Prostate-specific Antigen Kinetics Research Articles

Kinetics of serum prostate-specific antigen by vitamin d status among healthy males of Nigerian descent

Kinetics of serum prostate-specific antigen by vitamin d status among healthy males of Nigerian descent

Quantification of biochemical PSA dynamics after radioligand therapy with [177Lu]Lu-PSMA-I&T using a population pharmacokinetic/pharmacodynamic model

BackgroundThere is an unmet need for prediction of treatment outcome or patient selection for [177Lu]Lu-PSMA therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Quantification of the tumor exposure–response relationship is pivotal for further treatment optimization. Therefore, a population pharmacokinetic (PK) model was developed for [177Lu]Lu-PSMA-I&T using SPECT/CT data and, subsequently, related to prostate-specific antigen (PSA) dynamics after therapy in patients with mCRPC using a pharmacokinetic/pharmacodynamic (PKPD) modelling approach.MethodsA population PK model was developed using quantitative SPECT/CT data (406 scans) of 76 patients who received multiple cycles [177Lu]Lu-PSMA-I&T (± 7.4 GBq with either two- or six-week interval). The PK model consisted of five compartments; central, salivary glands, kidneys, tumors and combined remaining tissues. Covariates (tumor volume, renal function and cycle number) were tested to explain inter-individual variability on uptake into organs and tumors. The final PK model was expanded with a PD compartment (sequential fitting approach) representing PSA dynamics during and after treatment. To explore the presence of a exposure–response relationship, individually estimated [177Lu]Lu-PSMA-I&T tumor concentrations were related to PSA changes over time.ResultsThe population PK model adequately described observed data in all compartments (based on visual inspection of goodness-of-fit plots) with adequate precision of parameters estimates (< 36.1% relative standard error (RSE)). A significant declining uptake in tumors (k14) during later cycles was identified (uptake decreased to 73%, 50% and 44% in cycle 2, 3 and 4–7, respectively, compared to cycle 1). Tumor growth (defined by PSA increase) was described with an exponential growth rate (0.000408 h−1 (14.2% RSE)). Therapy-induced PSA decrease was related to estimated tumor concentrations (MBq/L) using both a direct and delayed drug effect. The final model adequately captured individual PSA concentrations after treatment (based on goodness-of-fit plots). Simulation based on the final PKPD model showed no evident differences in response for the two different dosing regimens currently used.ConclusionsOur population PK model accurately described observed [177Lu]Lu-PSMA-I&T uptake in salivary glands, kidneys and tumors and revealed a clear declining tumor uptake over treatment cycles. The PKPD model adequately captured individual PSA observations and identified population response rates for the two dosing regimens. Hence, a PKPD modelling approach can guide prediction of treatment response and thus identify patients in whom radioligand therapy is likely to fail.

DNA Ploidy as a Potential Adjunct Prognostic Marker of Low-Risk Prostate Cancer Progression after Radical Prostatectomy.

Post prostatectomy PSA kinetics and General Grade Groups (GGG) are the strongest prognostic markers of biochemical recurrence (BCR) and prostate cancer (PCa)-specific mortality after radical prostatectomy. Despite having low-risk PCa, some patients will experience BCR, for some, clinically significant BCR. There is a need for an objective prognostic marker at the time of prostatectomy to improve risk stratification within this population. In this study, we investigated the prognostic potential of DNA ploidy. Prostatectomy samples from 97 patients with GGG1 and GGG2 with a low-risk CAPRA-S score were included in this study. PCa tissue with the worst Gleason pattern underwent tissue disaggregation, cell isolation and staining with a DNA stoichiometric stain. Using image cytometry, DNA ploidy was measured and a Ploidy Score (PS) was generated. Among the 97 patients, 79 had no BCR, 18 experienced BCR, of which 14 had a PSA doubling time (PSA-DT) >1 year (low-risk group) and 4 had a PSA-DT of <1 year (high-risk group). Using Logistic regression analysis, only pathological T stage (pT) and PS independently predicted BCR with PS being the most significant (p = 0.001). The number of aneuploid cells was significantly higher in the high-risk group compared to the other groups (p = 1.7x10-11). PS combined with GGG diagnosis further stratified risk groups of biochemical recurrence free survival within CAPRA-S low-risk cohort. DNA ploidy is an independent prognostic marker of BCR in low-risk PCa after radical prostatectomy, which could early on identify potentially aggressive PCa recurrences and introduce a more personalized approach to salvage treatments.

Whole-body tumour burden on [18F]DCFPyL PET/CT in biochemical recurrence of prostate cancer: association with tumour biology and PSA kinetics.

