Prostate-specific Antigen Reduction Research Articles

Administering [177Lu]Lu-PSMA-617 Prior to Radical Prostatectomy in Men with High-risk Localised Prostate Cancer (LuTectomy): A Single-centre, Single-arm, Phase 1/2 Study

BackgroundHigh-risk localised prostate cancer (HRCaP) has high rates of biochemical recurrence; [177Lu]Lu-PSMA-617 is effective in men with advanced prostate cancer. ObjectiveTo investigate the dosimetry, safety, and efficacy of upfront [177Lu]Lu-PSMA-617 in men with HRCaP prior to robotic radical prostatectomy (RP). Design, setting, and participantsIn this single-arm, phase I/II trial, we recruited men with HRCaP (any of prostate-specific antigen [PSA] >20 ng/ml, International Society of Urological Pathology (ISUP) grade group [GG] 3–5, and ≥cT2c), with high tumour uptake on [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PSMA PET/CT), and scheduled for RP. InterventionCohort A (n = 10) received one cycle and cohort B (n = 10) received two cycles of [177Lu]Lu-PSMA-617 (5 GBq) followed by surgery 6 weeks later. Outcome measurements and statistical analysisThe primary endpoint was tumour radiation absorbed dose. Adverse events (AEs; Common Terminology Criteria for Adverse Events (CTCAE) version 5.0), surgical safety (Clavien-Dindo), imaging, and biochemical responses were evaluated (ClinicalTrials.gov: NCT04430192). Results and limitationsBetween May 29, 2020 and April 28, 2022, 20 patients were enrolled. The median PSA was 18 ng/ml (interquartile range [IQR] 11–35), Eighteen (90%) had GG ≥3, and six (30%) had N1 disease. The median (IQR) highest tumour radiation absorbed dose after cycle 1 for all lesions was 35.5 Gy (19.5–50.1), with 19.6 Gy (11.3–48.4) delivered to the prostate. Five patients received radiation to lymph nodes. Nine (45%) patients achieved >50% PSA decline. The most common AEs related to [177Lu]Lu-PSMA-617 were grade 1 fatigue in eight (40%), nausea in seven (35%), dry mouth in six (30%), and thrombocytopenia in four (20%) patients. No grade 3/4 toxicities or Clavien 3–5 complications occurred. Limitations include small a sample size. ConclusionsIn men with HRCaP and high prostate-specific membrane antigen (PSMA) expression, [177Lu]Lu-PSMA-617 delivered high levels of targeted radiation doses with few toxicities and without compromising surgical safety. Further studies of [177Lu]Lu-PSMA-617 in this population are worthwhile to determine whether meaningful long-term oncological benefits can be demonstrated. Patient summaryIn this study, we demonstrate that up to two cycles of [177Lu]Lu-PSMA-617 given prior to radical prostatectomy in patients with high-risk localised prostate cancer are safe and deliver targeted doses of radiation to tumour-affected tissues. It is tolerated well with minimal treatment-related adverse events, and surgery is safe with a low rate of complications. Activity measured through PSA reduction, repeat PSMA PET/CT, and histological response is promising.

Three Months PSA Response after PSMA-Guided Approach for Biochemical Relapse after Prostatectomy (PSICHE Trial).

Prostate bed salvage radiotherapy (SRT) is currently the main approach for early biochemical relapse (BR) after radical prostatectomy (RP). Nonetheless, 68Ga-PSMA-11 PET/CT implementation in this scenario prompted significant changes in patients' management. Our trial is aimed to prospectively assess the oncological outcomes after a pre-defined, 68Ga-PSMA-11 PET/CT based treatment strategy. In this analysis, we present early results focusing on three-months biochemical outcomes after treatment. Inclusion criteria were BR after RP (PSA ≥0.2 ng/ml; < 1 ng/ml) +/- postoperative SRT. All patients with PSA persistence after RP (PSA >0.2 ng/ml within 16 weeks from surgery) were excluded from the trial. After centralized 68Ga-PSMA PET/CT, a pre-defined treatment approach was proposed, consisting in Observation and re-staging at further PSA progression in case of negative 68Ga-PSMA PET/CT and previous postoperative RT, prostate bed SRT in case of negative imaging or positive imaging within prostate bed, Stereotactic body radiotherapy (SBRT) to all sites of disease in patients with pelvic nodal recurrence or oligometastatic disease (defined as (< 3 non-visceral metastatic lesions) or Androgen deprivation therapy +/- other systemic treatment indicated for hormone sensitive prostate cancer for widespread metastatic disease. PSA ≤0.2 ng/ml or ≤ 50% of baseline were defined as Complete or partial biochemical response (CBR or PBR), respectively. At present, 135 patients were enrolled within the protocol. Current analysis is focused on a cohort of patients with at least three months of follow up and excludes all patients who underwent only observation after re-staging due to previous prostate bed SRT (n = 42). In this subgroup, PBR or CBR were detected in 28 (66.7%) and 25 (59.5%) patients, respectively. PSA reduction if compared to baseline was detected in 34 patients, for an overall biochemical response rate of 80.9%. Biochemical progression after treatment was reported in 3 patients, who underwent a second 68Ga-PSMA PET/CT re-staging with detection of distant metastases. Promising results after a 68Ga-PSMA PET/CT targeted salvage treatment strategy were reported in terms of early biochemical response. This approach may allow to defer systemic treatment in this setting. Biochemical relapse free and progression free survival will be the objects of further analysis after longer follow-up.

