Prostate-specific Antigen Increase Research Articles

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.

Prostate-specific antigen (PSA) levels in men with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a rare genetic disorder typically characterized by body composition abnormalities, hyperphagia, behavioral challenges, cognitive dysfunction, and hormone deficiencies. Hypogonadism is common but knowledge on potential side effects of testosterone replacement is limited, in particular, the long-term effects on behavior and PSA. Patients and methodsRetrospective case studies of seven men, median age 46 years, with genetically verified PWS, testosterone treated hypogonadism and available PSA values were included. Long-term follow-up of PSA was accessible in four patients. Medical records were reviewed for adverse effects. ResultsFive men were treated with intramuscular testosterone undecanoate, two had no hypogonadism. Median PSA was 0.68 μg/L (0.23–1.3), median testosterone 15 nmol/L. After a median time of 17 years of testosterone replacement median PSA was 0.75 μg/L (range 0.46–1.4). Testosterone replacement was well tolerated, and no major behavioral changes were reported. Five were treated with growth hormone for >20 years. ConclusionLevels of PSA were low. Long-term treatment with testosterone was working well and did not result in any clinically meaningful increase in PSA. Our results indicate that testosterone replacement is neither associated with serious adverse events regarding changes in behavior or effect on PSA. However, larger studies are needed to confirm our results.

Triggers for transition from active surveillance to radical treatment of prostate cancer 2008-2020 - a case-control study.

To examine associations between objective signs of progression (triggers) and transition from active surveillance (AS) to radical treatment for prostate cancer (PC). This case-control study included men with low- or favourable intermediate-risk PC in the region of Halland, with data from The National Prostate Cancer Register (NPCR), Sweden, starting AS between 2008 and 2020. Cases were men who transitioned to radical treatment. For each case, 10 controls who remained in AS were selected without further matching. Triggers for transition to treatment were histopathological progression, magnetic resonance imaging (MRI) progression and increases in prostate-specific antigen (PSA) levels. We compared the probabilities for triggers between cases and controls, in 2008-2014 and 2015-2020, using logistic regression. Amongst 846 men, we identified 98 cases in 2008-2014 and 172 cases in 2015-2020. Histopathological progression was associated with transition, most strongly in the later period (2008-2014: odds ratios [OR] 6.88, 95% confidence interval [CI] 3.69-12.80; and 2015-2020: OR 75.29, 95% CI 39.60-143.17). MRI progression was associated with transition in 2015-2020 (OR 6.38, 95% CI 2.70-15.06), whereas an increase in PSA was weakly associated with transition in the early period. The absence of triggers was associated with no transition (2008-2014: OR 0.24, 95% CI 0.15-0.40, and 2015-2020: OR 0.09, 95% CI 0.06-0.14). The probability of no trigger was 27% in cases 2015-2020. The increase in association between histopathological trigger and transition to treatment indicates increased quality of AS. Still, amongst men treated from 2015 to 2020, 27% transitioned without any trigger.

The impact of positive vas deferens in the biochemical relapse in patients with stage T3b prostate cancer submitted to radical Prostatectomy

The study aimed to evaluate the influence of invasion of the vas deferens and seminal vesicles in patients undergoing radical prostatectomy for stage T3b tumor on biochemical recurrence.Methods: Retrospective analysis of 53 patients submitted to radical prostatectomy with anatomopathological stage T3b, at Hospital de Clínicas da Unicamp, between 1997 and 2014. After exclusion criteria were applied, statistical analysis of 32 participants separated into 2 groups, in which 20 patients (62.5 %) without involvement of the vas deferens (group 1) and 12 (37.5%) with invasion of the vas deferens (group 2). Biochemical recurrence was defined as an increase in prostate specific antigen (PSA) greater than or equal to 0.2 ng/ml after surgery. Results: Regarding the disease-free survival analysis, group 2 has a 3.05 times greater risk of having a biochemical recurrence compared to group 1 (HR 3.05, 95% CI 1.12-8.32, p=0.03), calculated by regression of Cox and Log Rank test. Conclusion: In conclusion, this study has identified an elevated risk of biochemical recurrence in patients with both ductus deferens and seminal vesicle invasion.