The objective was to assess the association between molecular imaging (mi) variables on [18F]DCFPyL-PET/CT with clinical and disease characteristics and prostate specific antigen (PSA) related variables in patients with biochemical recurrence of prostate cancer (BRPC). We analysed patients with BRPC after radical treatment. We obtained clinical and PSA variables: International Society of Urology Pathology (ISUP) grade group, European Association of Urology (EAU) risk classification, PSA (PSA≤1ng/ml, 1<PSA≤2, PSA>2), PSA doubling time (PSAdt) and PSA velocity (PSAvel). All PET/CT scans were reviewed with the assistance of automated Prostate Molecular Imaging Standardized Evaluation (aPROMISE) software and lesions' segmentation in positive scans was performed using this platform. Standardized uptake value (SUV) derived variables; tumour burden variables [whole-body tumour volume (wbTV), whole-body tumour lesion activity (wbTLA) and whole-body mi PSMA (wbPSMA)] and miTNM staging were obtained. Cut-off of PSA and kinetics able to predict PET/CT results were obtained. Associations between disease and mi variables were analysed using ANOVA, Kruskal-Wallis and Spearman's correlation tests. Multivariate analysis was also performed. Two hundred and seventy-five patients were studied. [18F]DCFPyL-PET/CT were positive in 165/275 patients. In multivariate analysis, moment of biochemical recurrence, ISUP group, PSA level and PSAvel showed significant association with the detection rate. miTNM showed significant association with PSA level (p<0.001) and kinetics (p<0.001), being higher in patients with metastatic disease. Both PSA and PSAvel showed moderate correlation with wbTV, wbTLA and wbPSMA (p<0.001). A weak correlation with SUVs was found. Mean wbTV, wbTLA and wbPSMA values were significantly higher in PSA > 2ng/ml, PSAdt ≤ 6 months and PSAvel ≥ 0.2ng/ml/month groups. Also, wbTV (p=0.039) and wbPSMA (p=0.020) were significantly higher in patients with ISUP grade group 5. PSA and PSAvel cut-offs (1.15 ng/ml and 0.065 ng/ml/month) were significantly associated with a positive PET/CT. Higher PSA values, unfavourable PSA kinetics and ISUP grade group 5 were robust predictive variables of larger tumour burden variables on [18F]DCFPyL PET/CT assessed by aPROMISE platform.

Hypofractionated radiation therapy combined with androgen deprivation therapy for high-risk localized prostate cancer.

This study aimed to analyse the treatment outcomes of moderately hypofractionated radiation therapy (RT) combined with androgen deprivation therapy (ADT) and the prognostic implications of prostate-specific antigen (PSA) kinetics in high-risk localized prostate cancer. The medical records of 140 patients who underwent definitive RT (70 Gy in 28 fractions) combined with ADT were retrospectively reviewed. ADT consists of a gonadotropin-releasing hormone agonist and an anti-androgen. Clinical outcomes included the biochemical failure rate (BFR), clinical failure rate (CFR), overall survival (OS) and prostate cancer-specific survival (PCSS). The BFR and CFR were stratified by the PSA nadir and the time to the PSA nadir, respectively. Acute and late genitourinary and gastrointestinal adverse events were also recorded. The 5-year BFR, CFR, OS and PCSS rates were 9.8%, 4.5%, 90.2% and 98.7%, respectively. Ninety-five (67.9%) patients achieved a PSA nadir of 0.01 ng/mL. Patients with a PSA nadir >0.01 ng/mL had a significantly higher BFR and CFR (BFR, P = 0.001; CFR, P = 0.027), even after adjusting for other prognostic factors [per 0.1 ng/mL; BFR, hazard ratio (HR) 4.440, P < 0.001; CFR, HR 4.338, P = 0.001]. However, the time to the PSA nadir and pre-RT PSA were not significantly associated with the BFR and CFR. Six patients (4.3%) reported grade 3 late adverse events, mostly haematuria and haematochezia. Definitive RT with moderate hypofractionation combined with long-term ADT showed good efficacy for high-risk localized prostate cancer. The lowest PSA nadir was significantly associated with a low recurrence rate, indicating the importance of PSA follow-up.

High-volume prostate biopsy core involvement is not associated with an increased risk of cancer recurrence following 5-fraction stereotactic body radiation therapy monotherapy