Prostatic Artery Embolization Using Polyethylene Glycol Microspheres: A 1-Year Follow-up Prospective Study Including 30 Patients

PurposeTo evaluate safety and effectiveness of prostatic artery embolization (PAE) using polyethylene glycol (PEG) microspheres in patients with moderate-to-severe benign prostatic hyperplasia (BPH). Materials and MethodsA single-center, prospective study of 30 patients who underwent PAE from August 2020 to December 2021 using PEG 400-μm microspheres was conducted. Patient evaluation data using International Prostate Symptom Score (IPSS), quality of life (QoL) score, prostate-specific antigen (PSA), peak urinary flow rate (Qmax), postvoid residual volume (PVR), and prostate volume (PV) at baseline and 3 and 12 months after PAE were obtained. ResultsBilateral PAE was performed in all patients. One patient had early clinical failure (3.3%) and another presented with lower urinary tract symptoms (LUTSs) recurrence (3.3%) at the 12-month follow-up. Twenty-eight patients (93.3%) experienced significant and durable LUTS improvement. Mean absolute (and relative) improvement at 3 and 12 months were: IPSS, 14.6 points (−69%) for both; QoL, 3.3 points (−70%) and 3.5 points (−74%); Qmax, 6.3 mL/s (+78%) and 8.6 mL/s (+100%); PSA reduction, 1.2 ng/mL (−22%) and 1.0 ng/mL (−15%); PVR reduction, 48 mL (−56%) and 58.2 mL (−49%); PV reduction, 23.4 cm3 (−29%) and 19.6cm3 (−25%); (P < .05 for all). No major adverse events were observed. Minor adverse events included urinary tract infection (4/30, 13.3%), prostatic tissue elimination (3/30, 10%), penile punctiform ulcer (1/30, 3.3%), and urinary retention (1/30, 3.3%). ConclusionsPAE using PEG microspheres was observed to be effective with sustained LUTS improvement at the 12-month follow-up. The incidence of urinary infection and prostatic tissue elimination was higher than previously reported for other embolics.

775 Incidental Prostate Cancer Following Holmium Laser Enucleation of Prostate

Abstract Aim To review the incidence and predictors of incidental prostate cancer (IPCa) following Holmium Laser Enucleation of Prostate (HoLEP). Method This was a departmental retrospective review of 148 patients undergoing HoLEP between 2017 to 2022. Demographic, perioperative, and pathologic data were gathered. For patients diagnosed with IPCa, information on work up, management, and oncologic outcome were gathered. Univariate and multivariate logistic regression were used to identify predictors of IPCa. Results 13 patients had IPCa (8.78%). The mean age was 73.4 years (SD 6.6); pre-procedural prostate volume 85.3ml (SD 32.9); pre-procedural PSA 6.7ng/ml (SD 6.1); PSA density 0.08ng/mL2 (SD 0.06); weight of enucleated tissue 52.8g (SD 39.4); enucleated tissue PSA density 0.14ng/mL2 (SD 0.10). Prostate volume was strongly correlated with weight of enucleated tissue (Pearson 0.8, P = 0.006). Lower pre-procedure prostate volume was the only significant predictor of IPCa (P = 0.018). A prostate volume of &amp;lt;99.0ml had sensitivity of 0.67 and specificity of 0.63 (Area under ROC = 0.70). Mean reduction in post-procedural PSA was 5.6ng/ml (SD 6.3). 61.5% (n = 8) patients had clinically significant IPCa (Gleason≥GG2 or &amp;gt;5% volume). 3 patients had radical treatment, and 5 patients were under active surveillance. The other 5 patients with insignificant IPCa continue on active surveillance (AS) (n = 3) and watchful waiting (WW) (n = 2). None with insignificant disease had disease progression. Conclusions Of patients with IPCa, 61.5% (n = 8) patients had clinically significant IPCa, and the optimal mode of detecting incidental clinically significant prostate cancer, prior to HoLEP might include pre-operative MRI in selected patients based on gland size.

Transperineal laser ablation (TPLA) with ultrasound/MRI fusion guidance in the treatment of localized radiotherapy-resistant prostate cancer

Objective The objective of this study was to assess the technical feasibility, safety, and efficacy of transperineal laser ablation (TPLA) guided by ultrasound/magnetic resonance (MR) fusion as a salvage treatment for refractory focal prostate cancer. Methods A total of five patients who had undergone radiation therapy (RT) for prostate carcinoma and biochemical recurrence, confirmed by both prostate-specific antigen (PSA) levels and MRI (3T mpMRI), were enrolled in this study. Focal ablation was performed using a 1064 nm diode laser. Post-ablation follow-up was conducted for a duration of 18 months, which included regular PSA sampling, 3T mpMRI, and ultrasound/MR fusion-guided biopsies systematic and targeted at the site of the focal treatment. Results The focal ablation procedure was carried out in an outpatient setting regimen with optimal clinical and biochemical outcomes. No recurrence was detected throughout the follow-up period. Conclusion TPLA focal treatment effectively manages local recurrences of RT refractory prostate cancer without side-effects or complications. Preservation of quality of life and functional outcomes, along with a &gt;70% reduction in PSA, were achieved. Advances in knowledge Our study investigated TPLA as a salvage treatment for low-risk recurrent prostate cancer after RT, demonstrating its tolerability, feasibility, and effectiveness.

The significance of metabolic response to neoadjuvant androgen deprivation therapy detected with [68Ga]Ga-PSMA-11-PET/CT in high-risk prostate cancer patients treated with definitive radiotherapy.