Possibilities of early diagnosis of localized prostate cancer in outpatient practice of a urologist at the regional level in the stavropol territory

Aim. To develop and implement an algorithm for early diagnosis of a localized form of prostate cancer based on the determination of the specificity of the prostate-specific antigen (PSA) marker in different age groups.Materials and methods. In the framework of a screening program for early detection of diseases of the urogenital system developed at the Stavropol Regional Clinical Specialized Uroandrological Center, middle-aged and elderly men were examined using the following characteristics: IPSS (International Prostate Symptom Score), serum PSA level, digital rectal exam, transrectal prostate ultrasound, urodynamic tests, as well as transrectal ultrasound-guided prostate biopsy in cases of elevated total PSA. The data (for 2010–2021) on the frequency of detection of localized prostate cancer depending on patient age (40–59 years, 60–69 years, ³70 years) and total PSA level were analyzed.Results. With an increase in total blood PSA &gt;4 ng/ml, there is a clear trend towards a decrease in the detection of benign prostatic hyperplasia and an increase in the detection of adenocarcinoma, which is confirmed by the data of histological examinations of biopsy specimens. In 81 % of cases, transrectal multifocal biopsy of the prostate gland (adenocarcinoma and prostatic intraepithelial neoplasia was detected) under transrectal ultrasound control is justified, including when PSA values are in the “gray zone”, which shows a rather high value of this method.Conclusion. Total serum PSA level is a readily available indicator for differential diagnosis of prostate diseases including detection of localized prostate cancer in out-patient conditions. The obtained data points at high specificity of this marker in men over 40 years old. Measurement of serum PSA level at the age of 40–49 years is necessary for early detection of oncological pathology. For total serum PSA level &gt;4 ng/mL, mandatory transrectal multifocal prostate biopsy is recommended at any age.

Comparative effects of finasteride and laser-irradiated silver nanoparticles on testicular function and histology in testosterone induced benign prostatic hyperplasia in rats

AimsThe objective of this study was to compare the effects of finasteride, a medication used to treat benign prostatic hyperplasia (BPH), and laser irradiated silver nanoparticles (AgNPs), a potential candidate for BPH therapy (Sanchez-Salas, 2017; Marghani et al., 2022) [1,2], on the sex hormone profiles, sperm quality, steroidogenesis, testicular oxidative stress, and histomorphology changes in BPH rats. Materials and methodsBPH was induced in male Sprague-Dawley (SD) rats via intramuscular (i.m.) injection of 5 mg/kg BW testosterone propionate (TP) for 14 days. Once the BPH model was induced, rats were divided into four groups (n = 6) as follows: the control group; the BPH group; the BPH/Fina group, which received 5 mg/kg BW finasteride by oral gavage daily for 14 days; and the BPH/AgNPs group, which received a daily intraperitoneal (i.p.) injection of 50 mg/kg BW AgNPs, followed by 5min of exposure to a 532 nm NIR laser in the prostatic area for the constitutive 14 days. Key findingsOn day 14, the BPH rats had a significant increase in prostate specific antigen (PSA), dihydrotestosterone, and prostate weights, while testicular weights and sperm quality were significantly lower than in the control rats. On day 28, laser irradiated AgNps treated BPH rats showed improved sex hormone balance, testicular weights, sperm quality, steroidogenesis, and an ameliorative effect on testicular histopathology compared to finasteride. SignificanceSurprisingly, these findings suggest that laser irradiated AgNPs can be used as an alternative therapy to finasteride for the treatment of BPH without causing negative effects on the testes.

Diagnostic Performance of 68Ga-PSMA-11 Positron Emission Tomography/Computed Tomography to Monitor Treatment Response in Patients with Metastatic Prostate Cancer: The Concordance Between Biochemical Response and Prostate-specific Membrane Antigen Results

