Prostate-specific Antigen Monitoring Research Articles

Radiographic Progression Without Corresponding Prostate-specific Antigen Progression in Patients with Metastatic Castration-sensitive Prostate Cancer Receiving Apalutamide: Secondary Analysis of the TITAN Trial

Background and objectiveIn prostate cancer treated with androgen deprivation therapy (ADT), the initial sign of treatment resistance is often prostate-specific antigen (PSA) progression, followed by radiographic progression. However, the association between these two forms of progression remains unclear, especially in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with androgen receptor pathway inhibitors. We sought to evaluate the association between radiographic progression, PSA progression, and outcomes of apalutamide therapy in mCSPC. MethodsWe analyzed individual participant-level data for patients randomized within the TITAN trial who experienced radiographic progression during follow-up (N = 326). This study investigated radiographic progression without simultaneous or preceding PSA progression, as defined by the Prostate Cancer Working Group 2 (discordant progression), and explored the association of such progression with radiographic progression-free survival. Key findings and limitationsAmong the patients who developed radiographic progression, 115 (35.3%) had been treated with apalutamide plus ADT (the apalutamide group) and 211 (64.7%) with placebo plus ADT (the placebo group). Discordant progression occurred in 52.2% of patients (60 of 115) in the apalutamide group and 27.5% (58 of 211) in the placebo group (p < 0.001). A multivariable logistic regression analysis showed that discordant progression was associated with apalutamide treatment. We found evidence of an association between discordant progression and shorter radiographic progression-free survival. Conclusions and clinical implicationsThis study found that nearly half of the patients with mCSPC treated with apalutamide who experienced radiographic progression developed it without corresponding PSA progression, suggesting that heavy reliance on PSA monitoring may be inadequate for assessing disease activity in this context. Patient summaryIn patients who have metastatic castration-sensitive prostate cancer (mCSPC) and are being treated with apalutamide, radiographic images may show cancer progression even if prostate-specific antigen tests indicate no change. This highlights the importance of regular imaging when using apalutamide to manage mCSPC.

A multidisciplinary approach to address unmet needs in the management of patients with non-metastatic castration-resistant prostate cancer.

With the availability of second-generation androgen receptor inhibitors (SGARIs), the treatment landscape has changed dramatically for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). In clinical trials, the SGARIs (apalutamide, enzalutamide, darolutamide) increased metastasis-free survival (MFS), overall survival (OS), and patient quality of life compared to placebo. These drugs were subsequently integrated into nmCRPC clinical practice guidelines. With advances in radiographic imaging, disease assessment, and patient monitoring, nmCRPC strategies are evolving to address limitations related to tracking disease progression using prostate-specific antigen (PSA) kinetics. A panel of 10 multidisciplinary experts in prostate cancer conducted reviews and discussions of unmet needs in the management and monitoring of patients with nmCRPC in order to develop consensus recommendations. Across the SGARI literature, patient MFS and OS are generally comparable for all treatments, but important distinctions exist regarding short- and long-term drug safety profiles and drug-drug interactions. With respect to disease monitoring, a substantial proportion of patients using SGARIs may experience disease progression without rising PSA levels, suggesting a need for enhanced radiographic imaging in addition to PSA monitoring. Recent data also indicate that novel prostate-specific membrane antigen positron emission tomography radiotracers provide enhanced accuracy for disease detection, as compared to conventional imaging. Clinical decision-making in nmCRPC has become more complex, with new opportunities to apply precision medicine to patient care. Multidisciplinary teams can ensure that patients with nmCRPC receive optimal and individualized disease management.

Irreversible electroporation as a focal therapy for localized prostate cancer: A systematic review.

Irreversible electroporation (IRE) is a new and promising focal therapy for the treatment of localized prostate cancer. In this systematic review, we summarize the literature on IRE for prostate cancer published over the last decade. PubMed and EMBASE were searched with the end date of May 2023 to find relevant publications on prostate cancer ablation using IRE. Original studies with focal IRE as the primary curative treatment which reported on functional or oncological outcomes were included. The bibliography of relevant studies was also scanned to identify suitable articles. A total of 14 studies reporting on 899 patients treated with IRE for localized prostate cancer were included. Of all the studies reviewed, 77% reported on recurrence within the zone of ablation, and it ranged from 0% to 38.9% for in-field and 3.6% to 28% for out-of-field recurrence. Although, a standardised follow-up protocol was not followed, all the studies employed serial prostate-specific antigen monitoring, a multiparametric magnetic resonance imaging, and a biopsy (6-12 months post-treatment). Across all the studies, 58% reported that the urinary continence returned to the pretreatment levels and 25% reported a minor decrease in the continence from the baseline at 12-months of follow-up. Erections sufficient for intercourse varied from 44% to 75% at the baseline to 55% to 100% at 12-months of follow-up across all the studies. IRE, as a focal therapy, shows promising results with minimal complications and reasonably effective oncological control, but the data comparing it to the standard of care is still lacking. Future research should focus on randomized definitive comparisons between IRE, radical prostatectomy, and radiation therapy.

Validation of schedules for optimal prostate-specific antigen monitoring after radical prostatectomy.