We examined the prognostic significance of early changes in primary tumor SUV measured with Gallium-68-labeled prostate-specific membrane antigen positron emission tomography ([68Ga]Ga-PSMA-11-PET/CT) and serum PSA values after neoadjuvant androgen deprivation treatment (nADT) in high-risk prostate cancer (PCa) patients treated with definitive radiotherapy (RT). The clinical data and SUV parameters of 71 PCa patients were reviewed retrospectively. The serum PSA and primary tumor SUV values were calculated before and after the start of ADT. Using univariable and multivariable analyses, the prognostic factors predicting biochemical disease free survival (bDFS) and prostate cancer specific survival (PCSS) were investigated. In addition, logistic regression analysis was used to identify predictors of biochemical failure (BF). All but one patient responded with a 98.8% reduction in serum PSA (21.8ng/mL vs. 0.3ng/mL; p < 0.001), and 64 patients (91.1%) had a median 66.6% decrease in primary tumor SUV after ADT (13.2 vs. 4.8, p < 0.001). The primary tumor SUV response rate was significantly higher in patients with Gleason score (GS) of 7 than in patients with GS > 7 (59.5% vs. 40.5%; p = 0.04), and it was significantly lower in patients with inadequate treatment response than in those with complete (CR) or partial response (PR) (1.1% vs. 66.1%; p < 0.001). There was a strong and significant correlation (Spearman = 0.41, p < 0.001) and a high concordance (91.5%) between PSA response and SUV response after ADT. With a median follow-up time of 76.1months, the 5-year bDFS and PCSS rates were 77.2% and 92.2%, respectively. Nineteen patients (26.7%) patients had recurrence at a median of 44.6months after the completion of RT. In multivariate analysis, lymph node metastasis, GS greater than 7, and SD/PD after nADT were independent predictors of worse bDFS. However, no significant factor for PCSS was identified. In the multivariable logistic regression analysis, advanced age, GS of > 7 disease, lymph node metastasis, and SD or PD after nADT were independent predictors of BF. These results imply that the metabolic response measured with [68Ga]Ga-PSMA-11-PET/CT after nADT could be used to predict progression in high-risk PCa patients treated with definitive RT.

Saw Palmetto may fight prostate cancer.

Saw Palmetto may fight prostate cancer.

Clinical outcomes in patients with metastatic castrate-resistant prostate cancer treated with abiraterone with or without ongoing androgen deprivation therapy: A retrospective case-control study.

Abiraterone and concurrent androgen deprivation therapy (ADT) are used in the treatment of patients with metastatic castration-resistant prostate cancer. Recently, it has been suggested that the use of abiraterone alone (without ADT) may have comparable efficacy to abiraterone with ongoing ADT. Here, we sought to assess the impact of ADT cessation in patients beginning abiraterone for castration-resistant prostate cancer. We identified 39 patients at our institution who received abiraterone alone (with discontinuation of ADT) between 2011 and 2022. We then procured a comparable group of 39 patients (matched by age, Gleason score, and prostate-specific antigen [PSA] level) who received abiraterone with ongoing ADT during the same period. We assessed and compared clinical outcomes in the two groups (abiraterone-alone vs. abiraterone-ADT) with respect to PSA response rates, PSA progression-free survival, and overall survival. Results were adjusted using Cox proportional-hazards multivariable models. The median PSA before treatment initiation was 12.7 (range: 0.2-199) ng/mL in the abiraterone-alone group and 15.5 (range: 0.6-212) ng/mL in the abiraterone-ADT group. Use of abiraterone alone adequately suppressed testosterone levels in 35/37 (94.6%) patients. Patients receiving abiraterone alone had a median PSA reduction of 80.2% versus 79.5% in patients receiving abiraterone plus ADT. The median PSA progression-free survival in patients receiving abiraterone alone was 27.4versus 25.8 months in patients receiving abiraterone plus ADT (hazard ratio [HR] 1.10; 95% confidence interval [CI] 0.65-1.71; p = 0.82). In addition, abiraterone alone was associated with an overall survival of 3.6versus 3.1 years in patients receiving abiraterone plus ADT (HR 0.90; 95% CI 0.50-1.62; p = 0.72). There were no differences in PFS or OS between groups after performing Cox multivariable regression analyses. Use of abiraterone alone was associated with comparable clinical outcomes to patients who received abiraterone together with ADT. Further prospective studies are warranted to evaluate the impact of abiraterone alone on treatment outcomes and cost savings.

Variation of inflammatory indexes in patients with chronic abacterial prostatitis treated with an herbal compound/extract.

Inflammation is a highly prevalent finding in the prostate. Men with inflammation have higher IPSS score and increased prostate size. For men with prostatic inflammation, there is a significantly increased risk of developing acute urinary retention and the need of a surgical approach to the disease. Some laboratory tests (i.e. fibrinogen, C-reactive protein), can play a role in identifying patients at greatest risk of complications and adverse outcomes after surgery. There have been several experiences exploring the role of nutraceutical approach to the prostate inflammation. Aim of our study were to describe the variation in symptoms and inflammatory indexes in men affected by chronic abacterial prostatitis, treated with an herbal extract containing Curcuma Longa 500 mg, Boswellia 300 mg, Urtica dioica 240 mg, Pinus pinaster 200 mg and glycine max 70 mg. A prospective multicenter study was conducted from February 2021 and March 2022. One hundred patients, with a diagnosis of Chronic Prostatitis were enrolled in a multicentric phase III observational study. They were treated with the herbal extract, one capsule per day, for 60 days. No placebo arm was included. In each patient, inflammatory indexes, PSA, prostate volume, IIEF-5, PUF, uroflowmetry (Qmax), IPSS-QoL, NIH-CPPS were registered and statistically compared at baseline and at the follow up visit. The variation obtained on the inflammation indexes showed a global improvement after treatment, including the PSA reduction. We also recorded a significant improvement on IPSS-QoL, NIH-CPPS, PUF and Qmax scores. The herbal extract considered in our study may represent a promising and safe therapeutic agent leading to a reduction of inflammation markers, and could be used in the treatment of prostatitis and benign prostatic hyperplasia.