BackgroundTreatment response is traditionally monitored using prostate-specific antigen (PSA) and conventional imaging in patients with metastatic prostate cancer (mPCa). ObjectiveTo assess the diagnostic performance of prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) when monitoring mPCa patients receiving systemic treatment and also to investigate the concordance between PSMA PET response according to the PSMA PET progression (PPP) criteria and biochemical response. Design, setting, and participantsA total of 96 patients with 68Ga-PSMA-11 PET/CT-detected mPCa at baseline PSMA PET/CT (bPSMA) who underwent at least one follow-up scan after receiving systemic treatment were included in the study. PSA levels at bPSMA and follow-up PSMA PET (fPSMA) scans were recorded. The PPP criteria were used to define PSMA progression. Biochemical progression was defined as ≥25% increase in PSA. PSMA PET and PSA responses were dichotomized into progressive disease (PD) versus non-PD, and the concordance between PSA and PSMA responses was evaluated. Outcome measurements and statistical analysisThe concordance between PSA and PSMA PET responses was presented using frequencies, percentages, and Cohen’s kappa test. Results and limitationsA total of 345 serial PSMA PET/CT (96 bPSMA and 249 fPSMA) scans were evaluated. The positivity rates of PSMA PET scans for PSA levels of <0.01, 0.01–0.2, 0.2–4, and >4 ng/ml were 55.6%, 75.0%, 100%, and 98.8%, respectively. PSA and PSMA responses showed moderate-to-high concordance (Cohen’s κ = 0.623, p < 0.001). PSA-PSMA discordance was detected in 39 scans (17%). The most common cause of discordance was the discordant results between different metastatic lesions (16/28, 57.1%) in patients with PPP without PSA progression and local progression in prostate (n = 7/11, 63.6%) in patients with PSA progression without PPP. ConclusionsPSMA PET/CT showed very high detection rates of malignant lesions even at very low PSA values and showed significant concordance with PSA response when monitoring treatment response in patients receiving systemic treatment for mPCa. Patient summaryThis study describes that prostate-specific membrane antigen positron emission tomography (PSMA PET), a new sensitive imaging tool, can detect malignant lesions even at very low prostate-specific antigen values when monitoring metastatic prostate cancer. The PSMA PET response and biochemical response showed significant concordance, and the reason for discordant results seems to be the different responses of metastatic lesions and prostatic lesions to systemic treatment.

MP44-08 RELATIONSHIP BETWEEN COVID 19 VACCINATION AND PSA LEVEL

You have accessJournal of UrologyCME1 Apr 2023MP44-08 RELATIONSHIP BETWEEN COVID 19 VACCINATION AND PSA LEVEL David Ahlborn, Ilene Staff, Tara Mclaughlin, Joseph Tortora, Jeff Mather, and Joseph Wagner David AhlbornDavid Ahlborn More articles by this author , Ilene StaffIlene Staff More articles by this author , Tara MclaughlinTara Mclaughlin More articles by this author , Joseph TortoraJoseph Tortora More articles by this author , Jeff MatherJeff Mather More articles by this author , and Joseph WagnerJoseph Wagner More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003290.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Some reports have indicated that the COVID vaccine could affect parameters used for some cancer screenings. The effect of COVID vaccination on breast cancer screening mammograms has been hotly debated and anecdotal reports of a rise in prostate-specific antigen (PSA) after COVID vaccination have appeared in the media. We explored the relationship between PSA levels and COVID vaccination. METHODS: With IRB approval, we queried the electronic medical record for men who received at least two mRNA COVID vaccine injections (Pfizer or Moderna), at least one PSA test within two years prior to the first vaccine injection and at least one PSA within one year of their second injection and before any third injection. PSA results were grouped according to the timing of the post vaccination PSA. The pre-vaccine PSA closest to the first injection was used. Both within and between subject analyses were conducted. Wilcoxon signed rank tests were performed to compare PSAs pre- and post- vaccine for each time defined group. McNemar tests were used to assess the percentage of patients crossing a 4.0 ng/dl threshold when compared with their pre-vaccine PSA. Difference in relative PSA change across the groups was compared using a Kruskal Wallis test. RESULTS: 5713 men met inclusion criteria. Median pre-vaccine PSA was 1.2 ng/dl (IQR 0.6-2.7 ng/dl). The median time difference between vaccine injection 1 and 2 was 22 days (IQR 21-28 days). Within each time group, a significant increase in PSA was observed pre to post and a higher proportion of men went above 4.0 relative to those going below. However, no significant differences were observed across groups (Table 1). CONCLUSIONS: Due to the lack of intergroup differences, PSA increases most likely reflect natural progression rather than any temporal effect of vaccination. Source of Funding: Unfunded © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e613 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information David Ahlborn More articles by this author Ilene Staff More articles by this author Tara Mclaughlin More articles by this author Joseph Tortora More articles by this author Jeff Mather More articles by this author Joseph Wagner More articles by this author Expand All Advertisement PDF downloadLoading ...

