention in the AS setting. PATIENT SUMMARY: We looked at responses after an experimental prostate cancer vaccine in patients with prostate cancer on active surveillance (AS). Participants who received the vaccine did not show more favorable outcomes than those receiving the control. Despite these findings, this is the first report showing the feasibility and acceptability of immunotherapy for prostate cancer in patients on AS.

PurposeBoth the performance characteristics of prostate-specific membrane antigen positron emission tomography and insurance approval improves with increasing prostate-specific antigen (PSA) level causing some physicians to delay post-radical prostatectomy salvage radiation therapy (sRT) after PSA failure. Yet, it is unknown for men with at most one high-risk factor (ie, pT3/4 or prostatectomy [p] Gleason score 8-10) whether a PSA level exists above which initiating sRT is associated with increased all-cause mortality (ACM)-risk and was investigated.MethodsUsing a multinational database of 25,551 patients with pT2-4N0 or NXM0 prostate cancer, multivariable Cox regression analysis evaluated whether an association with a significant increase in ACM-risk existed when sRT was delivered above a prespecified PSA level beginning at 0.10 ng/mL and in 0.05 increments up to 0.50 ng/mL versus at or below that level. The model was adjusted for age at and year of radical prostatectomy, established prostate cancer prognostic factors, institution, and the time-dependent use of androgen deprivation therapy.ResultsAfter a median follow-up of 6.00 years, patients who received sRT at a PSA level >0.25 ng/mL had a significantly higher ACM-risk (AHR, 1.49; 95% CI, 1.11 to 2.00; P = .008) compared with men who received sRT when the PSA was ≤0.25 mg/mL. This elevated ACM-risk remained significant for all PSA cutpoints up to 0.50 ng/mL but was not significant at PSA cutpoint values below 0.25 ng/mL.ConclusionAmong patients with at most one high-risk factor, initiating sRT above a PSA level of 0.25 ng/mL was associated with increased ACM-risk.

BACKGROUND: Americans Indians and Alaska Natives face disparities in cancer care with lower rates of screening, limited treatment access, and worse survival. Prostate cancer treatment access and patterns of care remain unknown. METHODS: We used Surveillance, Epidemiology, and End Results data to compare incidence, primary treatment, and cancer-specific mortality across American Indian and Alaska Native, Asian and Pacific Islander, Black, and White patients. Baseline characteristics included prostate-specific antigen (PSA), Gleason score (GS), tumor stage, 9-level Cancer of the Prostate Risk Assessment risk score, county characteristics, and health-care provider density. Primary outcomes were first definitive treatment and prostate cancer-specific mortality (PCSM). RESULTS: American Indian and Alaska Native patients were more frequently diagnosed with higher PSA, GS greater than or equal or 8, stage greater than or equal to cT3, high-risk disease overall (Cancer of the Prostate Risk Assessment risk score ≥ 6), and metastases at diagnosis than any other group. Adjusting for age, PSA, GS, and clinical stage, American Indian or Alaska Native patients with localized prostate cancer were more likely to undergo external beam radiation than radical prostatectomy and had the highest rates of no documented treatment. Five-year PCSM was higher among American Indian and Alaska Natives than any other racial group. However, after multivariable adjustment accounting for clinical and pathologic factors, county-level demographics, and provider density, American Indian and Alaska Native patient PCSM hazards were no different than those of White patients. CONCLUSIONS: American Indian or Alaska Native patients have more advanced prostate cancer, lower rates of definitive treatment, higher mortality, and reside in areas of less specialty care. Disparities in access appear to account for excess risks of PCSM. Focused health policy interventions are needed to address these disparities.

BackgroundPartial gland ablation (PGA) is a new option for treatment of prostate cancer (PCa). Cryotherapy, an early method of PGA, has had favorable evaluations, but few studies have employed a strict protocol using biopsy endpoints in men with clinically significant prostate cancer (csPCa).Methods143 men with unilateral csPCa were enrolled in a prospective, observational trial of outpatient PGA-cryotherapy. Treatment was a 2-cycle freeze of the affected prostate part. Participants were evaluated with MRI-guided biopsy (MRGB) at baseline and at 6 months and 18 months after treatment. Absence of csPCa upon MRGB was the primary endpoint; quality-of-life at baseline and at 6 months after treatment was assessed by EPIC-CP questionnaires in the domains of urinary and sexual function.ResultsOf the 143 participants, 136 (95%) completed MRGB at 6 months after treatment. In 103/136 (76%), the biopsy revealed no csPCa. Of the 103, 71 subsequently had an 18-month comprehensive biopsy; of the 71 with 18-month biopsies, 46 (65%) were found to have no csPCa. MRI lesions became undetectable in 96/130 (74%); declines in median serum PSA levels (6.9 to 2.5 ng/mL), PSA density (0.15 to 0.07), and prostate volume (42 to 34cc) were observed (all p