Early detection of biochemical recurrence (BCR) after radical prostatectomy (RP) is crucial for early treatment and improving survival outcomes. The optimal prostate-specific antigen (PSA) monitoring remains unclear, and several models have been proposed. We aimed to externally validate four models for optimal PSA monitoring after RP and propose modifications to improve them. We reviewed the clinicopathological data of 896 patients who underwent robot-assisted RP between 2009 and 2022. We examined all PSA values and estimated the PSA value for four monitoring schedules at each time point in the virtual follow-up. We defined the ideal PSA for BCR detection between 0.2 and 0.4 ng/mL. During the median follow-up of 21.4 months, 128 (14.3%) patients presented BCR. The original and modified Keio models, National Cancer Center Hospital model, and American Urological Association/American Society for Radiation Oncology model detected BCR in 14 (10.9%), three (2.3%), 12 (9.4%), and 11 (8.6%) patients with PSA >0.4 ng/mL. Most patients experienced BCR detected with PSA >0.4 ng/mL during the first year postoperative. The modification of interval within 6 months postoperative avoided BCR detection with PSA >0.4 ng/mL within the first year postoperative in 8/9 (88.9%), 1/2 (50.0%), 5/6 (83.3%), and 4/4 (100%) for the original and modified Keio models, National Cancer Center Hospital model, and American Urological Association/American Society for Radiation Oncology model, respectively. We validated four models for PSA monitoring after RP to detect BCR and suggested modifications to avoid detections out of the desired range of PSA. These modifications could help to establish an optimal PSA monitoring schedule after RP.

Clinical Trial Protocol for PRIMARY2: A Multicentre, Phase 3, Randomised Controlled Trial Investigating the Additive Diagnostic Value of [68Ga]Ga-PSMA-11 Positron Emission Tomography/Computed Tomography in Men with Negative or Equivocal Multiparametric Magnetic Resonance Imaging for the Diagnosis of Clinically Significant Prostate Cancer

BackgroundMultiparametric magnetic resonance imaging (mpMRI) has an established role for the diagnosis of clinically significant prostate cancer (sPCa). The PRIMARY trial demonstrated that [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) was associated with a significant improvement in sensitivity and negative predictive value for sPCa detection. ObjectiveTo demonstrate that addition of prostate-specific membrane antigen (PSMA) radioligand PET/CT will enable some men to avoid transperineal prostate biopsy without missing sPCa, and will facilitate biopsy targeting of PSMA-avid sites. Design, setting, and participantsThis multicentre, two-arm, phase 3, randomised controlled trial will recruit 660 participants scheduled to undergo biopsy. Eligible participants will have clinical suspicion of sPCa with a Prostate Imaging-Reporting and Data System (PI-RADS) score of 2 and red flags, or a PI-RADS score of 3 on mpMRI (PI-RADS v2). Participants will be randomised at a 1:1 ratio in permuted blocks stratified by centre. The trial is registered on ClinicalTrials.gov as NCT05154162. InterventionIn the experimental arm, participants will undergo pelvic PSMA PET/CT. Local and central reviewers will interpret scans independently using the PRIMARY score. Participants with a positive result will undergo targeted transperineal prostate biopsies, whereas those with a negative result will undergo prostate-specific antigen monitoring alone. In the control arm, all participants undergo template transperineal prostate biopsies. Participants will be followed for subsequent clinical care for up to 2 yr after randomisation. Outcome measurements and statistical analysissPCa is defined as Gleason score 3 + 4 (≥10%) = 7 disease (grade group 2) or higher on transperineal prostate biopsy. Avoidance of transperineal prostate biopsy will be measured at 6 mo from randomisation. The primary endpoints will be analysed on an intention-to-treat basis. ConclusionsPatient enrolment began in March 2022, with recruitment expected to take 36 mo. Patient summaryFor patients with suspected prostate cancer who have nonsuspicious or unclear MRI (magnetic resonance imaging) scan findings, a different type of scan (called PSMA PET/CT; prostate-specific membrane antigen positron emission tomography/computed tomography) may identify men who could avoid an invasive prostate biopsy. This type of scan could also help urologists in better targeting of samples from suspicious lesions during prostate biopsies.

Patients with PSA below 0.2 ng/mL at 8 years post high-dose-rate brachytherapy have an extremely low risk of subsequent recurrence.

We have analyzed the long-term follow-up data of patients with prostate cancer (PCa) who underwent high-dose-rate brachytherapy (HDR-BT) and external beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT). The objective was to determine the optimal time for cessation of PSA monitoring after HDR-BT. We included 309 patients with clinical stage T1c-T4 N0-1 M0 PCa who received HDR-BT and EBRT combined with long-term ADT between 2005 and 2018. We stratified the patients based on their prostate-specific antigen (PSA) levels and identified the factors associated with biochemical recurrence (BCR) and clinical progression (CP). The median follow-up duration was 98 months (range: 31-207 months). Among the 306 patients, 76 developed BCR and 47 developed CP subsequently. We found that the PSA levels at 3, 5, and 8 years significantly correlated with the oncological outcomes of brachytherapy. No patient with a PSA level ≤ 0.2 ng/mL at 8 years later developed BCR or CP. Our long-term data suggest that in the presence of a PSA level ≤ 0.2 ng/mL at 8 years later, PSA monitoring may be safely discontinued due to the extremely low risk of subsequent oncological events. The data presented in this study will assist clinicians in determining the optimal management strategy for patients with PCa following HDR-BT and EBRT combined with long-term ADT.