Greenlight laser (XPS-180watt) prostatectomy for treatment of benign prostate obstruction, Pursuit of durability

ABSTRACT Objectives To report 5-year outcomes, need and predictors of retreatment post greenlight laser photoselective vaporization (GL.PVP) and vapo-enucleation (GL.PVEP), as long-term data on safety and efficacy of GL.PVP and GL.PVEP and on the prostate using XPSTM system are still pending. Patients and methods Primary outcome was the need for retreatment (medical treatment and reintervention) for recurrent BOO. Time-to-event (retreatment) analysis, perioperative events, change in the urinary outcome measures at different follow-up visits, early and late complications and PSA kinetics were reported. Results Between September 2014 and April 2017, 248 patients underwent GL/XPS procedures. GL.PVP and GL.PVEP were carried out for 157 (63.3%) and 91 (36.7%) patients with mean prostate sizes of 60 ± 18 and 100 ± 22 cc, respectively. After a mean duration of 62 ± 9-month follow-up, overall retreatment rate (medical and interventional) was 23% (57 patients). It was comparable between both GL.PVP and GL.PVEP cases: 38 (24.2%) and 19 (20.9%) patients, P = 0.5, respectively. Significantly more surgical reintervention rate was reported after GL.PVP compared to GL.PVEP (P = 0.03). In retreatment group, more intraoperative bleeding (P = 0.02), early postoperative hematuria (P = 0.03), higher median preoperative PSA (P = 0.02) and less postoperative one-year percent PSA reduction (P = 0.02) were detected. Lower postoperative one-year percent PSA reduction independently predicts retreatment with a cut-off point of 64.2% (58.2% sensitivity, 73.4% specificity, AUC 0.647, 95% CI 0.52–0.76). Median (range in months) time to event was 20 (1–60) for all cases and 13.5 (1–42) and 30 (18–60), P = 0.7, for GL.PVP and GL.PVEP groups, respectively. Conclusion Greenlight laser XPS is an effective, durable and versatile tool in treating benign prostatic obstruction. Durability of the outcome is predictable with more postoperative PSA reduction.

Prime-boost immunotherapeutic trial in men with biochemical recurrence after definitive local therapy for prostate cancer.

TPS5119 Background: VTP-850 is a heterologous prime-boost immunotherapeutic consisting of 2 nonreplicating viral-vectored components: ChAdOx1-PCAQ, based on an adenoviral vector, and MVA-PCAQ, based on a modified vaccinia virus Ankara (MVA) vector. Both components encode the same 4 prostate cancer antigens: prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), six transmembrane epithelial antigen of prostate 1 (STEAP1), and 5T4, an oncofetal antigen. Preclinical studies in inbred, outbred, and HLA-A2 transgenic mice show that VTP-850 is highly immunogenic. Immune responses were measured in splenocytes using IFN-γ ELISpot assay, multiparameter flow cytometry, and targeted in vivo killing assays. The results indicate that VTP-850 can elicit T cell responses to each of the 4 encoded antigens, with the responses to PSA of greatest magnitude in all mouse strains studied. Intravenous administration of the boost resulted in a 6-fold increase in the magnitude of antigen-specific T cells induced and increased in vivo killing relative to the intramuscular boosting route1. Methods: This is a first-in-human multicenter Phase 1/2 trial to evaluate safety, PSA response rate and duration, and immunogenicity of VTP-850 in men with biochemical recurrence of prostate cancer after definitive local therapy. Phase 1 (15-18 participants) will follow a 3+3 design to determine the recommended phase 2 regimen; dose level of both ChAdOx1-PCAQ and MVA-PCAQ, and route of administration of MVA-PCAQ (IM or IV). Phase 2 will consist of 2 stages. In Stage 1, 19 additional participants will be enrolled at the chosen Phase 2 regimen. If 4 or more of the 25 participants (including the 6 Phase 1 participants who received the same regimen) have a PSA response (defined as ≥50% reduction in serum PSA compared to baseline at any time, measured twice consecutively, at least 2 weeks apart), Stage 2 will enroll 100 additional participants. Participants will be followed for 6 months or until start of new therapy (e.g. ADT) or until development of metastatic disease. Participants who have a PSA response during the 6 months follow up will be followed for up to an additional 18 months. Patients who have undergone primary therapy for prostate cancer and have biochemical recurrence are eligible. Patients must have nonmetastatic (M0) disease; serum PSA of &gt; 0.3 ng/mL for participants with prior radical prostatectomy or serum PSA of 2 ng/mL above nadir for participants with prior external beam radiation or brachytherapy; PSA doubling time ≤12 months; and testosterone &gt; 75 ng/dL. They cannot have received ADT within 6 months prior to Day 1 and cannot have received prior chemotherapy, immunotherapy or experimental agent for prostate cancer. The trial is open in the USA, with sites in Spain and Italy planned to open later in 2023. 1. Vardeu A et al 2022. Clinical trial information: NCT05617040 .

Circulating tumor cells (CTCs) in patients with metastatic castration resistant prostate cancer (mCRPC) treated with olaparib plus 177lutetium-prostate specific membrane antigen-617 (177Lu-PSMA-617) in the LuPARP trial.