PSICHE (NCT05022914) is a prospective trial to test a [68Ga]Ga- PSMA-11 PET/CT imaging tailored strategy. All evaluable patients had biochemical relapse after surgery and underwent centralized [68Ga]Ga-PSMA-11 PET/CT imaging. The treatment was performed according pre-defined criteria. Observation and re-staging at further PSA progression were proposed to patients with negative PSMA and previous postoperative RT. Prostate bed SRT was proposed to all patients with a negative staging or positive imaging within prostate bed. Stereotactic body radiotherapy (SBRT) to all sites of disease was used for all patients with pelvic nodal recurrence (nodal disease

PurposeProstate cancer (PCa) screening, which relies on prostate-specific antigen (PSA) testing, is a contentious topic that received negative attention due to the low sensitivity and specificity of PSA to detect clinically significant PCa. In this context, due to the higher sensitivity and specificity of magnetic resonance imaging (MRI), several trials investigate the feasibility of "MRI-only" screening approaches, and question if PSA testing may be replaced within prostate cancer screening programs.MethodsThis narrative review discusses the current literature and the outlook on the potential of MRI-based PCa screening.ResultsSeveral prospective randomized population-based trials are ongoing. Preliminary study results appear to favor the "MRI-only" approach. However, MRI-based PCa screening programs face a variety of obstacles that have yet to be fully addressed. These include the increased cost of MRI, lack of broad availability, differences in MRI acquisition and interpretation protocols, and lack of long-term impact on cancer-specific mortality. Partly, these issues are being addressed by shorter and simpler MRI approaches (5-20 min bi-parametric MRI), novel quality indicators (PI-QUAL) and the implementation of radiomics (deep learning, machine learning).ConclusionAlthough promising preliminary results were reported, MRI-based PCa screening still lack long-term data on crucial endpoints such as the impact of MRI screening on mortality. Furthermore, the issues of availability, cost-effectiveness, and differences in MRI acquisition and interpretation still need to be addressed.

BackgroundGenetic scores may provide an objective measure of prostate cancer risk and thus inform screening decisions. We evaluated whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with prostate cancer risk in a diverse population, including Black men, who have higher average risk of prostate cancer death but are often treated as a homogeneously high-risk group.MethodsThis was a retrospective analysis of the Million Veteran Program, a national, population-based cohort study of US military veterans conducted 2011-2021. Cox proportional hazards analyses tested for association of genetic and other risk factors (including self-reported race and ethnicity and family history) with age at death from prostate cancer, age at diagnosis of metastatic (nodal or distant) prostate cancer, and age at diagnosis of any prostate cancer.ResultsA total of 590 750 male participants were included. Median age at last follow-up was 69 years. PHS290 was associated with fatal prostate cancer in the full cohort and for each racial and ethnic group (P

PurposeThe sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT).Materials and methodsIndividual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4-6 months) with RT for localized disease were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. Inverse probability of treatment weighting (IPTW) was performed with propensity scores derived from age, initial prostate-specific antigen, Gleason score, T stage, RT dose, and mid-trial enrollment year. Metastasis-free survival (primary end point) and overall survival (OS) were assessed by IPTW-adjusted Cox regression models, analyzed independently for men receiving PORT versus WPRT. IPTW-adjusted Fine and Gray competing risk models were built to evaluate distant metastasis (DM) and prostate cancer-specific mortality.ResultsOverall, 7,409 patients were included (6,325 neoadjuvant/concurrent and 1,084 concurrent/adjuvant) with a median follow-up of 10.2 years (interquartile range, 7.2-14.9 years). A significant interaction between ADT sequencing and RT field size was observed for all end points (P interaction < .02 for all) except OS. With PORT (n = 4,355), compared with neoadjuvant/concurrent ADT, concurrent/adjuvant ADT was associated with improved metastasis-free survival (10-year benefit 8.0%, hazard ratio [HR], 0.65; 95% CI, 0.54 to 0.79; P < .0001), DM (subdistribution HR, 0.52; 95% CI, 0.33 to 0.82; P = .0046), prostate cancer-specific mortality (subdistribution HR, 0.30; 95% CI, 0.16 to 0.54; P < .0001), and OS (HR, 0.69; 95% CI, 0.57 to 0.83; P = .0001). However, in patients receiving WPRT (n = 3,049), no significant difference in any end point was observed in regard to ADT sequencing except for worse DM (HR, 1.57; 95% CI, 1.20 to 2.05; P = .0009) with concurrent/adjuvant ADT.ConclusionADT sequencing exhibits a significant impact on clinical outcomes with a significant interaction with field size. Concurrent/adjuvant ADT should be the standard of care where short-term ADT is indicated in combination with PORT.