Initial Postoperative Prostate Specific Antigen and Prostate Specific Antigen Velocity Are Important Indicators of Underlying Malignancy After Simple Prostatectomy.

Background: There is a paucity of guidelines for prostate-specific antigen (PSA) monitoring after simple prostatectomy (SP) despite these patients remaining at risk for prostate cancer (PCa). Our objective was to determine if PSA kinetics can be a potential indicator of PCa after SP. Methods: A retrospective review was performed of all simple prostatectomies at our institution from 2014 to 2022. All patients who met criteria were included in the study. Relevant clinical variables were collected preoperatively, including PSA value, prostate size, and voiding symptoms. Surgical and urinary function outcomes were analyzed. Results: A total of 92 patients were divided into two groups based on malignancy status. Sixty-eight patients did not have PCa, while 24 patients had known PCa before surgery (14) or were diagnosed as having incidental PCa from the pathological specimen (10). Patients with benign prostates had an initial postoperative PSA value of 0.76 ng/mL compared with 1.68 ng/mL for those with cancer (p < 0.01). PSA velocity for the first 24 months after surgery was 0.042 ± 1.61 ng/(mL·year) for the benign cohort compared with 1.29 ± 1.02 ng/(mL·year) for the malignant cohort (p = 0.01). Voiding improvements were noted by objective (postvoid residual and flow rate) and subjective (American Urological Association symptom score and quality of life score) measures in both groups. Conclusions: PSA interpretation and monitoring after SP have not been well established. Our study indicates that initial postoperative PSA value and PSA velocity are important indicators of underlying malignancy in patients after SP. Further efforts are needed to establish threshold values and formal guidelines.

Abstract 3370: Liquid biopsy approaches to determine tumor cell heterogeneity in advanced prostate cancer

Abstract Aggressive variants of prostate cancer (AVPC) emerge from prostate adenocarcinoma following enduring therapeutic pressure. They grow independent of the androgen receptor, progress rapidly and can show traits of neuroendocrine (NE) differentiation. As progression to AVPC is not well detected by prostate specific antigen monitoring, new biomarkers are urgently needed. The aim of this study is to evaluate the detection of circulating tumor cells (CTCs) in combination with gene expression analysis of NE genes to identify AVPC patients with neuroendocrine traits. Blood samples were collected from patients suffering from AVPC (n=78, including 25 patients with histological evidence of NEPC) as well as from patients with hormone-sensitive prostate cancer (HSPC) as controls (n=12) at the University Medical Center Hamburg-Eppendorf. CTC counts were determined by CellSearch analysis. In parallel, CTCs were immuno-magnetically enriched using the AdnaTest and bulk gene expression of prostate-specific and NE genes was analyzed by semi-quantitative PCR. From a subset of patients, CTCs were additionally enriched by Parsortix to compare gene expression of CTCs with EpCAM-based or size-based CTC enrichment. Using CellSearch analysis, CTCs were found in 88.9 % of AVPC patients. CTC counts ranged between 0 – 20,000 CTCs/7.5 ml of blood with a median of 32 CTCs/7.5 ml. Similarly, 81.8 % of NEPC patients were positive for CTCs with a median count of 35 CTCs/7.5 ml (range 0-13,000). In contrast, CTCs were found in only 50 % of HSPC patients at lower concentrations (median count of 0.5 CTCs/7.5 ml, range 0-34). CTC counts were significantly elevated in AVPC and NEPC patients compared to HSPC (p = 0.002, p = 0.012), but no significant differences were found between AVPC and NEPC samples.In 93.8 % of AVPC samples, CTCs expressed prostate-specific genes such as KLK3 or PSMA. At least one of the NE transcripts was detected in 37.5 % of AVPC patients. In CTCs from NEPC patients, the positivity for prostate markers was significantly reduced to 66.6 % (p = 0.01) and the positivity for NE markers was increased to 61.1 %. A random Forrest model trained on all analyzed transcripts allowed for a distinction of HSPC and NEPC with an AUC of 79.5 %. Comparison of CTC enrichment strategies in a subset of 13 patients showed similar NE marker detection by size-based enrichment (53.8 % NE-positive) compared to the AdnaTest (61.5 % NE-positive). AVPC and NEPC patients show a high CTC burden that will allow subsequent molecular analyses, and CTC counts allowed a distinction between blood samples from HSPC and NEPC patients. Gene expression analysis revealed a high degree of inter-patient heterogeneity for neuroendocrine-specific transcripts with a reduction of prostate markers in NEPC patients. Future molecular characterization and longitudinal monitoring of CTCs will shed more light on the evolution of AVPC and NEPC. Citation Format: Lina Merkens, Sarah Greimeier, Sabine Riethdorf, Klaus Pantel, Gunhild von Amsberg, Stefan Werner. Liquid biopsy approaches to determine tumor cell heterogeneity in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3370.

