Prostate-specific Antigen Reduction Research Articles

Abstract CT137: Efficacy and immunological outcomes of non-fucosylated anti-CTLA-4 (BMS-986218) + degarelix acetate vs. degarelix acetate alone in men with high-risk localized prostate cancer (Neo-Red-P)

Abstract Background: Men with high-risk localized prostate cancer are at significant risk for disease recurrence and there is currently no role for neoadjuvant therapy. Although androgen deprivation therapy (ADT) is immunomodulatory and can increase CD8 T cell infiltration, these effects are counterbalanced by the expansion of suppressive regulatory T cells (Tregs). We therefore designed a correlative-rich clinical trial for men with high-risk localized prostate cancer to test whether BMS-986218 - a novel afucosylated anti-CTLA-4 antibody optimized for antibody-dependent cell-mediated cytotoxicity (ADCC) - depletes Tregs and augments response to ADT. Methods: Neo-Red-P is a single-center, two-arm, open-label pilot study assessing degarelix (ADT) versus ADT + anti-CTLA-4-NF (BMS-986218) in patients with treatment naïve high-risk localized prostate cancer. Key eligibility criteria included histologically confirmed adenocarcinoma with Gleason sum of ≥4+3 and clinical stage T1c-T3bN0M0. All patients received degarelix (ADT; 240mg SQ) 2 weeks before radical prostatectomy (RP). Patients were randomized to Arm A (ADT only), or Arm B (ADT + BMS-986218 [20mg IV] 2 doses Q2w starting 3 weeks before RP). The primary endpoint was the safety and feasibility of neoadjuvant BMS-986218 in prostate cancer. Secondary endpoints included the pathologic complete response rate, rate of undetectable PSA at 12 months, PSA response rate (>50% decrease pre-RP), and time-to-PSA recurrence. Fresh tumor specimens were collected at RP for single-cell RNA-sequencing, cytometry by time-of-flight, next-generation sequencing, and multiplex immunofluorescence. A treatment naïve cohort of matching demographic and pathological characteristics was collected for comparative analysis (n=14). Results: Between February 26, 2020, and November 15, 2022, 24 patients were enrolled. Severe treatment-related adverse events (TRAE; Grade ≥ 3) were rare in both arms; 0% in the ADT alone arm and 4% in the combination arm, suggesting a tolerable safety profile with the addition of BMS-986218. In the combination arm, 54% of subjects achieved a 50% reduction in PSA versus 33% in the ADT alone arm. In the ADT alone arm, 80% of patients had an undetectable PSA at 12 months, with a median recurrence-free survival of 1.61 years (IQR: 1.50-1.99 years). In the combination group, 75% had an undetectable PSA at 12 months, with a median recurrence-free survival of 1.82 years (IQR: 0.89-2.07 years). The overall recurrence rate in patients treated with combination therapy was 25% (3 of 12 patients) versus 20% (2 of 10 patients) in the ADT alone arm. Correlative studies suggest that aCTLA4-NF mitigates ADT-induced Treg accumulation through enhanced Fc receptor activity and augmented CTL activation, indicating an enhanced anti-tumor response with combination therapy. Conclusions: The neoadjuvant combination of ADT + aCTLA-4-NF (BMS-986218) is feasible, well tolerated, and induces significant remodeling of the immune TME through enhanced Fc receptor and CTL activity. Rates of disease recurrence following surgery were low in this high-risk population, warranting further investigation of combination immuno-hormonal therapy in the neoadjuvant setting for high-risk prostate cancer. Clinical Trial Information: NCT04301414 Citation Format: Patrick J. McCann, Casey R. Ager, Aleksandar Z. Obradovic, Matthew G. Chaimowitz, Samuel Pan, Caroline J. Laplaca, Parin Shah, Renu K. Virk, Christopher B. Anderson, Catherine S. Spina, Karie D. Runcie, Mark N. Stein, Charles G. Drake, Matthew C. Dallos. Efficacy and immunological outcomes of non-fucosylated anti-CTLA-4 (BMS-986218) + degarelix acetate vs. degarelix acetate alone in men with high-risk localized prostate cancer (Neo-Red-P) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT137.

Abstract CT138: Evaluating nivolumab (nivo) plus ipilimumab (ipi) in patients with metastatic castration-resistant prostate cancer (mCRPC): Clinical and translational results from the AMADEUS prostate expansion cohort