OBJECTIVE: To evaluate how blood levels of prostate-specific antigen (PSA) relate to prostate volume of benign tissue, Gleason pattern 3 (GP3) and Gleason pattern 4 (GP4) cancer. METHODS: The cohort included 2209 consecutive men undergoing radical prostatectomy at 2 academic institutions with pT2N0, Grade Group 1-4 prostate cancer and an undetectable postoperative PSA. Volume of benign, GP3, and GP4 were estimated. The primary analysis evaluated the association between PSA and volume of each type of tissue using multivariable linear regression. R2, a measure of explained variation, was calculated using a multivariable model. RESULTS: Estimated contribution to PSA was 0.04/0.06 ng/mL/cc for benign, 0.08/0.14 ng/mL/cc for GP3, and 0.62/0.80 ng/ml/cc for GP4 for the 2 independent cohorts, respectively. GP4 was associated with 6 to 8-fold more PSA per cc compared to GP3 and 15-fold higher compared to benign tissue. We did not observe a difference between PSA per cc for GP3 vs. benign tissue (P = 0.2). R2 decreased only slightly when removing age (0.006/0.018), volume of benign tissue (0.051/0.054) or GP3 (0.014/0.023) from the model. When GP4 was removed, R2 decreased 0.051/0.310. PSA density (PSA divided by prostate volume) was associated with volume of GP4 but not GP3, after adjustment for benign volume. CONCLUSION: Gleason pattern 4 cancer contributes considerably more to PSA and PSA density per unit volume compared to GP3 and benign tissue. Contributions from GP3 and benign are similar. Further research should examine the utility of determining clinical management recommendations by absolute volume of GP4 rather than the ratio of GP3 to GP4.

PurposeTo develop techniques and establish a workflow using hyperpolarized carbon-13 (13 C) MRI and the pyruvate-to-lactate conversion rate (kPL ) biomarker to guide MR-transrectal ultrasound fusion prostate biopsies.MethodsThe integrated multiparametric MRI (mpMRI) exam consisted of a 1-min hyperpolarized 13 C-pyruvate EPI acquisition added to a conventional prostate mpMRI exam. Maps of kPL values were calculated, uploaded to a picture archiving and communication system and targeting platform, and displayed as color overlays on T2 -weighted anatomic images. Abdominal radiologists identified 13 C research biopsy targets based on the general recommendation of focal lesions with kPL  >0.02(s-1 ), and created a targeting report for each study. Urologists conducted transrectal ultrasound-guided MR fusion biopsies, including the standard 1 H-mpMRI targets as well as 12-14 core systematic biopsies informed by the research 13 C-kPL targets. All biopsy results were included in the final pathology report and calculated toward clinical risk.ResultsThis study demonstrated the safety and technical feasibility of integrating hyperpolarized 13 C metabolic targeting into routine 1 H-mpMRI and transrectal ultrasound fusion biopsy workflows, evaluated via 5 men (median age 71 years, prostate-specific antigen 8.4 ng/mL, Cancer of the Prostate Risk Assessment score 2) on active surveillance undergoing integrated scan and subsequent biopsies. No adverse event was reported. Median turnaround time was less than 3 days from scan to 13 C-kPL targeting, and scan-to-biopsy time was 2 weeks. Median number of 13 C targets was 1 (range: 1-2) per patient, measuring 1.0 cm (range: 0.6-1.9) in diameter, with a median kPL of 0.0319 s-1 (range: 0.0198-0.0410).ConclusionsThis proof-of-concept work demonstrated the safety and feasibility of integrating hyperpolarized 13 C MR biomarkers to the standard mpMRI workflow to guide MR-transrectal ultrasound fusion biopsies.