The effect of encomir-93 mimic transfection on the expression of miR-93 and PSA and androgen receptor in prostate cancer LNcap cell line.

Prostate cancer (PCa) is one of the most common cancers in men with high mortality rate which is a major concern for men's health. However, the molecular mechanisms remain poorly understood. miR-93 is an important oncogene which may have important function inprostate cancer.So, this study aimed to predict that encomir-93 mimic transfection on the expression of miR-93 and PSA and AR in prostate cancer LNcap cell line. Lymph node carcinoma of the prostate (LNCaP) was cultured and then miR-93 mimics wasdesigned, synthesized and the transfected to LNCaP. Theexpression level of prostate-specific antigen (PSA) andandrogen receptor (AR) was determined via Real-time PCR after treated with 15pmol of miR-93 mimics. miR-93 mimic transfection led to significant increase in PSA and AR expression in comparison with control group (p≤0.05). The miR-93 and its target genes has important role in PCa progression via enhancement in PSA and AR expression. Further research on the function of the miR-93 and its target genes in tumorgenesis and progression PCa could be helpful for the treatment of prostate cancer.

Oncologic outcomes of postoperative adjuvant versus salvage radiotherapy in prostate cancer.

The aim of this study was to compare the long-term oncological results of patients with the diagnosis of prostate cancer who underwent open radical retropubic prostatectomy (RRP) and subsequent adjuvant (ART) or salvage radiotherapy (SRT). A total of 145 patients underwent open RRP for prostate cancer and subsequent ART or SRT postoperatively between 2010 and 2019. ART (n = 56) is defined as the group of patients with prostate-specific antigen (PSA) <0.2 ng/mL or with positive lymph nodes without PSA increase who received radiotherapy within the first 6 months of urinary continence. SRT (n = 89) is defined as the group of patients with PSA >0.2 ng/mL who received RT before PSA amounted to 0.5 ng/mL. Statistically no significant difference was found between groups in terms of age, prostate volume, final pathology Gleason scores, lymphadenectomy, duration of androgen deprivation therapy (ADT), time to relapse after radiotherapy, development of biochemical recurrence and disease progression. Extraprostatic extension, seminal vesicle invasion and surgical margin positivity were significantly higher in the ART group. No difference was found between the groups in terms of biochemical recurrence-free survival, while cancer-specific survival and overall survival rates were significantly higher in the SRT group. It was found that cancer-specific and overall survival was better in the SRT group. It will be more appropriate to follow-up until the recurrence and then to perform SRT after the relapse in the postoperative period.

Serum Prostate Specific Antigen and Mast Cells in Distinguishing Benign Prostatic Hyperplasia from Prostatic Carcinoma: Is there a Correlation?

Introduction: Benign Hyperplasia of the Prostate (BHP) and prostate cancer comprise about 90% of all diseases of the prostate gland. An increase in serum Prostate Specific Antigen (PSA) is an indicator of underlying hyperplasia, inflammation, or cancer. Mast cells are found in both inflamed and tumour tissue. Aim: To find the correlation of mast cell count with age, weight of prostate, and serum PSA level, and thereby distinguishing between the benign or inflammatory prostatic enlargement against prostatic carcinoma. Materials and Methods: This cross-sectional observational study was conducted over a period of 18 months from November 2013 to April 2015 in a tertiary care hospital in West Bengal, India. Patients coming for treatment of enlarged prostate were included in this study as a convenience sample. Their age in years, weight of the gland by ultrasonography, serum PSA level, and mast cell count were recorded for analysis. The data between benign and malignant lesions were compared by the Mann-Whitney U test and the Spearman correlation coefficient was calculated to find correlation among the continuous variables. Chi-square test was done to compare categorical data. Microsoft Excel 2010 (Microsoft Inc, USA) and International Business Machines (IBM) Statistical Package for the Social Sciences (SPSS) Statistics 20.0 (IBM, New York, USA) software were used for conducting the statistical tests. Results: A total of 48 males with a median age of 63.5 years were studied. The weight of the prostate gland, serum PSA, and mast cell count were significantly higher in carcinoma of the gland. The weight of prostate gland (rs= 0.34, p-value= 0.02) and serum PSA (rs= 0.61, p-value &lt;0.0001) was significantly positively correlated with mast cell count in overall sample. The PSA (p-value &lt;0.001) significantly contributed to predicting the mast cells in linear regression. Conclusion: The serum level of PSA and mast cells were higher in carcinoma of the prostate. Higher prostate gland size and PSA would have higher mast cell infiltration. This study showed a correlation of serum PSA level with mast cell density, which may be used as an additional tool in distinguishing BHP versus prostatic carcinoma. Further studies are needed to find a more generalisable regression equation.