Abstract Background: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, offering durable responses for some patients. However, response to ICIs remains limited for many solid tumors, including metastatic castration-resistant prostate cancer (mCRPC). The AMADEUS primary cohort (NCT03651271) and CheckMate 650 (NCT02985957) trials demonstrated promising durable antitumor responses in a subset of mCRPC patients treated with nivo in combination with ipi at 1 mg/kg or 3 mg/kg, respectively. The AMADEUS prostate expansion cohort was initiated to evaluate the safety and efficacy of a higher ipi dose (5 mg/kg) in combination with nivo. Methods: This open-label, multicenter cohort enrolled mCRPC patients with no restriction on the number of prior treatments. The first 10 patients with < 15% tumoral CD8 T cells were randomized 1:1 to receive either ipi at 3 mg/kg (ipi3) or 5 mg/kg (ipi5) IV Q6W for up to 2 doses. In addition, all patients received nivo 1 mg/kg IV Q3W for 4 doses, followed by nivo 480 mg IV Q4W until PD or intolerable toxicity. After a safety pause, 10 additional patients were enrolled to the ipi5 arm. Co-primary endpoints were DCR (CR, PR, or SD ≥ 6 months) and conversion of tumor %CD8 T cells from low (< 15%) to high (≥ 15%). Baseline and on-treatment tumor and blood samples were analyzed for multi-omic biomarkers. This cohort was not powered for formal statistical analysis. Results: DCR was 20% in both ipi3 (N=1/5) and ipi5 (N=3/15) arms. In patients with an on-treatment biopsy, CD8 conversion from low to high occurred in 33% (1/3) of patients in ipi3 and 13% (1/8) in ipi5. However, 50% (4/8) of patients in ipi5 had on-treatment CD8 ≥ 14.8%. Baseline CD8 T cell frequencies and CD8 conversion were not associated with disease control or PSA reduction. The frequency and severity of AEs was consistent with the known safety profile of ipi/nivo, although more patient in ipi5 discontinued treatment owing to an AE (33% vs 0% in ipi3). Both arms showed increased activated (ICOS+, CD38+) and proliferating (Ki67+) CD4 T cells, CD8 T cells, Tregs, inflammatory cytokines (IFNg), chemokines (CXCL9, CXCL10), and soluble PD-1 in circulation. Conclusions: Across both arms, ipi/nivo induced clinical responses and increased %CD8 in a subset of “cold” mCRPC tumors with low CD8 cells. Additionally, the safety profile of ipi 5 mg/kg combined with nivo was consistent with previous trials that tested lower doses of ipi. Further translational analyses may inform which mCRPC patients could benefit from immunotherapy treatment. Trial registration: ClinicalTrials.gov (NCT03651271) Citation Format: Apostolia M. Tsimberidou, Alexandra Drakaki, Danny N. Khalil, Kwame Okrah, Mike Schachter, Shikha Gautam, Diane M. Da Silva, Farah A. Alayli, Christine N. Spencer, Wai Chin Foo, Matthew Adamow, Phillip Wong, Justin Fairchild, Jamie Arnott, Ute Dugan, Silvia Boffo, Lisa Salvador, Christopher R. Cabanski, Sumit K. Subudhi, Padmanee Sharma. Evaluating nivolumab (nivo) plus ipilimumab (ipi) in patients with metastatic castration-resistant prostate cancer (mCRPC): Clinical and translational results from the AMADEUS prostate expansion cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT138.

Transperineal Laser Ablation (TPLA) Treatment of Focal Low-Intermediate Risk Prostate Cancer.

Background: This interventional pilot study aimed to evaluate the short-term (3 years) efficacy of focal laser ablation (FLA) in treating the index lesion of low-intermediate-risk prostate cancer, along with assessing the safety of the procedure (ClinicalTrials.gov ID NCT04045756). Methods: Forty patients aged between 46 and 86 with histologically proven organ-confined prostate cancer and low-to-intermediate progression risk were included. FLA was performed under percutaneous fusion magnetic resonance/ultrasound guidance in a Day Hospital setting under local anesthesia. Patients underwent regular clinical and functional assessments through the international index of erectile function (IIEF-5) and the International Prostatism Symptom Score (IPSS), PSA measurements, post-procedure MRI scans, and biopsies at 36 months or if positive findings were detected earlier. Statistical analyses were conducted to assess trends in PSA levels and cavity dimensions over time. Results: Forty patients were initially included, with fifteen lost to follow-up. At 36 months, a mean PSA reduction of 60% was observed, and 80% of MRI scans showed no signs of in-field clinically significant residual/recurrent cancer. Biopsies at 36 months revealed no malignant findings in 20 patients. No deterioration in sexual function or urinary symptoms was recorded. Conclusions: FLA appears to be safe, feasible, and effective in the index lesion treatment of low-intermediate-risk prostate cancer, with a high rate of tumor eradication and preservation of quality of life.

Validation of Prognostic and Predictive Models for Therapeutic Response in Patients Treated with [177Lu]Lu-PSMA-617 Versus Cabazitaxel for Metastatic Castration-resistant Prostate Cancer (TheraP): A Post Hoc Analysis from a Randomised, Open-label, Phase 2 Trial

BackgroundPrognostic models have been developed using data from a multicentre noncomparative study to forecast the likelihood of a 50% reduction in prostate-specific antigen (PSA50), longer prostate-specific antigen (PSA) progression-free survival (PFS), and longer overall survival (OS) in patients with metastatic castration-resistant prostate cancer receiving [177Lu]Lu-PSMA radioligand therapy. The predictive utility of the models to identify patients likely to benefit most from [177Lu]Lu-PSMA compared with standard chemotherapy has not been established. ObjectiveTo determine the predictive value of the models using data from the randomised, open-label, phase 2, TheraP trial (primary objective) and to evaluate the clinical net benefit of the PSA50 model (secondary objective). Design, setting, and participantsAll 200 patients were randomised in the TheraP trial to receive [177Lu]Lu-PSMA-617 (n = 99) or cabazitaxel (n = 101) between February 2018 and September 2019. Outcome measurements and statistical analysisPredictive performance was investigated by testing whether the association between the modelled outcome classifications (favourable vs unfavourable outcome) was different for patients randomised to [177Lu]Lu-PSMA versus cabazitaxel. The clinical benefit of the PSA50 model was evaluated using a decision curve analysis. Results and limitationsThe probability of PSA50 in patients classified as having a favourable outcome was greater in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (odds ratio 6.36 [95% confidence interval {CI} 1.69–30.80] vs 0.96 [95% CI 0.32–3.05]; p = 0.038 for treatment-by-model interaction). The PSA50 rate in patients with a favourable outcome for [177Lu]Lu-PSMA-617 versus cabazitaxel was 62/88 (70%) versus 31/85 (36%). The decision curve analysis indicated that the use of the PSA50 model had a clinical net benefit when the probability of a PSA response was ≥30%. The predictive performance of the models for PSA PFS and OS was not established (treatment-by-model interaction: p = 0.36 and p = 0.41, respectively). ConclusionsA previously developed outcome classification model for PSA50 was demonstrated to be both predictive and prognostic for the outcome after [177Lu]Lu-PSMA-617 versus cabazitaxel, while the PSA PFS and OS models had purely prognostic value. The models may aid clinicians in defining strategies for patients with metastatic castration-resistant prostate cancer who failed first-line chemotherapy and are eligible for [177Lu]Lu-PSMA-617 and cabazitaxel. Patient summaryIn this report, we validated previously developed statistical models that can predict a response to Lu-PSMA radioligand therapy in patients with advanced prostate cancer. We found that the statistical models can predict patient survival, and aid in determining whether Lu-PSMA therapy or cabazitaxel yields a higher probability to achieve a serum prostate-specific antigen response.