BackgroundWe compared six commonly used logistic regression methods for accommodating missing risk factor data from multiple heterogeneous cohorts, in which some cohorts do not collect some risk factors at all, and developed an online risk prediction tool that accommodates missing risk factors from the end-user.MethodsTen North American and European cohorts from the Prostate Biopsy Collaborative Group (PBCG) were used for fitting a risk prediction tool for clinically significant prostate cancer, defined as Gleason grade group ≥ 2 on standard TRUS prostate biopsy. One large European PBCG cohort was withheld for external validation, where calibration-in-the-large (CIL), calibration curves, and area-underneath-the-receiver-operating characteristic curve (AUC) were evaluated. Ten-fold leave-one-cohort-internal validation further validated the optimal missing data approach.ResultsAmong 12,703 biopsies from 10 training cohorts, 3,597 (28%) had clinically significant prostate cancer, compared to 1,757 of 5,540 (32%) in the external validation cohort. In external validation, the available cases method that pooled individual patient data containing all risk factors input by an end-user had best CIL, under-predicting risks as percentages by 2.9% on average, and obtained an AUC of 75.7%. Imputation had the worst CIL (-13.3%). The available cases method was further validated as optimal in internal cross-validation and thus used for development of an online risk tool. For end-users of the risk tool, two risk factors were mandatory: serum prostate-specific antigen (PSA) and age, and ten were optional: digital rectal exam, prostate volume, prior negative biopsy, 5-alpha-reductase-inhibitor use, prior PSA screen, African ancestry, Hispanic ethnicity, first-degree prostate-, breast-, and second-degree prostate-cancer family history.ConclusionDevelopers of clinical risk prediction tools should optimize use of available data and sources even in the presence of high amounts of missing data and offer options for users with missing risk factors.

BackgroundProstate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.MethodsIn total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.ResultsThe final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.ConclusionsWe demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

PURPOSE: We assessed whether Prostate Health Index results improve prediction of grade reclassification for men on active surveillance. METHODS AND MATERIALS: We identified men in Canary Prostate Active Surveillance Study with Grade Group 1 cancer. Outcome was grade reclassification to Grade Group 2+ cancer. We considered decision rules to maximize specificity with sensitivity set at 95%. We derived rules based on clinical data (R1) vs clinical data+Prostate Health Index (R3). We considered an or-logic rule combining clinical score and Prostate Health Index (R4), and a 2-step rule using clinical data followed by risk stratification based on Prostate Health Index (R2). Rules were applied to a validation set, where values of R2-R4 vs R1 for specificity and sensitivity were evaluated. RESULTS: We included 1,532 biopsies (n = 610 discovery; n = 922 validation) among 1,142 men. Grade reclassification was seen in 27% of biopsies (23% discovery, 29% validation). Among the discovery set, at 95% sensitivity, R2 yielded highest specificity at 27% vs 17% for R1. In the validation set, R3 had best performance vs R1 with Δsensitivity = -4% and Δspecificity = +6%. There was slight improvement for R3 vs R1 for confirmatory biopsy (AUC 0.745 vs R1 0.724, ΔAUC 0.021, 95% CI 0.002-0.041) but not for subsequent biopsies (ΔAUC -0.012, 95% CI -0.031-0.006). R3 did not have better discrimination vs R1 among the biopsy cohort overall (ΔAUC 0.007, 95% CI -0.007-0.020). CONCLUSIONS: Among active surveillance patients, using Prostate Health Index with clinical data modestly improved prediction of grade reclassification on confirmatory biopsy and did not improve prediction on subsequent biopsies.