Salvage high-dose-rate interventional radiotherapy (brachytherapy) for locally relapsed prostate cancer after radical prostatectomy and subsequent external irradiation.

To report the use of high-dose-rate (HDR) interventional radiotherapy (brachytherapy, IRT) as a salvage treatment for macroscopic histologically confirmed local relapse of prostatic cancer after prostatectomy and subsequent external irradiation. A retrospective study of patients with prostate adenocarcinoma, treated with HDR-IRT for an isolated local relapse after prostatectomy and external irradiation at our institution (2010-2020). Treatment results and treatment related-toxicity were recorded. Clinical outcomes were analyzed. Ten patients were identified. The median age was 63 years (range, 59-74 years), and the median follow-up time was 34 months (range, 10-68 months). Four patients had a biochemical relapse, and the mean time to prostate specific antigen (PSA) increase was 13 months. One-year biochemical failure-free survival (bFFS), 3-year bFFS, and 4-year bFFS were 80%, 60%, and 60%, respectively. Most of the treatment-related toxicities were grade 1-2. Two patients experienced grade 3 late genitourinary toxicity. HDR-IRT seems to be an effective treatment option showing acceptable toxicity for prostate cancer patients with isolated macroscopic histologically confirmed local relapse after prostatectomy and subsequent external irradiation.

Prostate Cancer after Percutaneous Arterial Embolization of the Prostate: A Case Report.

We report a patient with prostate cancer found 2 years after percutaneous arterial embolization (PAE) of the prostate with a rapid increase in prostate specific antigen (PSA) 3 months later, even though the initial result was low. He did not consult a urologist during or after PAE until acute urinary retention developed. The clinical stage was cT2cN1M1b with Gleason grade 5 + 5 = 10. An increase in PSA a short interval after PAE may suggest the presence of prostate cancer. We suggest that patients undergoing PAE should consult a urologist, and that PSA levels should be checked every 3 months in the first year after PSA.

Recurrent Disseminated Intravascular Coagulation in Metastatic Castration-Resistant Prostate Cancer: A Case Report.

Disseminated intravascular coagulation (DIC) is a systemic disease characterized by simultaneous thrombosis, bleeding, and partially excessive fibrinolysis. Systemic shock, trauma, bacterial toxins, and procoagulants-expressing solid and hematologic malignancies are common causes of this life-threatening hemorrhagic complication and often require treatment in intensive care units. We describe a case of an elderly man with recurrent severe bleeding events in the cause of DIC, including epistaxis, hemoptysis, hematuria, and gastrointestinal bleeding. Laboratory investigations revealed elevated prostate-specific antigen (PSA), suggesting an underlying prostate cancer. Despite intensified coagulatory therapy, the coagulation disorder could not be stabilized. A single injection of degarelix, a gonadotropin-releasing hormone (GnRH) receptor antagonist, led to rapid stabilization of the coagulation and decreased PSA within days. One year after initiating androgen-deprivation therapy, there were recurrent transfusion-requiring bleeding events, and a concomitant PSA increase occurred, suggesting metastatic castration-resistant disease associated with DIC. This case emphasizes DIC as a possible primary phenomenon and indicator for the progression of the underlying malignancy, as well as the importance of etiological therapies in the management of DIC.

Time to second biochemical recurrence as a prognostic indicator in postprostatectomy patients who undergo salvage radiation therapy: An RTOG 9601 based post hoc analysis.