PurposePercentage of positive cores involved on a systemic prostate biopsy has been established as a risk factor for adverse oncologic outcomes and is a National Comprehensive Cancer Network (NCCN) independent parameter for unfavorable intermediate-risk disease. Most data from a radiation standpoint was published in an era of conventional fractionation. We explore whether the higher biological dose delivered with SBRT can mitigate this risk factor.MethodsA large single institutional database was interrogated to identify all patients diagnosed with localized prostate cancer (PCa) treated with 5-fraction SBRT without ADT. Pathology results were reviewed to determine detailed core involvement as well as Gleason score (GS). High-volume biopsy core involvement was defined as ≥ 50%. Weighted Gleason core involvement was reviewed, giving higher weight to higher-grade cancer. The PSA kinetics and oncologic outcomes were analyzed for association with core involvement.ResultsFrom 2009 to 2018, 1590 patients were identified who underwent SBRT for localized PCa. High-volume core involvement was a relatively rare event observed in 19% of our cohort, which was observed more in patients with small prostates (p < 0.0001) and/or intermediate-risk disease (p = 0.005). Higher PSA nadir was observed in those patients with low-volume core involvement within the intermediate-risk cohort (p = 0.004), which was confirmed when core involvement was analyzed as a continuous variable weighted by Gleason score (p = 0.049). High-volume core involvement was not associated with biochemical progression (p = 0.234).ConclusionsWith a median follow-up of over 4 years, biochemical progression was not associated with pretreatment high-volume core involvement for patients treated with 5-fraction SBRT alone. In the era of prostate SBRT and MRI-directed prostate biopsies, the use of high-volume core involvement as an independent predictor of unfavorable intermediate risk disease should be revisited.

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.

Prognostic Value of the Modeled Prostate-Specific Antigen KELIM Confirmation in Metastatic Castration-Resistant Prostate Cancer Treated With Taxanes in FIRSTANA.

In a previous exploratory study, modeled early longitudinal prostate-specific antigen (PSA) kinetics observed within the 100-first treatment days with androgen deprivation therapy with or without docetaxel was associated with progression-free survival (PFS) and overall survival (OS) in patients with prostate cancer with rising PSA levels after primary local therapy. This prognostic value had to be confirmed in different settings. The objectives were to assess PSA kinetics modeling in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with chemotherapy in FIRSTANA trial and to investigate modeled PSA kinetic parameters prognostic/predictive value. FIRSTANA phase III trial (ClinicalTrials.gov identifier: NCT01308567) assessed whether cabazitaxel is superior to docetaxel in terms of PFS/OS in patients with chemotherapy-naïve mCRPC. PSA longitudinal kinetics was assessed using the previous kinetic-pharmacodynamics model. Patient modeled ELIMination rate constant K (PSA.KELIM) was used to categorize favorable/unfavorable PSA declines (standardized PSA.KELIM < or ≥ 1.0 days-1) and further correlated with PFS/OS. In total, 1,050 of 1,168 enrolled patients were assessable for PSA.KELIM estimation. The median PSA.KELIM was 0.02 days-1. In univariate analyses, PSA.KELIM exhibited a significant prognostic value regarding survival: unfavorable versus favorable PSA.KELIM; median PFS, 3.6 months (95% CI, 3.0 to 4.2) versus 4.7 months (95% CI, 3.9 to 5.2), P = .002; median OS, 17.4 months (95% CI, 14.8 to 19.3) versus 28.4 months (95% CI, 26.7 to 31.6), P < .001. In multivariate analyses, PSA.KELIM was significant for PFS (hazard ratio [HR], 0.79 [95% CI, 0.67 to 0.93], P = .005) and OS (HR, 0.51 [95% CI, 0.44 to 0.60], P < .001), together with baseline radiological tumor progression and PSA doubling time. PSA.KELIM predictive value was not significant across treatment arms. This external validation study confirmed previous results about modeled PSA longitudinal kinetics prognostic value regarding PFS/OS in patients with mCRPC treated with taxanes. PSA.KELIM could be used to identify a subpopulation with poor prognosis, who may benefit from treatment intensification.

(213) Assessing Primary Care Physicians Awareness of 5-Alpha Reductase Inhibitors for Men with Benign Prostatic Hyperplasia

Abstract Introduction Primary care physicians (PCPs) commonly prescribe 5-alpha-reductase inhibitors (5-ARIs) for the management of benign prostatic hyperplasia (BPH). 5-ARIs can affect prostate-specific antigen (PSA) kinetics by decreasing PSA levels by approximately half, and therefore delay the early detection of prostate cancer (PCa). Objective To determine PCPs’ level of awareness and indications for urology referral in patients treated with 5-ARIs. Methods After IRB approval, an anonymous survey was emailed to affiliated PCPs at an academic urban institution. Questions focused on residency graduation year, patient volume, knowledge of 5-ARIs and their effects on PSA, role of 5-ARIs in PCa prevention, and indications for prostate biopsy referral. PCPs were stratified by residency graduation year before or after 2010, or medical specialty of Family Medicine or Internal Medicine. Survey responses were summarized with descriptive statistics and responses between groups (residency graduation year or medical specialty) were compared using Chi-squared test. Results A total of 182 PCPs were emailed, of which 30 responded (16.5% response rate). Thirteen PCPs (43.3%) graduated residency before 2010 and 17 (56.7%) after 2010. Sixteen PCPs (53.3%) were Family Medicine physicians and 14 (46.7%) were Internists. The majority of PCPs reported that every 6 months, they saw at least one patient with BPH (96.7%), ordered at least one PSA test (86.7%), and referred at least one patient for a prostate biopsy (56.7%). Forty percent of PCPs were not aware of the suppressive effects of 5-ARIs on PSA, 70.0% would not refer a patient for a prostate biopsy who is taking 5-ARIs and has an elevated corrected PSA, 70.0% were not sure or thought that 5-ARIs may decrease the risk of high-grade PCa, and 43.3% were not sure or thought that 5-ARIs are approved for the prevention of PCa. There were no significant differences in the knowledge of 5-ARIs and their effects on PSA, role of 5-ARIs in PCa prevention, or indications for prostate biopsy referral between PCPs who graduated residency before 2010 and after 2010, or between PCPs who were Family Medicine physicians and Internists (p&amp;gt;0.05 for all). Conclusions There is a general lack of awareness amongst PCPs on the knowledge of 5-ARIs and indications for biopsy referral in patients treated with 5-ARIs. An educational opportunity exists to optimize usage of 5-ARIs and avoid delaying PCa detection. Disclosure No.