Our objective was to develop version 1.0 of a novel framework for response evaluation criteria in prostate-specific membrane antigen (PSMA) PET/CT (RECIP) and a composite response classification that combines responses by prostate-specific antigen (PSA) measurements and by RECIP 1.0 (PSA + RECIP). Methods: This was an international multicenter, retrospective study. One hundred twenty-four men with metastatic castration-specific prostate cancer (mCRPC) who underwent 177Lu-PSMA therapy and received PSMA PET/CT at baseline and at an interim time point of 12 wk were included. Pairs of baseline interim PET/CT scans were interpreted by consensus among 3 masked readers for appearance of new lesions. Tumor lesions were segmented, and total PSMA-positive tumor volume (PSMA-VOL) was obtained. Appearance of new lesions and changes in PSMA-VOL were combined to develop RECIP 1.0, which included classifications of complete response (RECIP-CR: absence of any PSMA-ligand uptake on interim PET/CT), partial response (RECIP-PR: decline ≥ 30% in PSMA-VOL and no appearance of new lesions), progressive disease (RECIP-PD: increase ≥ 20% in PSMA-VOL and appearance of new lesions), and stable disease (RECIP-SD: any condition but RECIP-PR or RECIP-PD). Changes in PSA levels at 12 wk by Prostate Cancer Working Group Criteria 3 were recorded. PSA + RECIP results were defined as response (PSA decline ≥ 50% or RECIP-PR/CR) or progression (PSA increase ≥ 25% or RECIP-PD). The study's primary outcome measure was the prognostic value of RECIP 1.0 for overall survival (OS). The secondary outcome measure was the prognostic accuracy (C-index) of PSA + RECIP versus PSA responses. Results: Patients with RECIP-PD (n = 39; 8.3 mo) had a shorter OS than patients with stable disease (RECIP-SD) (n = 47; 13.1 mo; P < 0.001) or RECIP-PR (n = 38; 21.7 mo; P < 0.001). In identifying responders and progressors, PSA + RECIP had C-indices superior to those of PSA only: 0.65 versus 0.62 (P = 0.028) and 0.66 versus 0.63 (P = 0.044), respectively. Conclusion: PSMA PET/CT by RECIP 1.0 is prognostic for OS and can be used as a response biomarker to monitor early efficacy of 177Lu-PSMA in men with mCRPC. PSA + RECIP may be used as a novel composite endpoint in mCRPC clinical trial design.

PurposeWith the improvement in overall survival with 177Lu-PSMA 617, radioligand therapy (RLT) is now a viable option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, responses are variable, in part due to low PSMA expression in 30% of patients. Herein, we evaluated whether the cell surface protein CUB domain-containing protein 1 (CDCP1) can be exploited to treat mCRPC with RLT, including in PSMA-low subsets.Experimental designCDCP1 levels were evaluated using RNA sequencing from 119 mCRPC biopsies. CDCP1 levels were assessed in 17 post-enzalutamide- or abiraterone-treated mCRPC biopsies, 12 patient-derived xenografts (PDX), and prostate cancer cell lines. 4A06, a recombinant human antibody that targets the CDCP1 ectodomain, was labeled with Zr-89 or Lu-177 and tested in tumor-bearing mice.ResultsCDCP1 expression was observed in 90% of mCRPC biopsies, including small-cell neuroendocrine (SCNC) and adenocarcinomas with low FOLH1 (PSMA) levels. Fifteen of 17 evaluable mCRPC biopsies (85%) demonstrated membranous CDCP1 expression, and 4 of 17 (23%) had higher CDCP1 H-scores compared with PSMA. CDCP1 was expressed in 10 of 12 PDX samples. Bmax values of approximately 22,000, 6,200, and 2,800 fmol/mg were calculated for PC3, DU145, and C4-2B human prostate cancer cells, respectively. 89Zr-4A06 PET detected six human prostate cancer xenografts, including PSMA-low tumors. 177Lu-4A06 significantly suppressed growth of DU145 and C4-2B xenografts.ConclusionsThe data provide the first evidence supporting CDCP1-directed RLT to treat mCRPC. Expanded studies are warranted to determine whether CDCP1 is a viable drug target for patients with mCPRC.