The prognostic significance of a "second" biochemical recurrence (sBCR) after salvage radiation therapy (sRT) with/without hormonal therapy following primary radical prostatectomy in men with prostate cancer has not been examined. We hypothesized that a shorter time to sBCR will be associated with worse cancer control outcomes. The RTOG 9601 study included 760 patients with tumor stage pT2/T3, pN0, who had either persistently elevated prostate-specific antigen (PSA) postradical prostatectomy or developed subsequent biochemical recurrence with PSA levels between 0.2 and 4.0 ng/ml. All patients received sRT (with or without 2 years of Bicalutamide) from 1998 to 2015. For our study, we focused on 421 patients who had sBCR after sRT-which was defined as a PSA increase of at least 0.3 ng/ml over the first nadir. Patients were divided into two categories: early sBCR (n = 210) and late sBCR (n = 211) using median time to sBCR (3.51 years). All patients who experienced sBCR received salvage hormonal therapy. Competing-risk analysis was used to examine the impact of early versus late sBCR on prostate cancer specific mortality (CSM), after accounting for available covariates. The majority of patients were age 60 years or older (75.8%), had pT3 disease (74.8%), and Gleason score 7 (75.2%). Overall, 13.8% had persistent PSA initially after surgery. At 10 years, starting at the time of sBCR, CSM rate was 31.3% in the early sBCR group versus 20.0% in the late sBCR group. In competing-risk analysis, time to sBCR was an independent predictor of CSM, where patients with early sBCR had 1.7-fold higher CSM risk (p = 0.026) than their counterparts with late sBCR. Time to sBCR after sRT (with or without concomitant Bicalutamide) is a significant predictor of CSM following initial radical prostatectomy. This information can be used to guide subsequent treatments, and to counsel patients.

MCRPC patients with PSA fluctuations under radioligand therapy have comparable survival benefits relative to patients with sustained PSA decrease

IntroductionIn men with metastatic castration-resistant prostate cancer (mCRPC) scheduled for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), biochemical response is assessed based on repeated measurements of prostate-specific antigen (PSA) levels. We aimed to determine overall survival (OS) in patients experiencing sustained PSA increase, decrease, or fluctuations during therapy.Materials and methodsIn this bicentric study, we included 176 mCRPC patients treated with PSMA-directed RLT. PSA levels were determined using blood samples prior to the first RLT and on the admission days for the following cycles. We calculated relative changes in PSA levels compared to baseline. Kaplan–Meier curves as well as log-rank test were used to compare OS of different subgroups, including patients with sustained PSA increase, decrease, or fluctuations (defined as change after initial decrease or increase after the first cycle).ResultsSixty-one out of one hundred seventy-six (34.7%) patients showed a sustained increase and 86/176 (48.8%) a sustained decrease in PSA levels. PSA fluctuations were observed in the remaining 29/176 (16.5%). In this subgroup, 22/29 experienced initial PSA decrease followed by an increase (7/29, initial increase followed by a decrease). Median OS of patients with sustained decrease in PSA levels was significantly longer when compared to patients with sustained increase of PSA levels (19 vs. 8 months; HR 0.35, 95% CI 0.22–0.56; P < 0.001). Patients with PSA fluctuations showed a significantly longer median OS compared to patients with sustained increase of PSA levels (18 vs. 8 months; HR 0.49, 95% CI 0.30–0.80; P < 0.01), but no significant difference relative to men with sustained PSA decrease (18 vs. 19 months; HR 1.4, 95% CI 0.78–2.49; P = 0.20). In addition, in men experiencing PSA fluctuations, median OS did not differ significantly between patients with initial decrease or initial increase of tumor marker levels (16 vs. 18 months; HR 1.2, 95% CI 0.38–4.05; P = 0.68).ConclusionInitial increase or decrease of PSA levels is sustained in the majority of patients undergoing RLT. Sustained PSA decrease was linked to prolonged survival and men with PSA fluctuations under treatment experienced comparable survival benefits. As such, transient tumor marker oscillations under RLT should rather not lead to treatment discontinuation, especially in the absence of radiological progression.

Relationship of prostate volume and prostate-specific antigen levels in Sri Lankan men with Benign Prostatic Hyperplasia