5064 Background: LuPARP (NCT03874884) is evaluating the safety and efficacy of olaparib in combination with 177Lu-PSMA-617 in patients (pts) with mCRPC who have progressed on an androgen receptor pathway inhibitors and docetaxel. We aim to identify potential prognostic and predictive biomarkers from serial CTC profiling. Methods: Twenty-six pts with high PSMA expression on PSMA-PET received 7.4 GBq of 177Lu-PSMA-617 every 6 weeks (wk) together with an escalating dose-schedule of olaparib (50mg BD – 300mg BD, days 2 to 14 or days -4 to 14) for up to 6 cycles. For CTC analysis, 10 mls of blood was collected at baseline, 12-weekly for 48 wk, and thereafter every 24 wk and at disease progression. CK+, CD45-, and DAPI+ CTCs were enumerated from 3 mls of blood and immunoassayed for PSMA expression using the Epic Sciences platform. Correlations between total and PSMA+ CTC counts and PSA50 response (PSA reduction of ≥ 50%) were evaluated. Low pass whole genome sequencing (lpWGS) was performed on baseline and longitudinal CTC samples to identify copy number alterations. Results: At baseline, 23 of 26 pts (88%) had detectable CTCs (median 2.9 CTC/ml, range 0-30), and of these 23 pts, 17 (74%) had detectable PSMA+ CTCs (median 0.9 CTC/ml, range 0.3-27), indicating heterogeneity of PSMA expression in CTCs. The CTC positivity rates (% of cases ≥1 CTC) at week (w)12, w24, w36, w48 and at disease progression were 57%, 58%, 75%, 36% and 100%, and the PSMA positivity rates (% of cases ≥1 PSMA+ CTC) were 38%, 36%, 22%, 50% and 56%, respectively. Fifteen of 20 (75%) evaluable pts with paired baseline and w12 CTCs had a ≥50% decline in total CTC count, of which 9/15 (60%) pts also achieved a PSA50 response. Five of these 9 (56%) pts had 100% CTC clearance at w12. In terms of PSMA+ CTCs, 14/15 (93%) evaluable pts had ≥50% PSMA+ CTC decline with 13 pts (93%) achieving complete CTC clearance by w12. Six of the 13 pts with complete PSMA+ CTC clearance at w12 also achieved a PSA50 response. Beyond PSMA expression, genomic heterogeneity was evident in baseline and on-treatment CTCs, including recurrent loss of PTEN, TP53, BRCA2, ATM, and RB1, and gain of AR and MYC. lpWGS in 10 baseline samples identified 5 cases with BRCA2 loss and 5 cases with ATM loss. Two pts with BRCA2 loss and 3 pts with ATM loss had a PSA50 response by w12. Conclusions: We observed high rates of total and PSMA+ CTCs in PSMA-expressing mCRPC. Total and PSMA+ CTCs decline with combined olaparib and 177Lu-PSMA-617 treatment. Early declines in total and PSMA+ CTCs including 12w CTC clearance paralleled PSA responses. Notably, total and PSMA+ CTCs rise again in the setting of disease progression. Serial CTC profiling may assist in tracking response to 177Lu-PSMA-617 therapy. Clinical trial information: NCT03874884 .

Therapy with metronomic cyclophosphamide (mCyc) in metastatic castrate resistant prostate cancer (mCRPC) and genomic correlates.

e17041 Background: Multiple historic studies demonstrated activity of mCyc in various solid tumors, including mCRPC. Low doses of oral mCyc can lead to enhanced immune stimulation by depleting regulatory T-cells. Its adverse effect profile is well established, with grade 3 and 4 toxicities being rare. In recent years, use of mCyc in mCRPC has fallen out of favor with development of novel therapies. Methods: We conducted a retrospective study of all patients with mCRPC, who received therapy with mCyc for at least 4 weeks at the University of California Irvine and Thomas Jefferson University between 6/1/17 and 1/31/23. Different oral mCyc regimens were included - 50 mg daily continuously, 50 mg daily on days 1 to 14 out of a 28-day cycle, and 250 mg daily on days 1 to 14 out of a 28-day cycle. Results: A total of 20 patients were included, from 62 to 92 years in age. At prostate cancer (PCa) diagnosis, 60.0% (12/20) had de novo metastatic disease. Duration of mCyc therapy was 4 to 41 weeks. Median number of unique PCa therapies received prior to mCyc was 4 [range: 1 to 9], with 75.0% (15/20) pretreated with taxane-based chemotherapy. 25.0% (5/20) of patients achieved a 50% drop in PSA (PSA50), while 30.0% (6/20) achieved PSA reduction but less than PSA50. 10.0% (2/20) had PSA stability without reduction, but experienced improvement in cancer-related symptoms. In those with PSA50, median duration of therapy was 16.3 weeks [range: 14 to 41]. In PSA responders, median time to PSA nadir was 7.2 weeks [range: 1 to 28]. After starting mCyc, 38.5% (5/13) of patients with any PSA or clinical response (i.e. responders) had a transient PSA rise followed by PSA decline, which is suggestive of tumor flare. In responders, 15.4% (2/13) had liver metastasis and 7.7% (1/13) had bone marrow involvement with associated cytopenias. In responders with previous prostate biopsies, 66.6% (6/9) had Gleason 9 or 10 disease. 53.8% (7/13) of responders had genomic data available with a liquid biopsy or tissue sequencing, revealing 3 patients with TP53 mutations and 1 patient with BRCA2 and RB1 co-mutations. 15.0% (3/20) of patients required dose reduction and 20.0% (4/20) dose interruption due to toxicity, with no treatment discontinuations observed. Adverse reactions leading to dose modifications included cytopenias, anorexia, fatigue, nausea, and diarrhea. Conclusions: Despite availability of novel therapeutics for mCRPC, treatment options remain limited. Recognizing the small sample size of this retrospective dataset, oral mCyc showed promising activity with a quick onset of action and a tolerable toxicity profile in heavily pretreated mCRPC patients with aggressive disease features. Given its unique mechanism of action, this provides rationale for future clinical trials, including combining mCyc with other immunomodulating agents such as PD1/PD-L1 inhibitors.

Bone scan index (BSI) scoring by using bone scintigraphy and circulating tumor cells (CTCs): predictive factors for enzalutamide effectiveness in patients with castration-resistant prostate cancer and bone metastases

Reports of Bone Scan Index (BSI) calculations as imaging biomarkers to predict survival in patients with metastatic castration-resistant prostate cancer (mCRPC) have been mainly from retrospective studies. To evaluate the effectiveness of enzalutamide (ENZ) in Japanese patients with mCRPC and bone metastases using BSI (bone scintigraphy) and circulating tumor cell (CTC) analysis. Prospective, single-arm study at Juntendo University affiliated hospitals, Japan. Patients were administered 160 mg ENZ daily, with 3 monthly assessments: BSI, prostate specific antigen (PSA), CTC and androgen receptor splicing variant-7 (AR-V7) status. Primary endpoint: BSI-decreasing rate after ENZ treatment. Secondary endpoints: PSA-decreasing rate and progression free survival (PFS). Statistical analyses included the Wilcoxon t-test, Cox proportional hazard regression analysis, and log-rank test. Median observation period: 17.9 months, and median PFS: 13.8 (2.0–43.9) months (n = 90 patients). A decrease in BSI compared to baseline as best BSI change on ENZ treatment was evident in 69% patients at the end of the observation period (29% patients showed a complete response, BSI 0.00). At 3 months 67% patients showed a ≥ 50% PSA reduction, and 70% after ENZ treatment. PSA decline (3 months) significantly associated with a prolonged median PFS: 18.0 (estimated) versus 6.4 months (HR 2.977 [95% CI 1.53–5.78], p = 0.001). Best BSI decline response significantly associated with a prolonged PFS: 18.1(estimated) versus 7.8 months (HR 2.045 [95% CI: 1.07–3.90], p = 0.029). CTC negative status (n = 20) significantly associated with a prolonged PFS: 13.4 [estimated] vs 8.6 months (HR 2.366, 95% CI 0.97–5.71, p = 0.041). CTC positive/AR-V7 positive status significantly associated with a shorter PFS: 5.9 months (HR 8.56, 95% CI 2.40–30.43, p = 0.0087). -reduction (3 months) and BSI-reduction (on ENZ treatment) were significant response biomarkers, and a negative CTC status was a predictive factor for ENZ efficacy in patients with mCRPC.