BackgroundMen with grade group 2 or 3 prostate cancer are often considered ineligible for active surveillance; some patients with grade group 2 prostate cancer who are managed with active surveillance will have early disease progression requiring radical therapy. This study aimed to investigate whether MRI-guided focused ultrasound focal therapy can safely reduce treatment burden for patients with localised grade group 2 or 3 intermediate-risk prostate cancer.MethodsIn this single-arm, multicentre, phase 2b study conducted at eight health-care centres in the USA, we recruited men aged 50 years and older with unilateral, MRI-visible, primary, intermediate-risk, previously untreated prostate adenocarcinoma (prostate-specific antigen ≤20 ng/mL, grade group 2 or 3; tumour classification ≤T2) confirmed on combined biopsy (combining MRI-targeted and systematic biopsies). MRI-guided focused ultrasound energy, sequentially titrated to temperatures sufficient for tissue ablation (about 60-70°C), was delivered to the index lesion and a planned margin of 5 mm or more of normal tissue, using real-time magnetic resonance thermometry for intraoperative monitoring. Co-primary outcomes were oncological outcomes (absence of grade group 2 and higher cancer in the treated area at 6-month and 24-month combined biopsy; when 24-month biopsy data were not available and grade group 2 or higher cancer had occurred in the treated area at 6 months, the 6-month biopsy results were included in the final analysis) and safety (adverse events up to 24 months) in all patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT01657942, and is no longer recruiting.FindingsBetween May 4, 2017, and Dec 21, 2018, we assessed 194 patients for eligibility and treated 101 patients with MRI-guided focused ultrasound. Median age was 63 years (IQR 58-67) and median concentration of prostate-specific antigen was 5·7 ng/mL (IQR 4·2-7·5). Most cancers were grade group 2 (79 [78%] of 101). At 24 months, 78 (88% [95% CI 79-94]) of 89 men had no evidence of grade group 2 or higher prostate cancer in the treated area. No grade 4 or grade 5 treatment-related adverse events were reported, and only one grade 3 adverse event (urinary tract infection) was reported. There were no treatment-related deaths.Interpretation24-month biopsy outcomes show that MRI-guided focused ultrasound focal therapy is safe and effectively treats grade group 2 or 3 prostate cancer. These results support focal therapy for select patients and its use in comparative trials to determine if a tissue-preserving approach is effective in delaying or eliminating the need for radical whole-gland treatment in the long term.FundingInsightec and the National Cancer Institute.

Biochemical recurrence develops in almost one-third of men with prostate cancer after treatment with local therapy. There are numerous options for management, including surveillance, salvage radiation, androgen deprivation therapy (ADT), and clinical trials. This article reviews the current approaches to radiation therapy, ADT, and molecular imaging in men with biochemically recurrent prostate cancer. First, radiation therapy, including selection of field, dose, and use of concurrent antiandrogen therapy, is reviewed. Next, molecular imaging is addressed, including prostate-specific membrane antigen PET imaging and its increased sensitivity in identifying sites of disease. Finally, the factors associated with starting ADT are explored, and the data supporting intermittent over continuous ADT are reviewed. Lastly, the use of prostate-specific membrane antigen PET imaging and its potential role influencing therapy are discussed.

AIM: Despite increasing use for the detection of biochemically recurrent prostate cancer (rPC), the diagnostic accuracy of positron emission tomography/computed tomography (PET/CT) with [18F]PSMA-1007 remains only partially investigated. The aim of this study was to determine the sensitivity (SE), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) for PC-local recurrence and metastases on a per region basis. MATERIALS AND METHODS: One hundred seventy-seven consecutive patients undergoing [18F]PSMA-1007 PET/CT for rPC were retrospectively analysed. Six body regions were defined: prostate fossa, pelvic lymph nodes (LN), retroperitoneal LN, supradiaphragmatic LN, bones, and soft tissue. A region was counted positive if at least one PSMA-positive lesion suspicious for PC was observed. Confirmation of a true-positive PSMA-avid lesion was defined as positive by histopathology, fall in serum prostate-specific antigen (PSA) (> 50%) after targeted therapy or confirmatory further CT, MRI, PET/CT, or bone scan imaging. Regions where additional imaging was able to confirm the absence of suspicious PC lesions or regions outside exclusively targeted RT with serum PSA decline (> 50%) were counted as true-negative regions. SE, SP, PPV, and NPV were calculated for all six regions. RESULTS: The overall PET-positivity rate was 91%. Conclusive follow-up for affirmation or refutation of a PSMA-positive lesion was available for 81/152 patients on a per region basis. In this subgroup, overall sensitivity, specificity, PPV, and NPV were 95% (CI: 0.90-0.98), 89% (CI: 0.83-0.93), 86% (0.80-0.90), and 96% (CI: 0.92-0.98), respectively. On a per region basis, PPV was 97% (CI: 0.83-0.99) for local recurrence, 93% (CI: 0.78-0.98) for pelvic LN, 87% (CI: 0.62-0.96) for retroperitoneal LN, 82% (CI: 0.52-0.95) for supradiaphragmatic LN, and 79% (0.65-0.89) for bone lesions. The number of solid organ metastases (n = 6) was too small for an accurate statistical analysis. CONCLUSION: The known high PET-positivity rate of [18F]PSMA-1007 PET/CT in rPC was confirmed, with corresponding high (> 90%) sensitivity and NPV on a per region basis. However, overall PPV was limited (86%), particularly for bone lesions (79%), which are a potential diagnostic weaknesses when using this tracer.