Nadir Prostate-specific Antigen as an Independent Predictor of Survival Outcomes: A Post Hoc Analysis of the PROSPER Randomized Clinical Trial.

This post hoc analysis of PROSPER evaluated the relationship between depth of PSA decline and clinical outcomes in enzalutamide-treated men with nonmetastatic castration-resistant prostate cancer. PROSPER was an international, randomized, double-blind, placebo-controlled, phase 3 trial that demonstrated significantly improved metastasis-free survival and overall survival with androgen deprivation therapy plus enzalutamide vs placebo. A total of 905 enzalutamide-treated men were included in this post hoc analysis. Metastasis-free survival (primary endpoint) and overall survival (secondary endpoint) were evaluated for 4 mutually exclusive subgroups defined by PSA decline: <50% (reference); ≥50% to <90%; ≥90%, nadir ≥0.2 ng/mL; and ≥90%, nadir <0.2 ng/mL. Medians and 95% confidence intervals were determined using a 12-month landmark analysis; hazard ratios and P values were based on an unstratified Cox proportional analysis model. In enzalutamide-treated men, PSA declines of <50%, ≥50% to <90%, ≥90% with nadir ≥0.2 ng/mL, and ≥90% with nadir <0.2 ng/mL were associated with median metastasis-free survival in months (95% confidence intervals) of 22.1 (14.8-not reached), 34.2 (29.4-not reached), 36.6 (33.4-not reached), and not reached, respectively, and overall survival in months (95% confidence intervals) of 40.8 (31.7-44.9), 54.4 (49.0-67.0), 64.3 (63.4-not reached), and not reached, respectively. There was a statistically significant correlation between greater depth of PSA decline and improved clinical outcomes, suggesting a previously underappreciated relationship between changes in PSA levels and clinical outcomes in nonmetastatic castration-resistant prostate cancer.

Kinetic Analysis of Prostate-Specific Antigen Interaction with Monoclonal Antibodies for Development of a Magnetic Immunoassay Based on Nontransparent Fiber Structures.

Prostate cancer is the second most common cancer diagnosed in men worldwide. Measuring the prostate-specific antigen (PSA) is regarded as essential during prostate cancer screening. Early diagnosis of this disease relapse after radical prostatectomy requires extremely sensitive methods. This research presents an approach to development of an ultrasensitive magnetic sandwich immunoassay, which demonstrates the limit of PSA detection in human serum of 19 pg/mL at a dynamic range exceeding 3.5 orders of concentration. Such attractive performance stems, inter alia, from the kinetic analysis of monoclonal antibodies (mAbs) against free PSA to select the mAbs exhibiting best kinetic characteristics and specificity. The analysis is carried out with a label-free multiplex spectral-correlation interferometry compatible with inexpensive single-use glass sensor chips. The high sensitivity of developed PSA immunoassay is due to electronic quantification of magnetic nanolabels functionalized by the selected mAbs and three-dimension porous filters used as an extended solid phase. The assay is promising for PSA monitoring after radical prostatectomy. The proposed versatile approach can be applied for the rational design of highly sensitive tests for detection of other analytes in many fields, including in vitro diagnostics, veterinary, food safety, etc.

A facile integrated microfluidic chip based on Chitosan-Gold Nanoparticles-Anchored Three-Dimensional graphene fiber film for monitoring prostate specific antigen

Microfluidic electrochemical sensors are emerging as favorable platforms for rapid and precise detection of disease markers relying on their superiority of miniaturization, low electrolyte consumption, high precision and integration. Herein, an efficient and facile integrated microfluidic sensor with three-dimensional graphene fiber film/chitosan-gold nanoparticles (3D GF/CS-Au NPs) micro-nano composites as sensing interface was developed for the analysis of prostate specific antigen (PSA). The GF with 3D network structures modified by large amounts of CS-Au nanoparticles could facilitate the enhancement of electrochemical signals. The electrodes and microchannel were simply assembled and encapsulated by bolts, which made the microfluidic chip had excellent portability and operability. On the basis of this new microfluidic device and the 3D GF/CS-Au NPs composites, a sensitive determination of PSA could be realized with a low detection limit of 0.51 pg/mL and a wide response range from 0.001 − 200 ng/mL. Moreover, the proposed biosensor was further used to detect analytes in human blood samples, showing the satisfactory results. This novel microfluidic electrochemical immunosensor demonstrated superior performance for PSA detection, holding potential application in clinical diagnosis and personalized healthcare.