Comparison of prostate-specific antigen response in patients with metastatic castration-sensitive prostate cancer initiated on apalutamide or abiraterone acetate: A retrospective cohort study.

Deep prostate-specific antigen (PSA) response (≥90% reduction in PSA [PSA90]) is an important early response indicator of radiographic progression-free survival and overall survival in patients with metastatic castration-sensitive prostate cancer (mCSPC). This study compared PSA90 responses by 6 months between patients with mCSPC at first use of apalutamide or abiraterone acetate, both androgen receptor signaling inhibitors. Clinical data from 77 community urology practices in the United States were analyzed. Patients with mCSPC were classified into treatment cohorts based on their first filled prescription (index date) for apalutamide or abiraterone acetate on or after September 17, 2019 (approval date of apalutamide for mCSPC). Patients were followed from the index date until the earliest of index treatment discontinuation, treatment switch, end of clinical activity, or end of data availability (September 17, 2021). Inverse probability of treatment weighting (IPTW) was used to ensure similarity in distribution of baseline characteristics between cohorts. PSA90 was defined as the earliest attainment of ≥90% reduction in PSA relative to baseline (most recent value within 13 weeks pre-index). Time to PSA90 between cohorts was compared by weighted Kaplan-Meier analysis and with Cox proportional hazards models. A total of 364 patients treated with apalutamide and 147 treated with abiraterone acetate met the study criteria. Patient characteristics were well balanced after IPTW. By 6 months post-index, patients initiated on apalutamide were 53% more likely to achieve PSA90 than those initiated on abiraterone acetate (P = 0.016). Similar results were observed by 9 and 12 months post-index (both P ≤ 0.019). The median time to PSA90 was 3.5 months for the apalutamide cohort and not reached for the abiraterone acetate cohort. In real-world patients with mCSPC, significantly more patients achieved PSA90 with apalutamide than with abiraterone acetate, and this response was achieved earlier with apalutamide.

Attainment of early, deep prostate-specific antigen response in metastatic castration-sensitive prostate cancer: A comparison of patients initiated on apalutamide or enzalutamide.

Deep prostate-specific antigen (PSA) response, defined as a ≥90% decline in PSA (PSA90), is an important early response indicator for achieving radiographic progression-free and overall survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with a next-generation androgen signaling inhibitor (ASI), such as apalutamide or enzalutamide. The objective of this study was to compare deep PSA response among patients with mCSPC newly initiated on apalutamide or enzalutamide. Clinical data from 69 community urology practices in the United States were evaluated. Patients with mCSPC were classified into cohorts based on their first dispensation (index date) for apalutamide or enzalutamide and were followed until the earliest of treatment discontinuation, initiation of a new next-generation androgen receptor signaling inhibitor, end of clinical activity (including death), or end of data availability (03/05/2021). Inverse probability of treatment weights (IPTW) were used to reduce baseline confounding. PSA90 was defined as the earliest ≥90% PSA decline relative to baseline PSA. The proportion of patients achieving PSA90 and time to PSA90 were reported using weighted Kaplan-Meier analysis and weighted Cox proportional hazards models, respectively. The apalutamide and enzalutamide cohorts comprised 186 and 165 patients, respectively. Patient characteristics were generally well balanced after IPTW. By 6 months, patients initiated on apalutamide had a 56% greater likelihood of attaining PSA90 than those initiated on enzalutamide (P = 0.014). This result remained significant through the end of the observation period. The median time to achieving PSA90 was 3.1 months with apalutamide and 5.2 months with enzalutamide. This real-world study demonstrated that apalutamide initiation is associated with a significantly higher likelihood of achieving ≥90% reduction in PSA as compared to initiation of enzalutamide. Moreover, this deep PSA response was observed to occur earlier with apalutamide treatment than with enzalutamide.

MicroRNA-147b induces neuroendocrine differentiation of prostate cancer cells by targeting ribosomal protein RPS15A.