BACKGROUND: In men with a detectable prostate-specific antigen (PSA) level after prostatectomy for prostate cancer, salvage prostate bed radiotherapy (PBRT) results in about 70% of patients being free of progression at 5 years. A three-group randomised trial was designed to determine whether incremental gains in patient outcomes can be achieved by adding either 4-6 months of short-term androgen deprivation therapy (ADT) to PBRT, or both short-term ADT and pelvic lymph node radiotherapy (PLNRT) to PBRT. METHODS: The international, multicentre, randomised, controlled SPPORT trial was done at 283 radiation oncology cancer treatment centres in the USA, Canada, and Israel. Eligible patients (aged ≥18 years) were those who after prostatectomy for adenocarcinoma of the prostate had a persistently detectable or an initially undetectable and rising PSA of between 0·1 and 2·0 ng/mL. Patients with and without lymphadenectomy (N0/Nx) were eligible if there was no clinical or pathological evidence of lymph node involvement. Other eligibility criteria included pT2 or pT3 disease, prostatectomy Gleason score of 9 or less, and a Zubrod performance status of 0-1. Eligible patients were randomly assigned to receive PBRT alone at a dose of 64·8-70·2 Gy at 1·8 Gy per fraction daily (group 1), PBRT plus short-term ADT (group 2), or PLNRT (45 Gy at 1·8 Gy per fraction, and then a volume reduction made to the planning target volume for the remaining 19·8-25 ·2 Gy) plus PBRT plus short-term ADT (group 3). The primary endpoint was freedom from progression, in which progression was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A planned interim analysis of 1191 patents with minimum potential follow-up time of 5 years applied a Haybittle-Peto boundary of p3 months after radiotherapy) did not differ significantly between the groups, apart from more late grade 2 or worse blood or bone marrow events in group 3 versus group 2 (one-sided p=0·0060) attributable to the addition of PLNRT in this group. INTERPRETATION: The results of this randomised trial establish the benefit of adding short-term ADT to PBRT to prevent progression in prostate cancer. To our knowledge, these are the first such findings to show that extending salvage radiotherapy to treat the pelvic lymph nodes when combined with short-term ADT results in meaningful reductions in progression after prostatectomy in patients with prostate cancer. FUNDING: National Cancer Institute.

BackgroundThe optimal interval for repeat biopsy during active surveillance (AS) for prostate cancer is yet to be defined. This study examined whether risk of upgrading (to grade group ≥ 2) or risk of converting to treatment varied according to intensity of repeat biopsy using data from the GAP3 consortium's global AS database.Materials and methodsIntensity of surveillance biopsy schedules was categorized according to centers' protocols: (a) Prostate Cancer Research International Active Surveillance project (PRIAS) protocols with biopsies at years 1, 4, and 7 (10 centers; 7532 men); (b) biennial biopsies, that is, every other year (8 centers; 4365 men); and (c) annual biopsy schedules (4 centers; 1602 men). Multivariable Cox regression was used to compare outcomes according to biopsy intensity.ResultsOut of the 13,508 eligible participants, 56% were managed according to PRIAS protocols (biopsies at years 1, 4, and 7), 32% via biennial biopsy, and 12% via annual biopsy. After adjusting for baseline characteristics, risk of converting to treatment was greater for those on annual compared with PRIAS biopsy schedules (hazard ratio [HR] = 1.66; 95% confidence interval [CI] = 1.51-1.83; p

BackgroundActive surveillance (AS) is generally recognized as the preferred option for men with low-risk prostate cancer. Current guidelines use prostate-specific antigen (PSA) of 10-20 ng/mL or low-volume biopsy Gleason grade group (GG) 2 as features that, in part, define the favorable intermediate-risk disease and suggest that AS may be considered for some men in this risk category.MethodsWe identified 26,548 men initially managed with AS aged