Dietary Patterns and Risk of Gleason Grade Progression among Men on Active Surveillance for Prostate Cancer: Results from the Canary Prostate Active Surveillance Study

Modifiable lifestyle factors, such as following a healthy dietary pattern may delay or prevent prostate cancer (PCa) progression. However, few studies have evaluated whether following specific dietary patterns after PCa diagnosis impacts risk of disease progression among men with localized PCa managed by active surveillance (AS). 564 men enrolled in the Canary Prostate Active Surveillance Study, a protocol-driven AS study utilizing a pre-specified prostate-specific antigen monitoring and surveillance biopsy regimen, completed a food frequency questionnaire (FFQ) at enrollment and had ≥ 1 surveillance biopsy during follow-up. FFQs were used to evaluate adherence to the Dietary Guidelines for Americans (Healthy Eating index (HEI))-2015, alternative Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH) dietary patterns. Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals were estimated using Cox proportional hazards models. During a median follow-up of 7.8 years, 237 men experienced an increase in Gleason score on subsequent biopsy (grade reclassification). Higher HEI-2015, aMED or DASH diet scores after diagnosis were not associated with significant reductions in the risk of grade reclassification during AS. However, these dietary patterns have well-established protective effects on chronic diseases and mortality and remain a prudent choice for men with prostate cancer managed by AS.

Conditional Survival of Patients with Prostate Cancer Undergoing External-Beam Radiotherapy on RTOG 0126 and 0415

<h3>Purpose/Objective(s)</h3> Patients with low- and intermediate-risk prostate cancer (PCa) treated with radiation (RT) alone have excellent outcomes with anticipated long overall survival (OS). Although biochemical failure (BF) and OS rates are commonly reported from time of diagnosis, the relevance of such data diminishes over time for survivors. Conditional survival analyses can provide more relevant survival estimates for long-term survivors and help patients understand changing recurrence risks. The primary objective of this study was to report conditional OS and BF in patients with low- and intermediate-risk PCa treated with RT. A secondary objective was to determine if prognostic factors at initial treatment remain relevant later in survival. <h3>Materials/Methods</h3> We performed a pooled analysis of patients with low- or intermediate- risk PCa enrolled in RTOG 0126 or 0415 treated with RT alone. OS was calculated (Kaplan–Meier) at various survivorship timepoints. Cumulative incidence (Phoenix definition) was used to calculate BF rates. Risk factors (Gleason score [GS], T stage, prostate-specific antigen (PSA), and EQD2 of prescribed dose) were analyzed at different timepoints using multivariable Cox proportional hazards modeling (MVA). <h3>Results</h3> A total of 2,591 patients were included (median age, 69 y; median PSA, 6.4 ng/mL; 48.5% with GS 7; 34.2% with stage T2 disease). Median follow-up was 6.9 y. The 3-, 5-, and 8-y OS from time of treatment were 96.2%, 89.2%, and 41.0%, respectively. Patients with 1-, 3-, and 5y of survival, had an additional 5 y survival rate of 73.3%, 42.6%, and 20.8%, respectively. On MVA at diagnosis, GS 7 (HR 1.352, <i>P</i> = 0.003), increasing age (HR 1.054, <i>P</i> < 0.001), and increasing PSA (HR 1.054, <i>P</i> = 0.01), were associated with all-cause mortality. For patients who survived 5 y, only age (HR 1.071, <i>P</i> < 0.001) was predictive of mortality. The 3-, 5-, and 8-y rates of BF from time of treatment were 7.1%, 12.5%, and 22.3%, respectively. For patients surviving 1, 3, and 5 y without BF, the rates of BF in the next 5 y were 14.2%, 17.2%, and 18.8%, respectively. On MVA, GS 7 (HR 1.907, <i>P</i> < 0.001), T2 disease (HR 1.375, <i>P</i> < 0.001), and increasing PSA (HR 1.114, <i>P</i> < 0.001) were significantly associated with increased risk of BF, whereas increasing EQD2 was associated with decreased BF rates (HR 0.922, <i>P</i> < 0.001). For patients who survived 5 y without BF, all initial prognostic factors remained statistically significant: GS 7 (HR 2.401, <i>P</i> < 0.001), stage T2 (HR 1.344, <i>P</i> = 0.0396), PSA (HR 1.109, <i>P</i>< 0.001), and EQD2 (HR 0.887, <i>P</i> < 0.001). <h3>Conclusion</h3> Conditional risk of BF increases over time for patients with PCa initially treated with RT. Initial biologic and treatment variables remain prognostic at long-term follow-up, with dose-escalated RT continuing to be associated with decreased BF. This data can be used to counsel patients for their risk of BF in follow-up and to help decide on the frequency of PSA monitoring.

Emulation of a target trial with sustained treatment strategies: an application to prostate cancer using both inverse probability weighting and the g-formula.

As with many chronic illnesses, recurrent prostate cancer generally requires sustained treatment to prolong survival. However, initiating treatment immediately after recurrence may negatively impact quality of life without any survival gains. Therefore, we consider sustained strategies for initiating treatment based on specific characteristics of prostate-specific antigen (PSA), which can indicate disease progression. We define the protocol for a target trial comparing treatment strategies based on PSA doubling time, in which androgen deprivation therapy is initiated only after doubling time decreases below a certain threshold. Such a treatment strategy means the timing of treatment initiation (if ever) is not known at baseline, and the target trial protocol must explicitly specify the frequency of PSA monitoring until the threshold is met, as well as the duration of treatment. We describe these and other components of a target trial that need to be specified in order for such a trial to be emulated in observational data. We then use the parametric g-formula and inverse-probability weighted dynamic marginal structural models to emulate our target trial in a cohort of prostate cancer patients from clinics across the United States.