Enhancing continence post holmium laser enucleation of the prostate: assessment of novel technique through randomized clinical trial.

Transient urinary incontinence (UI) is distressing event following holmium laser enucleation of the prostate (HoLEP). Novel technique namely, veil sparing HoLEP (VS-HoLEP), was proposed to improve early continence outcome. In this trial (NCT03494049), VS-HoLEP was compared to standard HoLEP (St-HoLEP). VS-HoLEP entails early apical separation with sparing of ventral apical mucosal veil proximal to the verumontanum. Eligible symptomatic BPH patients were randomly allocated to St-HoLEP (91) and VS-HoLEP (89). The primary outcome was UI as depicted by one-hour pad test at one month postoperatively. Other outcome measures include all perioperative parameters, complications, and urinary outcome measures at different follow-up points. Median preoperative prostate size was 138 (50:282) and 128 (50:228) mL in St-HoLEP and VS-HoLEP groups respectively. At one month the number of patients with positive one-hour pad test was 21 (23.1%) and 10 (11.4%) in St-HoLEP and VS-HoLEP groups respectively (P 0.047). The difference was significantly in favor of VS-HoLEP considering the number of patients reporting UI, the number of patients with positive one-hour pad test as well as the grade of UI reported at one and 4 months. The difference was not statistically significant at 12 months. The median time to patients' reported continence was 8 (1-52) and 1.5 (1-52) weeks in St-HoLEP and VS-HoLEP groups respectively (P≤0.005). The technique independently predicted positive one-hour pad test at one and four months respectively. At twelve months presence of DM (diabetes mellitus) and more percent PSA reduction independently predicted positive one-hour pad test. Veil sparing HoLEP enhances significantly early postoperative urine continence both subjectively and objectively. Optimization of the surgical technique could cut short the number of leaking patients and reduce the degree as well as the duration of transient postoperative urine leak.

Transurethral bipolar enucleation using a TUEB loop for large benign prostatic hyperplasia: a retrospective cohort study.

We aimed to assess the efficacy and safety of transurethral enucleation with bipolar system (TUEB) regardless of the prostate size using a specially developed TUEB loop. A total of 251 patients who underwent TUEB were categorized into two groups depending on the prostate volume (PV): small-PV (≤ 80mL) group, 133 patients; large-PV (> 80mL) group, 118 patients. Comparisons of background information and treatment outcomes were performed between the groups. Operation (113.5 vs 166.4min), enucleation (49.4 vs 68.1min), and morcellation (11.4 vs 26.4min) times were longer and hemoglobin decreased significantly (0.84 vs 1.30g/dL) in the large PV group. However, the enucleation efficiency (enucleated weight per enucleation time; 0.71 vs 0.97g/min) and prostate-specific antigen reduction rate (24.6% vs 16.1%) were significantly better in the large-PV group, with similar enucleation rates (enucleated weight per transitional zone volume; 82% vs 81%). The International Prostate Symptom Score, uroflowmetry maximum flow rate, and post-void residual urine in both groups improved at 3, 6, and 12months compared with baseline. No patient underwent blood transfusion. There were no differences in the frequency of postoperative clot retention, urethral stricture, or stress incontinence at 3, 6, and 12months. TUEB using a TUEB loop resulted in high levels of satisfaction regarding the enucleation efficiency, efficacy, and safety for BPH surgery regardless of the prostate size. TUEB should be considered one of the best treatment options for large BPH that is uncontrollable with medication.

Real-world retrospective study of prostate-specific antigen and safety assessment with darolutamide plus androgen deprivation therapy for metastasis hormone-sensitive prostate cancer.