Real-world effectiveness of PARP inhibitors (PARPi) in metastatic castration-resistant prostate cancer (mCRPC) by genomic homologous recombination repair (HRR) alterations and homologous recombination deficiency signature (HRDsig).

186 Background: Multiple randomized controlled trials have demonstrated efficacy of poly ADP-ribose polymerase (PARP) inhibitors in patients with metastatic castration resistant prostate cancer (mCRPC) harboring deleterious BRCA1 or BRCA2 alterations (BRCAalt). Alterations in other DNA HRR gene pathways are common and the efficacy of PARPi in these populations is less clear. We sought to evaluate the real-world effectiveness of PARPi in commonly defined HRR groups and explore clinical validity of HRDsig to additionally predict outcomes on PARPi. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine Prostate Cancer clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (~800 sites of care). Patients with mCRPC and tumor genomic profiling (tissue or liquid) who underwent single agent PARPi treatment were included, grouped by biomarkers with deleterious alterations detected: BRCA, ATM, other HRR ( ATR, ATRX, BAP1, BARD1, BRIP1, CHEK1/2, CDK12, FANCA, FANCL, MRE11, RAD51B/C/D, RAD54L, PALB2), or no HRR. Separately, patients with mCRPC and tumor tissue profiling were grouped by HRDsig status (+ vs -) using a machine learning- based algorithm built using a diverse set of copy number features. Kaplan Meier estimates and multivariable Cox PH models assessed time to next therapy (TTNT), time to treatment discontinuation (TTD), and real-world overall survival (rwOS). Results: 313 patients with mCRPC met inclusion criteria, of which 162 had tissue specimens for genomics evaluations and 151 had liquid profiling. In the tissue cohort, BRCAalt had more favorable TTNT (median 10.0 months, 95% CI 8.0 – 14.1) relative to ATM (median 3.8 months, 95% CI 2.7 – 6.9), other HRR (median 4.9 months, 95% CI 3.6 – 7.2) and no HRR (median 4.9, 95% CI 3.6 – 7.2 months). Other proxies for drug effectiveness (TTD, PSA kinetics) and rwOS had consistent results. More granular mutational analyses and liquid profiling data will be presented at the conference. Among evaluable patients without BRCAalt on tissue biopsy receiving PARPi, 5 of 75 (7%) were HRDsig(+) and had directionally more favorable (vs. HRDsig(-)) TTNT (HR: 0.39, 95%CI 0.14 – 1.12), TTD (0.46, 95%CI 0.16 – 1.31) and rwOS (HR: 0.27, 95%CI 0.07 – 1.14). Conclusions: We observe no significant outcomes difference between non- BRCAalt groups (defined as ATM, other HRR, and no HRR) in this cohort with respect to proxies of drug effectiveness. These results are largely consistent with biomarker-defined subgroup analyses from completed clinical trials. However, HRDsig may be able to identify a small non-BRCAalt subgroup with enhanced benefit. Associations of BRCAalt(-)/HRDsig(+) and PARPi performance deserve further attention in additional cohorts.

Advancing the drug development process in metastatic prostate cancer through machine learning.