Purpose: Benign Prostatic Hyperplasia (BPH) is an important cause of morbidity for ageing men worldwide. However, the available study is limited on the natural history of BPH and dynamics of Prostate-Specific Antigen (PSA) in Sri Lankan population. This study aimed to assess the relationship between serums Prostate Specific Antigen (PSA), prostate volume (PV), and PSA density (PSAD) and to evaluate variations of above parameters with aging and to assess the mean prostate volume of Sri Lankan men with Benign Prostatic Hyperplasia (BPH). Material and methods: This was a retrospective study, men diagnosed with Benign Prostatic Hyperplasia from January 2009 was evaluated. This study was approved by the Ethics Review Committee of Colombo South Teaching Hospital and the patient informed written consent was received. Those with UTI, PSA &gt;10ng/dl and suspicious prostate in digital rectal examination (DRE) were excluded from the study. Data were statistically analyzed to determine the relationship of PSA, PV, PSAD and variations with age groups. Results: This study recruited a total number of 562 men, clustered into 5 age groups and their mean Prostate Volume (PV) was 42.9 (12.56SD). The median PSA was 2.5ng/dl with an inter quartile range of 0.37. The mean PSA density (PSA/PV) was 0.11 (0.023SD). The tendency towards increase in PSA and prostate volume with increasing age showed statistical significance (P&lt;0.05). PSA density was not changed much between different age group except 51-60 age group. It is noted PSAD was fluctuating around mean PSAD of 0.11 in majority of the age groups. Conclusion: PV and PSA increase with age. Mean PV is relatively small compare to blacks and Caucasians. .PSA density in Sri Lankan men is comparable to published data in other countries and could be used as a surrogate marker to evaluate the prostate and for therapeutic decision making.

Prostate-specific antigen age-specific reference ranges and the effect of metabolic syndrome factors in a Thai population Authors

Objectives: An appropriate prostate specific antigen (PSA) cut-off value in Thailand has not been investigated, nor has an age-specific PSA reference range. This study aims to evaluate the correlation between metabolic syndrome, metabolic factors, and age specific PSA level. Materials and Methods: A cross-sectional study in men who underwent medical checkups from September 2019 to December 2019. The 95th percentile PSA value was applied to the normal age-specific reference range. Correlations between PSA levels and a variety of factors were determined using linear regression. Results: A total of 507 men met the criteria to be included in the analysis. Age-specific PSA reference ranges for men aged 40-49, 50-59, and 60-70 years were 0-2.3, 0-3.4, and 0-4.2 ng/ml, respectively. The multivariate adjusted geometric mean PSA model indicated that the factors related to PSA were age, higher body mass index (BMI) and serum fasting blood sugar (FBS) ≥ 100 mg/dl. The age group 50-59 and 60-70 have a 43% and 99% increase in mean PSA compared to the age group 40-49, respectively (p &lt; 0.001). A higher BMI was associated with lower PSA (p &lt; 0.001). And the serum FBS ≥ 100 mg/dl showed a 15% reduction in mean PSA compared to FBS &lt; 100 mg/dl (p = 0.018). Conclusion: The age-specific PSA reference in Thai men was lower than reported in a previous study. Use of the lower PSA cut-off may increase the sensitivity of prostate cancer screening. This study demonstrates that age, BMI, and FBS may all influence the clinical interpretation of serum PSA levels. Screening for prostate cancer using PSA should be carried out with caution in those who have those risk factors.

Abstract 421: PLX-3618, a potent, selective monovalent BRD4 degrader demonstrates activity in models of prostate cancer

Abstract Prostate cancer is the second most common cause of cancer related deaths in men in the United States. Pathogenesis is driven by the androgen receptor (AR), which has led to front-line treatment modalities that are based on androgen deprivation therapy (ADT). About 10-20% of all prostate cancers evolve to resist ADT and are classified as castration-resistant prostate cancer (CRPC) indicating the continued need for new treatment options. Bromodomain-containing protein 4 (BRD4) is an acetylated-chromatin associating protein that is involved in transcriptional elongation, mRNA splicing, epigenetic bookmarking, and super-enhancer activity. The BRD4 protein has been shown to both bind and colocalize with AR at androgen response elements (AREs) on chromatin. Furthermore, elevated BRD4 expression is prognostic of increased prostate specific antigen (PSA) levels following radical prostatectomy and is correlated with higher Gleason scores and poor overall survival. The intertwined activity of BRD4 with multiple essential driver mechanisms of prostate cancer suggests it may be a key target for developing novel therapeutics. Using our ultra-high throughput cell-based screening platform, which directly measures degradation of pathogenic proteins upon exposure to diverse chemical libraries, we identified a series of novel monovalent BRD4 degraders that was optimized to produce our lead compound PLX-3618. A cancer cell panel screen for antiproliferative effects of PLX-3618 indicated enhanced sensitivity in subsets of prostate cancer lines. PLX-3618 elicited selective, rapid, and deep degradation of BRD4 protein in prostate cancer cell models, without degrading the closely related BRD2 and BRD3 proteins. Addition of either proteosome or neddylation inhibitors blocked BRD4 degradation indicating a ubiquitin-proteosome system mediated clearance mechanism. Degradation of BRD4 led to sustained multimodal inhibition of the AR pathway and disruption of key oncogene enhancer networks. When compared to pan-BET inhibitors, treatment of select prostate cancer cell lines with PLX-3618 resulted in increased levels of the tumor suppressors p53 and p21, an aberrant DNA damage response, and substantially amplified apoptosis. Finally, in in vivo preclinical models of prostate cancer, PLX-3618 showed far superior efficacy over a pan-BET inhibitor. Taken together, the selective degradation of BRD4 via the potent monovalent degrader PLX-3618 represents a novel strategy in treating prostate cancer. Citation Format: Kenneth Steadman, Gregory S. Parker, Geoffray Leriche, Sarah Fish, Julia Toth, Mary E. Spalding, Elizabeth Daniele, Aleksandar Jamborcic, Xiaoming Li, E Adam Kallel, Farhana Barmare, Kenneth Chng, Erika Green, Michael Hocker, Elliot Imler, Yi Zhang, Peggy A. Thompson, Simon Bailey. PLX-3618, a potent, selective monovalent BRD4 degrader demonstrates activity in models of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 421.