Outcome of Patients With Elevated Prostate-Specific Antigen and Lower Urinary Tract Symptoms Receiving Holmium Laser Enucleation of the Prostate.

PurposeThis study investigated functional outcomes in lower urinary tract symptoms (LUTS), the incidence of incidental prostate cancer (PCa), and changes in prostate-specific antigen (PSA) levels after holmium laser enucleation of the prostate (HoLEP) in patients with elevated PSA and benign prostatic hyperplasia (BPH).MethodsA retrospective review of a prospectively designed protocol for patients who underwent HoLEP at our institution from January 2010 to May 2020 was conducted. Patients were classified into low-PSA (<3.0 ng/mL) and high-PSA (≥3.0 ng/mL) groups at baseline. Follow-up for PSA was performed at the sixth postoperative month. Baseline and postoperative clinical parameters, functional parameters, PCa incidence, and postoperative changes in PSA were compared between the low- and high-PSA groups.ResultsThe baseline PSA of 1,296 patients (mean age, 69.7±6.8 years) was 4.0±4.1 ng/mL, with 712 patients (55.0%) in the low-PSA group (1.6±0.8 ng/mL), and 584 patients (45.0%) in the high-PSA group (6.9±4.7 ng/mL). Incidental PCa was detected in 82 patients (6.3%), with a similar incidence in the low-PSA (41 patients, 5.9%) and high-PSA (41 patients, 7.0%) groups (P>0.05). At 6 months postoperatively, both groups showed significant improvements in the maximum flow rate, postvoid residual volume, and all domains of the International Prostate Symptom Score (P<0.05). At postoperative 6 months, the PSA level significantly decreased by 66.6%±23.6% in all patients (54.3%±23.9% in the low-PSA group; 79.6%±14.7% in the high-PSA group) (P<0.05), and the PSA levels of 1,264 patients (97.6%) had normalized.ConclusionsIn patients with elevated PSA presenting with LUTS/BPH, our study demonstrated significant improvements in functional parameters and decreased PSA after HoLEP. The incidental PCa detection rate did not show a statistically significant difference between the low- and high-PSA groups. Timely surgery for LUTS/BPH without delay due to PSA monitoring should be considered.

Intermediate-term oncological outcomes after a negative endorectal coil multiparametric MRI of the prostate in patients without biopsy proven prostate cancer

PurposeInvestigate the intermediate-term oncological outcome after negative multiparametric MRI (mpMRI) of the prostate in patients without biopsy proven prostate cancer (PCa). MethodsThe retrospective study included 121 patients with negative mpMRI (Prostate Imaging Reporting and Data System version 2.1 category<3) performed at our institution between 2012 and 2017 without known biopsy proven PCa. Clinical and pathological data were collated including post-MRI prostatic tissue diagnoses with highest Grade Group and most recent prostate specific antigen (PSA) levels up to any definitive prostate cancer treatment. Mean PSA velocities between patients with and without a subsequent diagnosis of Grade Group 2 or higher (GG2+) PCa were compared, and an optimal threshold value was calculated. ResultsOutcome data available included PSA values in 117 patients and prostate tissue sampling in 52 patients. Over a median follow up interval of 49.8 months, only 11 of 121 patients (9.1%) were diagnosed with GG2+ PCa, 10 patients (8.3%) with GG1 PCa, and 31 patients (25.6%) had negative prostate tissue samples. Mean PSA velocity was significantly higher in the patients diagnosed with GG2+ PCa (3.87 ng/mL/year) compared to those not diagnosed with GG2+ PCa (−0.71 ng/mL/year, p < 0.001). A threshold PSA velocity of 0.27 ng/mL/year had a 100% sensitivity and 69.8% specificity for GG2+ PCa (AUC: 0.898). Conclusion<10% of patients with negative mpMRI without prior biopsy proven PCa were diagnosed with GG2+ PCa over median follow up of over four years and were associated with PSA velocity of ≥0.27 ng/mL/year. PSA monitoring may be a reasonable management strategy in patients with a negative mpMRI without biopsy proven PCa.

Progression patterns by types of metastatic spread, prostate-specific antigen (PSA), and clinical symptoms: Post-hoc analyses of ARAMIS.