192 Background: Despite advances in the development of systemic therapeutics, metastatic prostate cancer (mPC) remains a lethal disease. The drug approval process is slow, and delays in approving active agents translate into lives lost, and increased morbidity for men living with mPC. Clinical benefit end points proximate to survival that could support regulatory approval have been sought. Methods that accelerate the prediction of overall survival (OS) from baseline and short-term clinical data could dramatically accelerate the "readout" timeline for registrational studies. Methods: Curated, anonymized data from 5,679 mPC patients (pts) across six completed clinical trials were used: COU-AA-301, COU-AA302, ACIS, GALAHAD, LATITUDE, and TITAN. These trials comprise heterogeneous pts across castrate sensitive (TITAN, LATITUDE) and castrate resistant (COU-AA-301, COU-AA-302, ACIS, GALAHAD) populations. Transcriptomic profiles of primary tumors were available from a subset of these pts (N = 605) in COU-AA-302, ACIS, TITAN using the DECIPHER platform (Decipher Biosciences, Inc.). We harmonized pts study data and are developing machine learning models in an attempt to predict long term outcomes using baseline clinical features, short term PSA kinetics, and transcriptional profiling data. Associations between clinical and transcriptional signature profiles and overall survival were assessed with the Cox proportional hazards model. Results: Pts were assigned to training (N = 3167) and test (N = 2,512) cohorts. Cohorts were balanced by age, self-reported race, ECOG performance status, extent of disease, and disease site, and had statistically indistinguishable survival curves. At month 3 on study, 97% of pts had PSA data available; 88% had ≥ 2 PSA values. Matched genomic data was evaluated in 504 and 101 pts in training and test sets respectively. Training cohort pts with a 50% reduction in PSA by month 3 (m3-PSA50) had significantly longer OS (HR 0.51 [0.38-0.67]; p = 1.2 x 106, median 26 vs. 38 months). ANOVA analysis identified expression signatures in the Decipher GRID that significantly improved OS model performance when added to a model including only m3-PSA50. We stratified pts by a combined m3-PSA50 and signature score and identified signatures that improved model fit over m3-PSA50 alone and significantly stratified pts in the test cohort (P &lt; 0.05). Conclusions: In this early analysis (prior to applying machine learning), m3-PSA50 was significantly associated with OS in a heterogeneous group of mPC pts. Although the transcriptomic analysis was conducted on primary tumors obtained many years earlier, we identified transcriptional signatures that significantly improved OS models (independent of m3-PSA50) in men who subsequently developed mPC many years later. These results suggest adding genomic signature data to models for predicting outcome using PSA kinetics may provide improved predictive power.

Feasibility of Monitoring Response to Metastatic Prostate Cancer Treatment with a Methylation-Based Circulating Tumor DNA Approach

Background: Metastatic prostate cancer (mPCA) poses challenges in treatment response assessment, particularly in cases where prostate-specific antigen (PSA) levels do not reliably indicate a response. Liquid biopsy, focusing on circulating cell-free DNA (ccfDNA) methylation analysis as a proxy for circulating tumor DNA, offers a non-invasive and cost-effective approach. This study explores the potential of two methylation markers, short stature homeobox 2 (SHOX2) and Septin 9 (SEPT9), as on-mPCA-treatment biomarkers. Methods: Plasma samples were collected from 11 mPCA patients undergoing various treatments. Quantitative assessment of hypermethylated SHOX2 (mSHOX2) and SEPT9 (mSEPT9) levels in ccfDNA was conducted through methylation-specific real-time PCR. Early and overall dynamics of PSA, mSHOX2, and mSEPT9 were analyzed. Statistical evaluation employed Wilcoxon tests. Results: mSHOX2 demonstrated a significant decline post-treatment in patients with a radiographic treatment response as well as in an early treatment setting. mSEPT9 and PSA exhibited non-significant declines. In individual cases, biomarker dynamics revealed unique patterns compared to PSA. Discussion: mSHOX2 and mSEPT9 exhibit dynamics on mPCA treatment. This proof-of-concept study lays the groundwork for further investigation into these markers as valuable additions to treatment response monitoring in mPCA. Further validation in larger cohorts is essential for establishing clinical utility.

Comparative effectiveness of multiple androgen receptor signaling inhibitor medicines with androgen deprivation therapy for metastatic hormone-sensitive prostate cancer: a study in the real world.