ARASENS has demonstrated the efficacy and safety for darolutamide (DARO) with androgen deprivation therapy (ADT) plus docetaxel in metastasis hormone-sensitive prostate cancer (mHSPC). There is a lack of reports for DARO with ADT in mHSPC though the regimen is used in clinical from time to time. Moreover, recent studies have supported the importance of early and rapid prostate-specific antigen (PSA) reduction, which correlates with reduced disease progression and improved survival in patients with mHSPC. This study aims to evaluate PSA reduction as a primary endpoint for DARO with ADT in the treatment of mHSPC and to evaluate the real-world short-term PSA control of DARO with ADT from two leading medical centers in China. We retrospectively reviewed the clinical records of patients with mHSPC receiving ADT and DARO (600 mg, b.i.d.). The collection of data spanned from March 1, 2022, to July 31, 2023. The main observation indicators were PSA level and drug-related adverse events (AE) after medication. PSA levels were closely monitored prior to treatment initiation and at 2-week intervals, as well as at 1, 3, and 6 months after the initiation of treatment. We also conducted an analysis to determine the proportion of patients achieving a PSA reduction of 50% or more (PSA50) and 90% or more (PSA90) as well as the percentage of patients with a notable decrease in PSA level to 0.2 ng/mL and PSA nadir of ≤0.02 ng/mL. Fifty-one patients were included in the study, with a median age of 73 years. At diagnosis of HSPC, the majority of patients had a Gleason score ≥8 (n=40, 78.40%) and a median baseline PSA level of 88 ng/mL. Approximately 45.1% (n=23) of patients had a Charlson Comorbidity Index over 1 and were receiving one or more nontumor-related treatments. The median follow-up time was 9.3 months (range, 1.16-15.8 months). The median reductions in PSA levels compared to baseline were 84.37%, 91.48%, 94.67% and 99.81% at 2 weeks, 1 month, 3 months and 6 months after administration of DARO with ADT, respectively. The median time to PSA50, PSA90, significant PSA reduction (PSA <0.2 ng/mL), and PSA nadir (PSA <0.02 ng/mL) was 0.97, 1.27, 1.98, and 2.08 months, respectively. AE mainly included fatigue (two patients) and arm pain (one patient), all of which were grade I or II AE. No grade III or AE were observed. For treating prostate cancer, DARO with ADT has good early efficacy, demonstrating prompt and substantial control of PSA levels, with a favorable safety profile.

Antibacterial synergy between a phage endolysin and citric acid against the Gram-negative kiwifruit pathogen Pseudomonas syringae pv. actinidiae.

The phytopathogen Pseudomonas syringae pv. actinidiae (Psa) causes major impacts to kiwifruit horticulture, and the current control strategies are heavily reliant on copper and antibiotics. The environmental impact and increasing resistance to these agrichemicals are driving interest in alternative antimicrobials including bacteriophage-derived therapies. In this study, we characterize the endolysin from the Otagovirus Psa374 which infects Psa. When combined with citric acid, this endolysin displays an impressive antibacterial synergy to reduce viable Psa below the limit of detection. The use of citric acid as a synergistic agent with endolysins has not been extensively studied and has never been evaluated against a plant pathogen. We determined that the synergy involved a combination of the chelation activity of citric acid, acidic pH, and the specific activity of the ΦPsa374 endolysin. Our study highlights an exciting opportunity for alternative antimicrobials in agriculture.

Survival and fracture risk with radium-223 therapy in metastatic castrate-resistant prostate cancer (mCRPC): A real-world analysis.

50 Background: Radium-223 is a life-prolonging radionuclide therapy for men with bone-predominant metastatic castrate-resistant prostate cancer (mCRPC). It accumulates at sites of high bone turnover with emerging evidence suggesting use of radium-223 increases risk of pathologic fractures. Bone-protective agents (BPAs) reduce skeletal-related events including pathologic fractures in men with mCRPC. We evaluated real-world outcomes of patients treated with radium-223, including the effect of BPA use on pathologic fracture risk. Methods: This was a single institution retrospective cohort study that included patients with mCRPC treated with radium-223 in Manitoba, Canada from 2014 to 2021. Outcomes of interest included incidence of pathologic fracture, pain response, alkaline phosphatase (ALP) response, and overall survival. Kaplan-Meier method was used for time to event outcomes and multivariable Cox regression models were used to adjust for covariates. Results: We identified 92 patients who received radium-223 for mCRPC (Table). Thirty patients (33%) completed 6 cycles of radium-223. Documented pain relief occurred in 39% of patients. For those with elevated ALP at baseline (n = 46), 57% had at least 30% reduction in total ALP. PSA reduction occurred in 29% with 11% having at least 30% reduction in PSA. Median overall survival (OS) was 9.4 months (95% CI 5.8 to 15.9). Of those who did not receive concurrent BPA, 26% developed a pathologic fracture, compared to 3% who received concurrent BPA during a median follow up of 8.1 months. BPA use was associated with significant delay in time to pathologic fracture (median not reached vs. 15.9 months; HR = 0.20, 95% CI: 0.05 – 0.76, p &lt; 0.05) after adjusting for number of bone metastases and corticosteroid use. Conclusions: In this real-world study, concurrent BPA use was associated with significant reduction in risk of pathologic fractures in mCRPC patients receiving radium-223. BPA administration should be considered for patients receiving radium-223. [Table: see text]

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.

Patient characteristics, treatment patterns, and outcomes among early adopters of lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617): A real-world United States (US) study.