Prostate cancer (PCa) is the leading cause of cancer related deaths in men, often androgen deprivation therapy (ADT) leads to the progression of androgen independent PCa (AIPC) which further leads to Neuroendocrine PCa (NEPC). Identifying the molecular mechanisms which navigate the neuroendocrine differentiation(NED) of PCa cells is clinically relevant. It has been suggested that the micro RNAs (miRNAs) play an important role in the regulation of intrinsic mechanisms relevant to tumor progression, resistance as a result leads to poor prognosis. miR-147b has been transpiring as one of the deregulated miRNAs associated with the occurrence of multiple cancers. The present study has studied the role of miRNA-147b in inducing NEPC. To investigate the functional role of miR-147b in NEPC, we have expressed miRNA mimics or inhibitors in PCa cells and monitored the progression of NEPC along with PCa cell proliferation and survival. The molecular mechanism miRNA-147b follows was studied using western blot and reverse transcriptionpolymerase chain analysis. miRNA target prediction using bioinformatics tools followed by target validation using luciferase reporter assays was performed. In the present study, we found that miR-147b is highly expressed in AIPC cell lines in particular neuroendocrine cells NCI-H660 and NE-LNCaP derived from LNCaP. Mechanistic studies revealed that overexpression of miR-147b or miRNA mimics induced NED in LNCaP cells in in-vitro while its inhibitor reversed the NE features (increased NE markers and reduced prostate specific antigen) of PC3, NCI-H660 and NE-LNCaP cells. In addition, miR-147b reduced the proliferation rate of LNCaP cells via elevated p27kip1 and lowered cyclin D1 for promoting differentiation. In reporter assays, we have identified ribosomal protein S15A (RPS15A) is a direct target of miRNA-147b and RPS15A expression was negatively regulated by miR-147b in PCa cells. Furthermore, we also report that RPS15A is downregulated in NEPC cells and its expression is inversely correlated with NE markers. Targeting the miR-147b - RPS15A axis may overcome the progression of NEPC and serve as a novel therapeutic target to attenuate NED progression of PCa.

Activity and safety of KEES - an oral multi-drug chemo-hormonal metronomic combination regimen in metastatic castration-resistant prostate cancer

BackgroundMetastatic castration-resistant prostate cancer (mCRPC) remains a therapeutic challenge and evidence for late-line treatments in real-life is limited. The present study investigates the efficacy and safety of an oral metronomic chemo-hormonal regimen including cyclophosphamide, etoposide, estramustine, ketoconazole and prednisolone (KEES) administered in a consecutive biweekly schedule.MethodsA retrospective cohort study in two Swedish regions was conducted. Overall (OS) and progression-free survival (PFS), biochemical response rate (bRR) and toxicities were analyzed.ResultsOne hundred and twenty-three patients treated with KEES after initial treatment with at least a taxane or an androgen-receptor targeting agents (ARTA) were identified. Of those, 95 (77%) had received both agents and were the primary analysis population. Median (95% CI) OS and PFS in the pre-treated population were 12.3 (10.1–15.0) and 4.4 (3.8–5.5) months, respectively. Biochemical response, defined as ≥ 50% prostate-specific antigen (PSA) reduction, occurred in 26 patients (29%), and any PSA reduction in 59 (65%). PFS was independent of prior treatments used, and KEES seemed to be effective in late treatment lines. The bRR was higher compared to historical data of metronomic treatments in docetaxel and ARTA pre-treated populations. In multivariable analyses, performance status (PS) ≥ 2 and increasing alkaline phosphatase (ALP) predicted for worse OS. Nausea, fatigue, thromboembolic events and bone marrow suppression were the predominant toxicities.ConclusionsKEES demonstrated meaningful efficacy in heavily pre-treated CRPC patients, especially those with PS 0–1 and lower baseline ALP, and had an acceptable toxicity profile.

PD15-04 PREDICTION OF PROSTATE CANCER SPECIFIC MORTALITY IN MEN UNDERGOING RADIOTHERAPY WITH OR WITHOUT HORMONAL TREATMENT, RISK STRATIFICATION BASED ON CLINICAL CHARACTERISTICS AND PSA TREATMENT RESPONSE

You have accessJournal of UrologyCME1 Apr 2023PD15-04 PREDICTION OF PROSTATE CANCER SPECIFIC MORTALITY IN MEN UNDERGOING RADIOTHERAPY WITH OR WITHOUT HORMONAL TREATMENT, RISK STRATIFICATION BASED ON CLINICAL CHARACTERISTICS AND PSA TREATMENT RESPONSE Ugo Falagario, Darko Bogdanovic, Lars Björnebo, Ahmad Abbadi, Alexander Valdman, Martin Eklund, Tobias Nordström, Markus Aly, Henrik Grönberg, Peter Wiklund, and Anna Lantz Ugo FalagarioUgo Falagario More articles by this author , Darko BogdanovicDarko Bogdanovic More articles by this author , Lars BjörneboLars Björnebo More articles by this author , Ahmad AbbadiAhmad Abbadi More articles by this author , Alexander ValdmanAlexander Valdman More articles by this author , Martin EklundMartin Eklund More articles by this author , Tobias NordströmTobias Nordström More articles by this author , Markus AlyMarkus Aly More articles by this author , Henrik GrönbergHenrik Grönberg More articles by this author , Peter WiklundPeter Wiklund More articles by this author , and Anna LantzAnna Lantz More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003262.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: A detectable PSA within 4 to 8 weeks of surgery is considered treatment failure post-radical prostatectomy and may result from persistent local disease, pre-existing metastases or residual benign tissue. Conversely guidelines do not mention any definition of PSA persistence after Radiotherapy (RT) with or without hormonal treatment (HT).This study aimed to evaluate if detectable PSA values after RT with or without HT predict PCa mortality and can be defined as treatment failure. METHODS: This population-based study included all men in Stockholm County who underwent RT with curative intent (cM0) and PSA follow-up from 2003 to 2019. All PSA values before and after treatment were retrieved from datasets of three centralized laboratories. RESULTS: 5663 patients were included. Median follow-up was 88 months (54, 128). HT was administered in 4457 (79%). Median time to PSA nadir was 6 (5, 21) months. 5089 (89.9%) reached a PSA nadir value ≤0.1 ng/ml while in 191 (3.4%) patients PSA never dropped ≤5 ng/ml. Median PSA reduction was 8 (5, 15) ng/ml. The percentage of PSA reduction from pretreatment PSA to nadir values was ≥50% in 5461 (96.4%), and <50% in 108 (1.9%).At multivariable cox regression analysis adjusting for age, pretreatment PSA, cT stage, biopsy ISUP Gleason group, HT and time to PSA nadir, we found that PSA Nadir values between 0.1-5 ng/ml (HR: 6.07; CI: 4.79,7.68) or ≥5 ng/ml (HR: 12.34; CI: 8.57,17.77) and percentage of PSA drop from pre-treatment PSA to nadir (HR per unit: 0.92; CI: 0.87,0.97) significantly predicted PCa-specific mortality (C-index of the model 0.82). Unadjusted cancer specific survival according to post treatment PSA nadir and percentage PSA reduction from pretreatment PSA are shown in Figure 1. Similar results were found in a sensitivity analysis including patients undergoing RT without HT. CONCLUSIONS: PSA persistence and low PSA drop after RT were strongly correlated to PCa-specific mortality. A PSA nadir value >0.1 ng/ml and/or any reduction of PSA nadir <50% of pretreatment PSA values may be considered a treatment failure after RT with or without HT. Predictive models including these parameters may be used to assess the need for early treatment intensification after RT. Source of Funding: This research was supported by a grant of the European Urological Scholarship Programme awarded to U.G.F. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e419 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ugo Falagario More articles by this author Darko Bogdanovic More articles by this author Lars Björnebo More articles by this author Ahmad Abbadi More articles by this author Alexander Valdman More articles by this author Martin Eklund More articles by this author Tobias Nordström More articles by this author Markus Aly More articles by this author Henrik Grönberg More articles by this author Peter Wiklund More articles by this author Anna Lantz More articles by this author Expand All Advertisement PDF downloadLoading ...