The current treatment strategy for metastatic Hormone-Sensitive Prostate Cancer (mHSPC) is the combination of Androgen Receptor Signaling Inhibitors (ARSIs) medicines with androgen deprivation therapy (ADT). However, there is a lack of real-world data comparing the efficacy of different ARSI pharmaceuticals. Therefore, the objective of this study was to compare the effectiveness and safety of bicalutamide, abiraterone, enzalutamide, and apalutamide in combination with ADT for patients with mHSPC. We retrospectively analyzed 82 patients diagnosed with mHSPC, including 18 patients treated with abiraterone acetate with prednisone, 21 patients with enzalutamide, 20 patients with apalutamide, and 23 patients with bicalutamide. We evaluated PSA progression-free survival (PSA-PFS), imaging progression-free survival (r PFS), castration resistance progression-free survival (CRPC-PFS), and overall survival (OS) using Kaplan-Meier survival analyses. Additionally, we explored relevant factors affecting prognosis through univariate and multivariate Cox risk-proportionality models. PSA response rates at 3, 6, and 12 months, nadir PSA levels (nPSA), and time to nadir (TTN) in different medication subgroups after treatment were documented, and we used one-way ANOVA to determine the effect of these measures on patient prognosis. In comparison with bicalutamide, both enzalutamide and apalutamide have shown significant advantages in delaying disease progression among mHSPC patients. Specifically, enzalutamide has been found to significantly prolong PSA-PFS (HR 2.244; 95% CI 1.366-3.685, p=0.001), rPFS (HR 2.539; 95% CI 1.181-5.461; p= 0.007), CRPC-PFS (HR 2.131; 95% CI 1.295-3.506; p= 0.003), and OS (HR 2.06; 95% CI 1.183-3.585; P=0.005). Similarly, apalutamide has significantly extended PSA-PFS (HR 5.071; 95% CI 1.711-15.032; P= 0.003) and CRPC-PFS (HR 6.724; 95% CI 1.976-22.878; P=0.002) among patients. On the other hand, the use of abiraterone in combination with ADT did not demonstrate a significant advantage in delaying diseases progression when compared with the other three agents in mHSPC patients. There were no significant differences in overall adverse event rates among the four pharmaceuticals in terms of safety. Additionally, the observation of PSA kinetics revealed that enzalutamide, apalutamide, and abiraterone acetate had a significant advantage in achieving deep PSA response (PSA ≤ 0.2 ng/ml) compared with bicalutamide (p=0.007 at 12 months). Enzalutamide and apalutamide exhibited preeminence efficacy, with no substantial difference observed between the two medications. Abiraterone, enzalutamide, and apalutamide were found to significantly reduce and stabilize PSA levels in mHSPC patients more quickly and thoroughly than bicalutamide. Furthermore, enzalutamide and apalutamide were found to significantly prolong survival and delay disease progression in mHSPC patients compared with bicalutamide. It should be noted that abiraterone did not demonstrate a significant advantage in delaying disease compared with enzalutamide and apalutamide. After conducting drug toxicity analyses, it was determined that there were no significant differences among the four drugs.

Abstract C017: Comparing prostate specific antigen dynamics between Black patients and White patients

Abstract Black men have the highest prostate cancer (PCa) mortality across all US population groups. We hypothesize that this may be the result of low participation from black men in clinical trials and socioeconomic facotrs. We use a simple mathematical model to investigate differences in PSA dynamics between black and white men undergoing androgen deprivation therapy (ADT).   The model was calibrated to longitudinal PSA data from 57 PCa patients (N = 47 white, N = 10 black) receiving continuous androgen deprivation therapy (ADT). To compensate for the lack of data for black patients, propensity score matching was used to select 15 white patients that were most alike to the 10 black patients based on their Eastern Cooperative Oncology Group (ECOG) score, age, and tumor burden. Using a previously developed model of stem cell, non-stem, and prostate-specific antigen (PSA) dynamics, parameter analysis and leave-one-out process were used to determine which parameters should be uniform among all patients and which should be patient-specific to determine if any parameters showed a significant difference. Each patient’s parameter values were used to see if intermittent ADT (IADT) or adaptive ADT could extend the time to progression and narrow disparity gaps. We then sampled from the parameter distributions to create 50 black and 50 white in-silico patients to simulate continuous and intermittent ADT to further validate our results.   The leave-one-out analysis found that a uniform ADT cytotoxicity resulted in the best Akaike Information Criteria score for black and white patients. A nested optimization was subsequently used to determine race-specific uniform cytotoxicity rates, while the remaining patient-specific parameters were determined.  Statistical analysis found that black patients had a significantly higher stem cell self-renewal rate than the white patients. We hypothesize that this is primarily responsible for earlier progression in black patients. Simulations of continuous and intermittent ADT for real and in-silico patients showed that IADT and adaptive ADT can extend the time to progression (TTP) for both black and white patients. The TTP was extended by 50% for the black patients, and 25% for the white patients, thus the black patients had a greater benefit. However, the median TTP for black patients on IADT was less than that for white patients on continuous ADT. This suggests that further investigation of different treatments needs to be done to close disparity gaps.   Our results show that stem cell self-renewal is driving differences in PSA dynamics between white and black patients. Intermittent Androgen Deprivation Therapy could potentially be a step in addressing the higher stem-cell self-renewal rate in black patients and narrowing the health disparity gap between black and white Pca patients. This valuable information can be used in the future to design race-specific treatment modalities to maximally delay time to progression.   Citation Format: Alexandria Johnson, Renee Brady. Comparing prostate specific antigen dynamics between Black patients and White patients [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C017.