81 Background: In March 2022, the US Food and Drug Administration approved 177Lu-PSMA-617 for the treatment of patients with prostate-specific membrane antigen (PSMA) positive metastatic castration resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition (ARPI) and taxane-based chemotherapy. This real-world study aims to describe clinical characteristics, treatment use, clinical outcomes in patients treated with 177Lu-PSMA-617 in a growing US dataset. Methods: Adults (≥18 years) with ≥1 claim for 177Lu-PSMA-617 between 3/01/22 and 6/30/2023 in the IQVIA open-source pharmacy and medical claims databases were retrospectively identified and included in this analysis. Clinical characteristics and treatment use, including prior treatment exposures, were derived from this cohort. A subset of these patients with available PSA results were assessed for PSA response after initiation of 177Lu-PSMA-617. Baseline PSA was defined as the closest PSA value within 90 days prior to or on the first 177Lu-PSMA-617 claim (index date). Post-treatment PSA response was defined as the lowest PSA value ≥28 days after the index date. The proportion of patients with ≥ 50%, ≥80% and ≥90% PSA reductions were reported. Results: A total of 1,710 patients treated with 177Lu-PSMA-617, with mean (standard deviation) age was 72.2 (8.5) years, met eligibility and were included in the study. Common comorbidities included hypertension (34.7%), osteoarthritis (27.3%) and dyslipidemia (23.9%). Based on ICD-10 codes, 1,447 (84.6%) patients had bone metastases, and 575 (33.6%) had visceral metastases, of whom 128 (7.5%) had liver metastases. Only 59 (3.5%) patients had lymph node only metastasis. In the pre-index period, 83.4% patients had used prior ARPI and/or taxane chemotherapy, and 98% patients had used other systemic therapies. In a sub-analysis of 159 (9.3%) patients with pre- and post-index PSA values available (whose clinical characteristics are comparable to the overall cohort of 1,710 patients), median PSA at baseline before initiation of 177Lu-PSMA-617 was 61 ng/ml. Among these patients, 53.5%, 29.6% and 22.6% had PSA reductions of ≥50%, ≥80% and ≥90%, respectively, while on treatment. Rate of PSA response was similar regardless of history of ARPI or taxane use. Conclusions: To our knowledge, this is the first large-scale report of real-world US patients treated with 177Lu-PSMA-617. Clinical characteristics and PSA responses observed are consistent with results from the VISION clinical trial demonstrating benefit with 177Lu-PSMA-617 treatment. Subsequent analysis with longer follow up are needed to understand the long-term outcomes associated with 177Lu-PSMA-617 in real-world US patients.

Real-world clinical outcomes of patients treated with Lu-177-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC): A single-institution experience.

83 Background: The radiopharmaceutical Lu177-PSMA-617 (LuPSMA) was FDA approved in March 2022 for patients with mCRPC previously treated with both an androgen receptor signaling inhibitor (ARSI) and a taxane, if eligible based on PSMA PET. However, data regarding real world LuPSMA treatment outcomes are limited. Methods: This is a retrospective analysis of the first 100 mCRPC patients who received at least 1 cycle of LuPSMA at a single institution from June 2022 to August 2023. Demographic and clinical characteristics as well as laboratory values were collected. Central review of qualifying PSMA PET/CT was performed to assess disease distribution. A PSA decrease of 30%, 50%, or 90% from baseline at any point during treatment was the primary measure of response (PSA30, PSA50, and PSA90 respectively). Results: Of the 100 patients identified, 2 were excluded from analysis due to prior receipt of LuPSMA on clinical trial. Three patients were still receiving LuPSMA at the time of data collection. Median age was 72 (range, 50 - 93) and median number of treatments received was 4.0. On baseline PET/CT, 43 patients (44%) had bone + nodal metastases only, 19 (19%) had bone metastases only, 8 (8%) had nodal metastases only, and 11 (11%) had liver metastases. As for prior therapies, 47% had received ≥2 ARSIs (n=47/98), 48% had received 2 prior taxanes (n= 47/98), 42% had received 1 prior taxane (n=41/98), 17% received radium-223 (n=17/98), and 10% were treated off-label with no prior chemotherapy (n=10/98). Median follow up from the start of LuPSMA treatment was 7.6 months (range= 0.6-14.1 months, n=98). During treatment, 21 (21%) patients achieved a PSA90 response, 51 (52%) patients achieved a PSA50 response and 60 (61%) patients achieved a PSA30 response. An increase or no change in baseline PSA was seen in 28% (n=26/94 evaluable patients). Among patients with an initial rise in PSA after the first treatment, 10% had a subsequent reduction from baseline PSA (n=3/29). Conclusions: In this cohort of heavily pretreated mCRPC patients, we observed a PSA50 response of 54% and 21% of patients experiencing a PSA reduction ≥90%. This data supports the clinical benefit of LuPSMA in real-world clinical practice. Characterization of response rates within subgroups by prior treatment and disease characteristics are ongoing.

First-in-human phase 1 study of CC-94676, a first-in-class androgen receptor (AR) ligand-directed degrader (LDD), in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