MP29-01 RAPID, DURABLE, AND DEEP PROSTATE-SPECIFIC ANTIGEN RESPONSE FOLLOWING ADDITION OF DAROLUTAMIDE TO ANDROGEN-DEPRIVATION THERAPY AND DOCETAXEL IN ARASENS

You have accessJournal of UrologyCME1 Apr 2023MP29-01 RAPID, DURABLE, AND DEEP PROSTATE-SPECIFIC ANTIGEN RESPONSE FOLLOWING ADDITION OF DAROLUTAMIDE TO ANDROGEN-DEPRIVATION THERAPY AND DOCETAXEL IN ARASENS Fred Saad, Bertrand Tombal, Maha Hussain, Karim Fizazi, Cora N. Sternberg, E. David Crawford, Luke T. Nordquist, Ronald Tutrone, Neal D. Shore, Laurence Belkoff, Shivani Kapur, Jay Jhaveri, Jorge Ortiz, Shankar Srinivasan, Frank Verholen, and Matthew R. Smith Fred SaadFred Saad More articles by this author , Bertrand TombalBertrand Tombal More articles by this author , Maha HussainMaha Hussain More articles by this author , Karim FizaziKarim Fizazi More articles by this author , Cora N. SternbergCora N. Sternberg More articles by this author , E. David CrawfordE. David Crawford More articles by this author , Luke T. NordquistLuke T. Nordquist More articles by this author , Ronald TutroneRonald Tutrone More articles by this author , Neal D. ShoreNeal D. Shore More articles by this author , Laurence BelkoffLaurence Belkoff More articles by this author , Shivani KapurShivani Kapur More articles by this author , Jay JhaveriJay Jhaveri More articles by this author , Jorge OrtizJorge Ortiz More articles by this author , Shankar SrinivasanShankar Srinivasan More articles by this author , Frank VerholenFrank Verholen More articles by this author , and Matthew R. SmithMatthew R. Smith More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003257.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In ARASENS (NCT02799602), darolutamide (DARO) in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI 0.57–0.80; P<0.0001) vs ADT + docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We report on prostate-specific antigen (PSA) responses and kinetics data from ARASENS. METHODS: Patients with mHSPC were randomized 1:1 to DARO 600 mg twice daily or placebo (PBO), both with ADT + docetaxel. Serum PSA was measured at screening and every 12 weeks. Analyses included undetectable PSA (<0.2 ng/mL), ≥50% and ≥90% reductions in PSA from baseline (PSA50, PSA90), and times to PSA progression and PSA50/PSA90. Post hoc landmark analyses evaluated the association between undetectable PSA at weeks 24 and 36 with overall survival (OS) and time to PSA progression. RESULTS: For 1305 patients in the full analysis set (DARO, 651; PBO, 654), 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. Patients in the DARO group demonstrated rapid PSA90 response, with 67.6% achieving PSA90 within 12 weeks, 82.0% within 24 weeks, and 84.9% at any time compared with 42.8%, 54.4%, and 59.0% in the PBO group, respectively (Figure). DARO was associated with deep PSA response, with median PSA at nadir of 0.020 ng/mL vs 0.495 ng/mL for PBO. Undetectable PSA was achieved in more than twice the number of patients receiving DARO vs PBO at 24 weeks (48.7% vs 23.9%), continuing to increase at 36 and 52 weeks with DARO (57.1% and 60.2%). Compared with patients who did not achieve undetectable PSA, patients receiving DARO who achieved undetectable PSA at 24 and 36 weeks had improved OS (HR [95% CI] 0.47 [0.35–0.63] and 0.37 [0.28–0.49]) and prolonged time to PSA progression (HR [95% CI] 0.28 [0.18–0.42] and 0.23 [0.15–0.34]), showing durable PSA response that was maintained over time. CONCLUSIONS: Patients with mHSPC receiving DARO + ADT + docetaxel achieved rapid, durable, and deep PSA responses, correlating with improved OS and prolonged time to PSA progression vs PBO + ADT + docetaxel. Source of Funding: This trial was funded by Bayer AG and Orion Corporation. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e380 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Fred Saad More articles by this author Bertrand Tombal More articles by this author Maha Hussain More articles by this author Karim Fizazi More articles by this author Cora N. Sternberg More articles by this author E. David Crawford More articles by this author Luke T. Nordquist More articles by this author Ronald Tutrone More articles by this author Neal D. Shore More articles by this author Laurence Belkoff More articles by this author Shivani Kapur More articles by this author Jay Jhaveri More articles by this author Jorge Ortiz More articles by this author Shankar Srinivasan More articles by this author Frank Verholen More articles by this author Matthew R. Smith More articles by this author Expand All Advertisement PDF downloadLoading ...