5044 Background: Darolutamide (DARO), a highly potent and structurally distinct androgen receptor inhibitor, prolonged metastasis-free survival by nearly 2 years and reduced the risk of death by 31% vs placebo (PBO) with a favorable tolerability profile in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in ARAMIS. We present post-hoc analyses of ARAMIS to evaluate the association between metastatic progression with prostate-specific antigen (PSA) and clinical progression and to describe the distribution of metastatic progression between groups. Methods: Pts with nmCRPC were randomized 2:1 to DARO (n=955) or PBO (n=554) while continuing androgen-deprivation therapy. Descriptive analyses were performed using the primary data cutoff (Sept 3, 2018) for the double-blind period. Post-baseline metastases were based on central review of conventional radiographic imaging every 16 weeks. PSA and pain progression were defined per primary analysis ( N Engl J Med. 2019;380:1235-46). Results: Metastatic progression was observed in 13.6% of DARO and 28.5% of PBO pts. Most pts had isolated progression as bone (DARO 46%, PBO 39%) or lymph node (32%; 40%) metastasis (Table). Pts with radiographic progression had shorter median time from initial diagnosis to study treatment (DARO 72.9, PBO 74.4 months) vs the overall ARAMIS population (86.2, 84.2 months). Of all pts with metastatic progression, baseline PSA levels (ng/mL) were similar in DARO (12.6) and PBO pts (15.1); DARO pts had lower median PSA before metastasis (16.7) vs PBO pts (48.0) and median absolute/relative PSA decrease from baseline of -0.7/-3.2% vs an increase for PBO pts of 29.5/181%. PSA progression before metastasis was observed in 55.6% (160/288) of pts, occurring in fewer DARO (45.4%) vs PBO pts (63.9%) (treatment difference 18.5%; nominal 95% CI 6.5%–30.6%). The median time between PSA progression and metastasis was 7.0 months with DARO vs 5.6 months with PBO. Pain progression before metastatic progression was rare and similar between groups (DARO 16.9%, PBO 17.7%). Conclusions: DARO significantly reduced risk of metastatic progression and improved overall survival vs PBO without changing the pattern of metastatic progression. Many pts with nmCRPC experienced metastatic progression without PSA progression, and pain progression was rare. These results support the use of imaging with PSA monitoring to properly identify disease progression in pts with nmCRPC. Clinical trial information: TBC. [Table: see text]

Radiographic progression in the absence of prostate-specific antigen (PSA) progression in patients with metastatic hormone-sensitive prostate cancer (mHSPC): Post hoc analysis of ARCHES.

5072 Background: Enzalutamide (ENZA) + androgen deprivation therapy (ADT) significantly reduced the risk of radiographic progression and increased overall survival in men with mHSPC, regardless of baseline PSA levels (ARCHES; NCT02677896). This post hoc analysis investigated concordance between PSA progression and radiographic progression in patients with mHSPC. Methods: Patients with mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or placebo (PBO) + ADT. The concordance between radiographic progression and PSA progression, as defined by Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria, and between any rise in PSA above nadir was assessed. Results: In total, 267/1150 patients in ARCHES had radiographic progression (ENZA + ADT, n=79; PBO + ADT, n=188). At radiographic progression, the median (range) PSA for ENZA + ADT-treated patients was 2.25 ng/mL (0–1062.3 ng/mL) and 17.47 ng/mL (0–1779.5 ng/mL) for PBO + ADT-treated patients. Most patients (67%) treated with ENZA + ADT did not have PCWG2-defined PSA progression at radiographic progression, compared with 43% of those treated with PBO + ADT (Table). The median absolute and percentage rise in PSA from nadir to radiographic progression was 0.77 ng/mL and 200%, respectively, with ENZA + ADT compared with 12.23 ng/mL and 367%, respectively, with PBO + ADT. Conclusions: In this post hoc analysis of ARCHES, we found frequent discordance between radiographic progression and PSA progression by PCWG2 criteria or any PSA rise over nadir in patients with mHSPC treated with ENZA + ADT. Thus, regular imaging is recommended to detect radiographic progression among patients treated with potent androgen receptor pathway inhibitors, such as ENZA + ADT, as serial PSA monitoring alone may not be sufficient to detect radiographic progression in many patients. Clinical trial information: NCT02677896. [Table: see text]

Deep Prostate-specific Antigen Response following Addition of Apalutamide to Ongoing Androgen Deprivation Therapy and Long-term Clinical Benefit in SPARTAN

BackgroundApalutamide plus androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS), overall survival (OS), and time to prostate-specific antigen (PSA) progression in the placebo-controlled SPARTAN study of high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). ObjectiveTo assess the relationships between PSA kinetics, outcomes, and molecular subtypes in SPARTAN. Design, setting, and participantsThe authors conducted a post hoc analysis of nmCRPC patients randomized to receive apalutamide (n = 806) or placebo (n = 401) plus ADT and a subset stratified by molecular classifiers. InterventionApalutamide 240 mg/d. Outcome measurements and statistical analysisThe association between PSA kinetics and MFS, OS, time to PSA progression, and molecular subtypes was evaluated using the landmark analysis and Kaplan-Meier methods. Results and limitationsBy 3 mo, PSA decreased in most apalutamide-treated patients and increased in most placebo-treated patients. After apalutamide, the median time to PSA nadir, confirmed ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml were 7.4, 1.0, 1.9, and 2.8 mo, respectively. By 6 mo, 90%, 57%, and 32% of apalutamide patients had ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml, respectively, while only 1.5% of placebo patients experienced ≥50% PSA reduction. PSA reductions were observed within 3 mo and up to 12 mo of apalutamide treatment, and were similar across molecular subtypes. Deep PSA responses (≥90% PSA reduction or PSA ≤0.2 ng/ml) at landmark 6-mo apalutamide treatment were significantly associated with improved time to PSA progression (hazard ratio {HR} [95% confidence interval {CI}] 0.25 [0.18–0.33] or 0.13 [0.08–0.21]), MFS (0.41 [0.29–0.57] or 0.3 [0.19–0.47]), and OS (0.45 [0.35–0.59] or 0.26 [0.18–0.38]; p < 0.001 for all). ConclusionsApalutamide plus ADT produced rapid, deep, and durable PSA responses by 6-mo treatment regardless of assessed molecular prognostic markers. An early PSA response with apalutamide was associated with clinical benefits, supporting prognostic value of PSA monitoring. Patient summaryIn this report, we describe how prostate-specific antigen (PSA) levels relate to outcomes in patients with nonmetastatic castration-resistant prostate cancer treated with apalutamide plus androgen deprivation therapy (ADT). We found that treatment with apalutamide plus ADT resulted in rapid, deep, and durable PSA responses in the majority of patients, including those with high-risk molecular subtypes, which were associated with improved survival.