134 Background: Androgen receptor (AR) signaling is the principal driver of PC at all stages. CC-94676 (BMS-986365) is a heterobifunctional, first-in-class, orally bioavailable AR LDD designed to induce rapid, sustained, and highly selective AR degradation in pts who progressed on standard of care therapies. We report initial results from an open-label, multicenter study, NCT04428788, evaluating CC-94676 in pts with progressive mCRPC. Methods: Pts with mCRPC who progressed on androgen deprivation therapy, ≥ 1 second generation hormonal therapy (eg, enzalutamide [enza], abiraterone [abi], darolutamide, and apalutamide) and taxane chemotherapy (chemo) (unless refused or not indicated) were enrolled to evaluate the safety, tolerability, PK/PD, and preliminary efficacy of CC-94676. Escalation doses evaluated were 100–1200 mg QD and 600–900 mg BID; expansion doses were 600 mg QD and 400–900 mg BID. Results: As of Aug 21, 2023, 95 pts received CC-94676 (median age 71 yrs) with a median of 5 (range 2–12) prior therapies, including enza (80%), abi (72%), both enza &amp; abi (56%), and chemo (56%) (docetaxel 55%; cabazitaxel 20%). There were no ≥ Grade (G) 4 treatment-related adverse events (TRAEs) or discontinuations due to TRAEs. Of 27 pts treated in escalation, treatment (Tx) was well tolerated; 2 pts had non-serious G3 TRAEs at doses ≥ 800 mg QD, which were manageable with dose modifications. One dose-limiting toxicity of asymptomatic QTc prolongation was observed at 900 mg BID and resolved with dose interruption. The maximum tolerated dose was not reached. Of 68 pts treated in expansion, the most common TRAEs were dose-dependent: QTc prolongation (asymptomatic) (43%; G3: 9%), bradycardia (31%; ≥G3: none), and fatigue (24%; ≥G3: none). G3 TRAEs were manageable with dose modifications. The rate of pts with confirmed PSA reductions ≥ 30% (PSA30) increased dose-dependently from 400 to 900 mg BID. 23/68 (34%) pts across all dose levels achieved ≥ PSA30. At 900 mg BID, 11/20 (55%) pts showed PSA30; 7/20 (35%) and 2/20 (10%) had confirmed PSA declines of ≥50% and ≥90%, respectively. PSA responses and radiographic tumor shrinkage occurred across all dose levels, including in pts with AR wildtype (WT) , amplifications, and mutations (by cfDNA), and in heavily pretreated pts who progressed on abi, enza, and chemo. At 900 mg BID, the median duration of Tx was 182 days (range 21-448) and 9/20 (45%) pts remained free of radiographic progression with treatment ongoing at 6 months. Conclusions: CC-94676 is well tolerated with a manageable safety profile. CC-94676 shows promising and prolonged clinical activity in heavily pretreated mCRPC pts who progressed on abi, enza, and chemo with activity seen in pts with tumors expressing WT and mutant ARs. Selection of the recommended phase 2 dose is ongoing. Clinical trial information: NCT04428788 .

Phytotherapy Might Have a Role in Reducing Unnecessary Prostate Biopsies: Results from an Exploratory, Randomized Controlled Trial of Two Different Phytotherapeutic Agents.

We aimed to evaluate the impact of two different phytotherapeutic agents on decision making regarding prostate biopsy for patients with higher-than-normal prostate-specific antigen (PSA) levels. From June 2022 to May 2023, all patients attending two urological institutions due to higher-than-normal PSA levels were randomized to receive either oral capsules of Curcuma Longa, Boswellia, Pinus pinaster and Urtica dioica (Group A) or Serenoa Repens 320 mg (Group B) for 3 months. At the follow-up visit after 3 months, all patients underwent PSA tests and multiparametric magnetic resonance imaging (mpMRI). In the per-protocol analysis, data from 66 patients in Group A and 76 in Group B were analyzed. Fifty patients in Group A (75.7%) showed a significant reduction in total PSA compared to forty-nine in Group B (64.4%) (p < 0.001). Twenty-eight patients had PI-RADS III or higher in mpMRI: twelve in Group A and fourteen in Group B. Twenty-three patients (34.8%) in Group A and fifty-nine (77.6%) in Group B (p < 0.001) underwent prostate biopsy based on the mpMRI findings and PSA values. Three patients in Group A showed a significant reduction in total PSA values while having positive mpMRI findings (6%) compared with nine in Group B (19.5%) (p < 0.001). On the contrary, 7 patients in Group A did not show significant reduction in total PSA values and had negative mpMRI findings (43%) compared to 22 in Group B (81.4%) (p < 0.001). In conclusion, a three-month course of a combination of Curcuma Longa, Boswellia, Pinus pinaster and Urtica dioica seems to be an interesting tool to avoid unnecessary prostate biopsies among men with higher-than-normal PSA levels.

Five Fractions versus Seven Fractions SBRT for Intermediate- and High-Risk Prostate Cancer: A Propensity Score Matched Pair Analysis.

To compare two stereotactic body radiotherapy (SBRT) regimens in patients with intermediate- or high-risk prostate cancer with regards toxicity and efficacy. We retrospectively collected data from 198 patients treated with SBRT for prostate cancer at two different institutions. Patients received either 35-36.25 Gy in five fractions (group A) using Cyberknife robotic platform or 42.7 Gy in seven fractions (group B) using a C-arm LINAC (image-guided). Propensity score matching was done (2:1 nearest neighbor matching without replacement), resulting in 120 patients (80 patients for group A, 40 patients for group B). Toxicity, PSA nadir, biochemical failure and disease-free survival (DFS) were analyzed. Median follow up of all patients was 13 months (range 1-91 months). Overall, 23.3% of patients had ≥G2 acute GU toxicity (21.1% group A versus 30% group B (p = 0.222)) and 6.6% of patients ≥G2 GI toxicity (2.5% versus 15% (p = 0.010)). There was one acute G3 GU toxicity in arm A and one acute G4 rectal bleeding in group B (anticoagulated patient). Regarding late toxicity, 14.1% of patients had ≥G2 late GU toxicity (17.4% versus 6.6% (p = 0.159)) and 5.0% of patients had ≥G2 late GI toxicity (1.4% versus 13.3% (p = 0.013)). There was one G3 late GU toxicity in arm B and two G3 late GI toxicities, one in each arm. Relative median PSA reduction was 92.4% (-53.9-99.9%) from baseline PSA (93.7% (-53.9-99.9%) in group A versus 87.7% (39.8-99.9%) in group B (p = 0.043). In total, 4.2% of patients had biochemical relapse, 5.0% in group A and 2.5% in group B (p = 0.518). One-year DFS in the overall cohort was 97.3%, 98.8% in group A and 94.3% in group B (p = 0.318). Both SBRT regimens have acceptable acute and late toxicity and good efficacy. There are significantly more GI toxicities in the seven-fraction regimen. Longer follow-up is warranted for better comparison of long-term efficacy.