Association of prostate-specific antigen (PSA) response and overall survival (OS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the phase 3 ARASENS trial.

5078 Background: Reductions in PSA level have been associated with improved OS in patients (pts) with mHSPC. In ARASENS (NCT02799602), darolutamide (DARO) + androgen-deprivation therapy (ADT) in combination with docetaxel significantly reduced the risk of death by 32.5% (hazard ratio [HR] 0.675; 95% confidence interval [CI] 0.568–0.801; P&lt; 0.0001) vs ADT + docetaxel in pts with mHSPC. We report the association between PSA response and OS from ARASENS. Methods: Pts with mHSPC were randomized 1:1 to DARO 600 mg twice daily or matching PBO + ADT and docetaxel. Serum PSA was measured at screening and every 12 weeks. Exploratory analyses included time to PSA progression (≥25% increase from PSA nadir [lowest or at study entry] and PSA increase ≥2 ng/mL ≥12 weeks from nadir [both confirmed by a second value ≥3 weeks later]) and undetectable PSA (&lt; 0.2 ng/mL for 2 samples ≥3 weeks apart) at 24, 36, and 52 weeks and any time during treatment. Comparisons between treatment groups were performed using the Cochran-Mantel Haenszel test stratified by randomization stratification factors (metastatic spread according to TNM classification and alkaline phosphatase levels at study entry). Post hoc landmark analyses evaluated the association between undetectable PSA at weeks 24 and 36 and OS for the overall population. Results: Of 1306 randomized pts, 1305 were included in the full analysis set (DARO 651; PBO 654), both with ADT and docetaxel. Median (range) PSA levels at study entry were 30.3 (0.0–9219.0) and 24.2 (0.0–11,947.0) ng/mL, respectively. DARO significantly prolonged time to PSA progression (HR 0.255; 95% CI 0.208–0.313; P&lt; 0.0001). Undetectable PSA was achieved in more pts receiving DARO (48.7%) vs PBO (23.9%) at 24 weeks, and the rate continued to increase at 36 and 52 weeks in the DARO group to 57.1% and 60.2%, respectively, vs minimal change in the PBO group (25.1% and 26.1%). Undetectable PSA levels at any time were achieved in 67.3% in the DARO group and 28.6% in the PBO group. A treatment difference in undetectable PSA based on non-overlapping 95% CIs was observed at all time points. For the overall population, OS was improved for pts who achieved undetectable PSA levels vs those who did not at 24 weeks (HR 0.398; 95% CI 0.321–0.493) and 36 weeks (HR 0.351; 95% CI 0.284–0.434). Additional baseline and safety data by PSA level will be reported. Conclusions: The combination of DARO + ADT and docetaxel significantly prolonged the time to PSA progression and more pts receiving DARO vs PBO achieved undetectable PSA levels, reflecting strong PSA response over time. In pts with mHSPC, achievement of undetectable PSA at 24 and 36 weeks was associated with improved OS, with risk of death reduced by 60% and 65%, respectively, vs those who did not achieve undetectable PSA at 24 and 36 weeks. Clinical trial information: NCT02799602.