Carbon Ion Radiation Therapy for Nonmetastatic Castration-Resistant Prostate Cancer: A Retrospective Analysis

PurposeTreatment outcomes of definitive photon radiotherapy for nonmetastatic castration-resistant prostate cancer (nmCRPC) are reportedly unsatisfactory. Carbon ion radiotherapy (CIRT) has shown favorable tumor control in various malignancies, including radioresistant tumors. Therefore, we retrospectively evaluated the clinical outcomes of CIRT for nmCRPC. Methods and MaterialsPatients with nmCRPC (N0M0) treated with CIRT at a total dose of 57.6 Gy (relative biological effectiveness; RBE) in 16 fractions or 51.6 Gy (RBE) in 12 fractions were included. The castration-resistant status was diagnosed based on prostate-specific antigen kinetics showing a monotonic increase during primary androgen deprivation therapy (ADT) or the need to change ADT. Clinical factors associated with patient prognosis were explored. Twenty-three consecutive patients were identified from our database. The median follow-up period was 63.6 months (range, 14.1–120). ResultsSeven patients developed biochemical relapse, six had clinical relapse, and four died from the disease. The 5-year overall survival, local control rate, biochemical relapse-free survival, and clinical relapse-free survival were 87.5%, 95.7%, 70.3%, and 75.7%, respectively. One patient with diabetes mellitus requiring insulin injections and taking antiplatelet and anticoagulant drugs developed grade 3 hematuria and bladder tamponade after CIRT. None of the patients developed grade 4 or worse toxicity. ConclusionsThe present findings indicate the acceptable safety and favorable efficacy of CIRT, encouraging further research on CIRT for nmCRPC.

Nonregional Lymph Node Metastasis as a Predictor of Early Progression When Using Androgen Receptor Targeting Agents in Patients With Metastatic Castration-Resistant Prostate Cancer Without Previous Chemotherapy

Purpose: In present, the use of androgen receptor targeting agents (ARTA) is one of the standard treatments for metastatic castration-resistant prostate cancer (mCRPC) without previous chemotherapy. However, some patients may experience early progression despite ARTA use. Therefore, we analyzed predictors of early progression.Materials and Methods: We retrospectively analyzed patients treated with ARTA for mCRPC before chemotherapy at Inha University Hospital. Patients were divided into an early progression group and a late progression group. The 2 groups were defined as a group that used ARTA for more than 1 year without progression and a group that did not. Clinical and pathological parameters were analyzed to evaluate the oncologic outcomes. Univariate and multivariate logistic regression analyses were used to predict progression markers.Results: The final analysis included 70 patients. The mean progression-free duration with ARTA use was 334.90±364.716 days. There were 44 and 26 patients in the early and late progression groups, respectively. Univariate and multivariate logistic regression analyses did not show statistically significant results for the ARTA medication type, body mass index, Gleason grade group, visceral metastasis, bone metastasis, regional lymph node (LN) metastasis, time to CRPC, and prostate-specific antigen kinetics. In contrast, age (odds ratio [OR], 1.154; 95% confidence interval [CI], 1.043–1.251) and nonregional LN metastasis (OR, 8.819; 95% CI, 1.165–66.746) were significantly associated with the progression-free duration of ARTA use in multivariate logistic regression analysis.Conclusions: We think that nonregional LN metastasis is a predictor of early progression when using ARTA in patients with mCRPC without previous chemotherapy.

P112 - Analysis of prostate-specific antigen (PSA) kinetics in the third month of treatment with apalutamide in metastatic castration-sensitive prostate cancer (mCSPC)

P112 - Analysis of prostate-specific antigen (PSA) kinetics in the third month of treatment with apalutamide in metastatic castration-sensitive prostate cancer (mCSPC)

EAU Biochemical Recurrence Risk Classification and PSA Kinetics Have No Value for Patient Selection in PSMA-Radioguided Surgery (PSMA-RGS) for Oligorecurrent Prostate Cancer.

To assess the influence of biochemical recurrence (BCR) risk groups and PSA kinetics on the outcomes of radioguided surgery against prostate-specific membrane antigen (PSMA-RGS). Currently, neither BCR risk group nor PSA doubling time (PSA-DT), or PSA velocity (PSA-V) are actively assigned or relevant for counseling prior to PSMA-RGS. We retrospectively analyzed PSMA-RGS cases for oligorecurrent prostate cancer between 2014 and 2023. BCR risk groups, PSA-DT, and PSA-V were analyzed as predictors for complete biochemical response (cBR, PSA < 0.2 ng/mL), BCR-free, and therapy-free survival (BCRFS, TFS). Of 374 included patients, only 21/374 (6%) and 201/374 (54%) were classified as low- and high-risk BCR (no group assignment possible in 152/374, 41%). A total of 13/21 (62%) patients with low- and 120/201 (60%) with high-risk BCR achieved cBR (p = 1.0). BCR classification was no predictor for BCRFS (HR:1.61, CI: 0.70-3.71, p = 0.3) or subsequent TFS (HR:1.07, CI: 0.46-2.47, p = 0.9). A total of 47/76 (62%) patients with PSA-DT ≤ 6 mo and 50/84 (60%) with PSA-DT > 6 mo achieved cBR (p = 0.4). PSA-DT was not associated with cBR (OR: 0.99, CI: 0.95-1.03, p = 0.5), BCRFS (HR: 1.00, CI: 0.97-1.03, p = 0.9), or TFS (HR: 1.02, CI: 0.99-1.04, p = 0.2). Consistent negative findings were recorded for PSA-V. The BCR risk groups and PSA kinetics do not predict the oncological success of PSMA-RGS performed at low absolute PSA values. Indolent low-risk BCR is rarely treated by PSMA-RGS.