Therapeutic effects of finasteride: inhibition of disease progression and serum prostate-specific antigen reduction in patients with prostatic intraepithelial neoplasia.

The objective of this study was to evaluate the impact of finasteride on the progression of prostate intraepithelial neoplasia and levels of prostate-specific antigen (PSA) in patients. A total of 120 patients with high-grade prostatic intraepithelial neoplasia were included in this study from January 2013 to January 2018. All patients underwent prostate biopsies. Among them, 60 patients were assigned to the observation group and received a daily dosage of 5mg finasteride for 60 months, while the remaining 60 patients were assigned to the control group and did not receive finasteride. PSA levels were measured every six months, and imaging scans were conducted throughout the five-year study period. Additional biopsies were performed if PSA levels exceeded 10ng/mL or imaging suggested the presence of prostate cancer. Statistical analysis was applied to the collected data. In total, 25 cases of prostate cancer were identified in this study. Of these cases, 7 patients belonged to the observation group, whereas the remaining 18 patients were from the control group. The observation group exhibited significantly lower levels of total serum PSA (p <0.001) and Gleason scores (p <0.001) compared to the control group. Our study, which involved 120 participants, demonstrated that finasteride effectively reduces serum PSA levels and mitigates the severity of prostate cancer. These findings suggest that finasteride holds potential as a treatment option for patients with -high-grade prostatic intraepithelial neoplasia.

Therapy With Metronomic Cyclophosphamide (mCyc) for Previously-Treated Metastatic Castrate-Resistant Prostate Cancer (mCRPC)

IntroductionDespite the introduction of various novel therapies for management of metastatic castrate resistant prostate cancer (mCRPC) in recent decades, available treatment options are finite and remain limited. Multiple historical studies have demonstrated activity and a favorable toxicity profile of oral metronomic cyclophosphamide (mCyc) in prostate cancer (PCa). Unlike the cytotoxic immunosuppressive effects of high-dose intravenously-administered cyclophosphamide, continuous low doses of oral mCyc have a unique immune-stimulatory mechanism of action. Materials and MethodsThis is a retrospective, multi-institution study of men with 43 patients with mCRPC treated mCyc. Patient demographic information as well as clinical, pathologic, and genomic characteristics of their PCa were extracted. The primary endpoint was the rate of PSA decline by ≥ 50% (ie, PSA50). Additional efficacy and toxicity data as well as cost analysis compared to other commonly used agents in mCRPC was obtained. ResultsPSA50 was noted in 20.9% of patients, while an additional 25.6% patients achieved < PSA50 and 6.9% reported improvement in prostate cancer-related symptoms without any PSA reduction. Meanwhile, 9.3% of patients required mCyc dose reduction, 11.6% needed dose interruption due to toxicity, and no treatment discontinuations due to toxicity were observed. mCyc was also cost effective compared to other agents commonly used in mCRPC. ConclusionsDespite the small sample size and retrospective nature of this dataset, mCyc demonstrated promising rapid activity and a tolerable toxicity profile in a heavily pretreated mCRPC population with aggressive clinical, pathologic, and genomic disease features.

Real-world prostate-specific antigen reduction and survival outcomes of metastatic hormone-sensitive prostate cancer patients treated with apalutamide: An observational, retrospective, and multicentre study.

Backgroundetastatic hormone-sensitive prostate cancer (mHSPC) treatment has changed drastically during the last years with the emergence of androgen receptor–targeted agents (ARTAs). ARTA combined with androgen deprivation therapy has demonstrated better oncological and survival outcomes in these patients. However, the optimal choice among different ARTAs remains uncertain due to their analogous efficacy. ObjectivesThe objective of this study was to describe prostate-specific antigen (PSA) response and oncological outcomes of patients with mHSPC treated with apalutamide. Material and methodsMedical records from three different hospitals in Spain were used to conduct this study. Patients diagnosed with mHSPC and under apalutamide treatment were included between March 2021 and January 2023. Data regarding PSA response, overall survival (OS), and radiographic progression-free survival (rPFS) were collected and stratified by metastasis volume, timing, and stating. Results193 patients were included; 34.2% of patients were de novo mHSPC, and the majority was classified as m1b. The 18-month OS and rPFS were 92.5% and 88.9%, respectively. Patients with PSA levels ≤0.2 ng/ml showcased an 18-month OS rate of 98.7%, contrasting with 65.3% for those with PSA >0.2 ng/ml. Similar trends emerged for rPFS (97.4% and 53.7%, respectively). When differentiating between low-volume and high-volume metastasis, the OS rate stood at 98.4% and 80.7%, respectively, while the rPFS rates were 93% and 81.6%, respectively. No significant differences were found between groups stratified by metastasis timing. ConclusionThis real-world study on patients with mHSPC treated with apalutamide plus androgen deprivation therapy revealed robust oncological outcomes, aligning with the emerging evidence. The study's hallmark finding highlights the significance of rapid and deep PSA response as a predictor of improved oncological and survival outcomes.