O03 Continuation of golimumab (anti-TNF) in a patient with SpA and low-risk prostate cancer, what is the right decision?

Case report - IntroductionGolimumab is an anti-TNF alpha drug used in the treatment of inflammatory arthritis including spondyloarthritis (SpA). The introduction of this drug class has revolutionised the treatment of SpA over the last 20 years with significantly improved patient outcomes.Despite their treatment benefits multiple adverse effects of TNF-alpha inhibition have been reported through clinical trials including a possible increased risk of malignancy.We describe a case of a patient with known ankylosing spondylitis (AS) on golimumab who was diagnosed with low-grade prostate carcinoma and discuss the factors taken into consideration in guiding our decision-making process regarding ongoing treatment. Case report - Case descriptionA 57-year-old gentleman with known AS presented to the rheumatology clinic for routine review. His AS was well controlled, and he had been taking golimumab for the past 3 years. Upon review he was in clinical remission with a CRP <1 and ESR 5. Prior to the initiation of anti-TNF therapy his disease had been poorly controlled. However, following commencement his symptoms had significantly improved and he was able to work as a professional sports coach whilst bringing up a young family.On review he had recently been diagnosed with low-risk cancer of the prostate by his urologist. A prostate biopsy found Gleason 3 + 3 adenocarcinoma involving 2 out of 22 cores on each side, with a prostate specific antigen (PSA) of 3.95ng/ml. An MRI had shown chronic prostatitis. He was in the lowest risk category of grade group 1 prostate cancer and no treatment for his prostate cancer was indicated. The plan from his urology team was active surveillance with PSA monitoring.Whilst being investigated for possible malignancy his golimumab had been held for six months and during this period he had a significant flare in symptoms. He experienced severe back pain that forced him to stop working. Following his prostate cancer diagnosis, golimumab was restarted by his urologist with a subsequent improvement in his AS symptoms.To guide ongoing treatment his case was reviewed in the local biologics multi-disciplinary team meeting, alongside close communication with his urologist. The patient was informed of the risks of continuing golimumab in relation to his malignancy. Despite this he was reluctant to stop anti-TNF therapy or switch to another treatment, citing concerns about the impact it might have on his symptoms and ability to work.Case report - Discussion This case highlights the complexities involved in the management of a patient on anti-TNF therapy, who receives a diagnosis of malignancy, particularly when the diagnosis is classed as low risk. Traditionally anti-TNF therapy was contraindicated for patients with a history of a solid organ tumour within the previous five years. The British Society of Rheumatology (BSR) guidelines recommends that patients should be advised that there is no conclusive evidence for an increased risk of solid organ tumours but that on-going vigilance is required.A holistic patient-centred approach needs to be taken in these contexts, and consideration of cases on an individual basis is needed. Inter-disciplinary and multi-speciality team input, with the effective use of a biologics MDT, is crucial. The patient was understandably reluctant to stop his treatment due to the significant impact this may have on his quality of life.On liaison with his urologist his prostate cancer was in the lowest risk category with 99% 5-year survival rates with low risk of disease progression or spread.Evidence in this field to date has been conflicting and studies have predominantly focused on the safety of anti-TNFs in rheumatoid arthritis patients. Recent large national registry data has been reassuring. Few studies have looked at the AS and psoriatic arthritis anti-TNF treated population; however, a meta-analysis of RCTs found no evidence of increased incidence of malignancy.Taking into account his low-risk cancer, the patient’s wishes and clinical evidence in this field we have made to decision to continue anti-TNF treatment for now but with ongoing surveillance for any tumour progression. The patient will undergo urology follow up alongside regular PSA monitoring, and there will be a low threshold to stop or switch treatment in the futureCase report - Key learning pointsTreatment with anti-TNF therapy in patients with concomitant inflammatory arthritis and malignancy pose a specific challenge that require close co-ordination of care between rheumatologists, oncologists, other relevant teams and may benefit from the use of local biologics MDT to guide ongoing drug therapy.It is important to take a patient centred approach and consider cases on an individual basis taking into account their cancer diagnosis, extent of disease, histology findings and their response to TNF treatment.Patients must always be counselled on the risk of continuing anti-TNF and be involved in the decision-making process.Further research is required to look at the safety of anti-TNF particularly in SpA and if there is an increased risk of malignancy.