Association of Prostate Specific Antigen Kinetics after Testosterone Recovery with Subsequent Recurrence: Secondary Analysis of a Phase III Randomized Controlled Trial.

The combination of short-term androgen deprivation therapy (ST-ADT) with prostate radiotherapy (RT) is a standard of care for patients with localized prostate cancer (LPCa). After cessation of ST-ADT, it takes about 8 to 10 months for the testosterone (T) to recover to supracastrate levels, which could drive changes in PSA kinetics. It largely remains unknown whether early changes in PSA kinetics after T recovery could predict for subsequent biochemical relapse. We performed a secondary analysis of a phase III randomized controlled trial in which patients with newly diagnosed LPCa with Gleason score £7, clinical stage T1b to T3a, and PSA <30 ng/mL were randomly allocated to neoadjuvant and concurrent ADT for 6 months starting 4 months before prostate RT (76 Gy in 38 fractions over 7.5 weeks) or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate RT. Clinical assessment and laboratory investigations were repeated 1 month after completion of ADT, every 4 months for the first 2 years, every 6 months for the next 3 years, and annually thereafter. We calculated the PSA doubling time (PSADT) based on PSA values up to 18 months after recovery of T to a supracastrate level (>50 ng/dL). Patients with ³3 PSA measurements after T recovery to supracastrate level were included in this analysis. Fine and Gray cumulative incidence of biochemical recurrence (BCR) was calculated in patients with PSADT at or above median versus below median. Deaths were considered as competing events. All endpoints were calculated from the time of T recovery to supracastrate level. Subdistribution hazard ratios (sHR) with 95% confidence intervals (CI) were estimated for association of PSADT with relative incidence of recurrence using competing risk regression after adjusting for tumor stage, pre-treatment PSA, Gleason score, treatment regimen, and age at randomization. Overall, 311 patients were eligible for this analysis. Median PSADT was 8 months. Cumulative incidence of BCR at 10 years was 31.0% and 20.7% in patients with PSADT <8 months and ³8 months, respectively. Longer PSADT was associated with a significantly lower risk of cumulative incidence of BCR (sHR for PSADT as a continuous variable 0.43, 95% CI: 0.28-0.66; sHR for PSADT ³8 months 0.54, 95% CI: 0.30-0.99). After adjustment for time to recovery of T to supracastrate level in addition to the aforementioned variables, longer PSADT (³8 months) was associated with lower risk of cumulative incidence of BCR (sHR: 0.53, 95% CI: 0.27-1.01). These findings suggest that early PSA kinetics within 18 months of recovery of T to a supracastrate level predict for subsequent biochemical failure. Taking account of early changes in PSA after testosterone recovery may allow for recognition of potential failures earlier in the disease course and thereby permit greater personalization of management decisions.

Prostate-specific antigen kinetics in hypofractionated radiation therapy alone for intermediate- and high-risk localized prostate cancer.

This study aimed to evaluate the treatment outcomes and define the prostate-specific antigen (PSA) kinetics as potential prognostic factors in patients with intermediate- or high-risk localized prostate cancer (PCa) who underwent moderately hypofractionated radiation therapy. The study retrospectively reviewed the medical records of 149 patients with intermediate- or high-risk localized PCa who underwent definitive radiation therapy (70Gy in 28 fractions) without androgen deprivation therapy. Clinical outcomes were analyzed based on risk stratification (favorable-intermediate, unfavorable-intermediate, and high-risk). The biochemical failure rate (BFR) and clinical failure rate (CFR) were stratified based on the PSA nadir and the time to the PSA nadir to identify the prognostic effect of PSA kinetics. Acute and late genitourinary and gastrointestinal adverse events were analyzed. Significant differences were observed in the BFR and CFR according to risk stratification. No recurrence was observed in the favorable intermediate-risk group. The 7-year BFR and CFR for the unfavorable intermediate-risk and high-risk groups were 19.2% and 9.8%, and 31.1% and 25.3%, respectively. Patients with a PSA nadir >0.33ng/mL or a time to the PSA nadir <36months had a significantly greater BFR and CFR. The crude rate of grade 3 late adverse events was 3.4% (genitourinary: 0.7%; gastrointestinal: 2.7%). No grade 4-5 adverse event was reported. A significant difference in clinical outcomes was observed according to risk stratification. The PSA nadir and time to the PSA nadir were strongly associated with the BFR and CFR. Therefore, PSA kinetics during follow-up are important for predicting prognosis.