Real life experience of compassionate use of 177Lu-PSMA-1 for metastatic castration-resistant prostate cancer patients in Leon Berard Cancer Centre

PurposeWe present a retrospective feedback of PSMA-targeted radioligands therapy (PRLT) using onsite radiolabeled 177Lu-PSMA-1 to treat metastatic castration-resistant prostate cancer patients (mCRPC) progressing after conventional treatments. MethodsOnsite radiolabeling of the PSMA-1 with 177Lu was authorized by the National Agency for the Safety of Medicines and Health Products (ANSM) after IMPD (Investigational Medicinal Product Dossier) approval allowing to treat patients before 177Lu-PSMA-617 national agreement. Patients were screened on 68Ga-PSMA and 18F-FDG PET-CTs and would be included in case of significant PSMA uptake in the majority of known lesions without mismatch between FDG and PSMA especially in liver metastases, following the THERAP trial procedure. Treatments would consist in 6 injections of 7.4GBq of 177Lu-PSMA-1 every 6 weeks following the VISION phase III trial. A clinical, biological and radiological follow-up during the treatment allowed the detection of possible adverse effects or tumor progression that should lead to treatment discontinuation, and the monitoring and characterization of the expected benefits, according to PCWG3 criteria. Whole-body SPECT-CT was performed in all patients 24hours after injection at each cycle using the VERITON® - Spectrum Dynamics to monitor lesions 177Lu-PSMA-1 uptake. ResultsBetween April 2021 and July 2022, 21 of the 24 patients screened could be included after clinical, biological and imaging screening. Ten received at least 4 injections, and 6 received all 6 injections. Three patients demonstrated a 50% reduction in PSA (PSA50), and 3 others any significant PSA evolution. The safety profile was favorable, with however grade 3 toxicities leading to permanent discontinuation of the treatment. ConclusionOn-site radiolabeled 177Lu-PSMA-1 appeared safe and lead to clinical benefit in most patients. The benefit-risk balance seems to be favorable for these multitreated mCRPC progressive patients in the absence of therapeutic alternatives. It requires a close multidisciplinary and multiprofessional collaboration within the nuclear medicine department. Further studies are necessary to specify the modalities of scans analysis, the impact of post-therapy scans, the length of the benefits observed, and the position of PRLT in the management of prostate cancers.

Carboplatin in Patients With Metastatic Castration-Resistant Prostate Cancer Harboring Somatic or Germline Homologous Recombination Repair Gene Mutations: Phase II Single-Arm Trial.

Approximately 20%-25% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor a deleterious germline or somatic mutation in the homologous recombination repair (HRR) pathway genes, which is involved in the repair of double-stranded DNA damage. Half of these mutations are germline, while the remaining are exclusively somatic. While polyadenosine 5'diphosphoribose [poly (ADP-ribose)] polymerase inhibitors, such as olaparib and rucaparib, are effective in this subgroup, their widespread use is limited due to the associated high cost, especially in resource-constrained settings. Notably, platinum agents like carboplatin have exquisite sensitivity to cells with defective DNA repair machinery. Carboplatin, a conventional, inexpensive chemotherapeutic agent, offers a potential alternative treatment in such patients. Several retrospective small case series support this hypothesis. However, there are no prospective clinical trials of carboplatin in patients with mCRPC with HRR mutations. The primary objective is to assess the objective response rate of 3 weekly carboplatin treatments in patients with mCRPC harboring deleterious mutations in the HRR pathway genes and previously treated with a taxane or a novel antiandrogen agent. The secondary objectives include progression-free survival, health-related quality of life, and safety profile of carboplatin. Patients diagnosed with mCRPC harboring HRR pathway mutations previously treated with docetaxel or novel antiandrogen agents (abiraterone, enzalutamide, apalutamide, or darolutamide) or both will be eligible. Genes involved directly or indirectly in the HRR pathway will be tested. In this single-arm phase II study, we will screen approximately 200 patients to enroll 49 patients, and carboplatin (dosing at the area under curve=5) will be administered every 3 weeks until progression or intolerable side effects. The primary end point will be assessed as the proportion of patients with a reduction of serum prostate-specific antigen by more than 50% from enrollment. Secondary outcomes include progression-free survival-soft-tissue disease progression (by response evaluation criteria in solid tumors, version 1.1, and bone lesion progression using Prostate Cancer Clinical Trials Working Group 3 criteria), health-related quality of life during carboplatin treatment using the Functional Assessment of Cancer Therapy-Prostate questionnaire and the European Organisation for Research and Treatment of Cancer questionnaire and safety profile of carboplatin (National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0). The trial started enrollment in September 2023. This trial is ongoing, and 12 patients have been recruited to date. All 49 participants will be enrolled according to plan. This prospective phase II trial represents a critical step toward addressing the therapeutic gap in patients with mCRPC harboring HRR pathway mutations, particularly in demographic regions with limited access to poly (ADP-ribose) polymerase inhibitors. Outcomes from this study will inform clinical practice and guide future phase III randomized trials, ultimately improving patient outcomes globally. Clinical Trials Registry of India CTRI/2023/04/051507; https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=Njc0NjU=&Enc=&userName=. DERR1-10.2196/54086.