Prostate-specific Antigen Reduction Research Articles

Phase II trial of multi-tyrosine kinase inhibitor ESK981 in combination with PD-1 inhibitor nivolumab in patients with metastatic castration-resistant prostate cancer.

Increasing the response rates of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC) presents a significant challenge. ESK981 is a multi-tyrosine kinase and PIKfyve lipid kinase inhibitor that augments immunotherapeutic responses. In this phase II study, ESK981 was combined with the PD-1 blocking monoclonal antibody nivolumab to test for potentially improved response rates in patients with mCRPC who have progressed on androgen receptor (AR)-targeted agents and chemotherapy. Eligible patients received ESK981 orally once daily for five consecutive days, followed by a two-day break. Patients were also treated with nivolumab intravenously on Day 1 of each 28-day cycle. The primary endpoints were a 50% reduction in prostate-specific antigen (PSA50), and safety. Secondary endpoints included radiographic progression free survival (rPFS) and overall survival (OS). Additional investigations included whole exome sequencing in patients. Ten patients were enrolled. The maximum PSA decline from baseline of 14% was achieved in only one patient. Grade 3 treatment-related adverse events (AEs) included fatigue, anemia, and lymphopenia. There were no Grade 4 events. The median rPFS was 3.7 months (95% CI, 1.6-8.4). The median OS was 9.6 months (95% CI, 1.8-22.4). The study was terminated due to futility after 10 patients. Whole exome sequencing identified AR amplification in 63% of patients (5/8). ESK981 + nivolumab showed no antitumor activity in patients with AR-positive (AR+) mCRPC. Further evaluation of ESK981 combined with the PD-1 inhibitor nivolumab in AR + mCRPC patients is not warranted. (Trial registration: ClinicalTrials.gov NCT04159896. Registration date: November 12, 2019.).

Outcomes for Patients with Metastatic Castration-Resistant Prostate Cancer and Liver Metastasis Receiving [177Lu]Lu-PSMA-617.

It is well known that patients with liver metastasis from metastatic castration-resistant prostate cancer have poor or only transient responses to many forms of systemic therapy. Data on outcomes after treatment with [177Lu]Lu-PSMA-617 (LuPSMA) are scarce. The VISION trial reports a hazard ratio for overall survival (OS) in the subgroup of patients with liver metastasis without disclosing the absolute duration of survival. Using real-world clinical data, we examined this important subgroup of patients, describing prostate-specific antigen (PSA) response and OS. Methods: A single-institution database was assembled to include all patients receiving LuPSMA at Mayo Clinic in Rochester, Minnesota, for whom treatment was initiated between March 2022 and March 2023. Baseline clinicopathologic and imaging characteristics were abstracted. Patients were then categorized by presence or absence of liver metastasis on pretreatment prostate-specific membrane antigen (PSMA) PET. PSA response and OS for the 2 groups (liver metastasis vs. no liver metastasis) were compared using χ2 testing and the Kaplan-Meier method, respectively. A multivariate Cox regression analysis was performed, including established prognostic factors. Finally, those with pretreatment circulating tumor DNA as determined in an 83-gene panel were assessed for the presence of pathogenic and likely pathogenic alterations. These findings were summarized using descriptive statistics and compared between the 2 cohorts using the Fisher exact test. Results: The overall cohort consisted of 273 patients, including 43 (15.75%) with liver metastasis on pretreatment PSMA PET/CT. The median number of cycles received was 3 (range, 1-6) for patients with liver metastasis and 5 (range, 1-6) for those without hepatic involvement. The 50% or greater reduction in PSA from baseline response rate was lower for those with liver metastasis than for those without (30.23% [13/43] vs 49.77% [106/213], P = 0.019). At a median follow-up of 10 mo (interquartile range, 9-13 mo), there was a significant difference in median OS (8.35 mo vs. not reached, P < 0.001). On multivariate analysis, the presence of liver metastasis was independently associated with shorter survival (hazard ratio, 4.06; P < 0.001). Conclusion: Our data suggest that the presence of liver metastasis predicts poorer outcomes in patients receiving LuPSMA treatment. Alternative and combination approaches should be explored to maximize the antitumor activity of radiopharmaceutical therapy in the liver.

Effect of lycopene on prostate cancer among native African men: A protocol for an open-label randomized clinical trial in Tanzania

Background Prostate cancer (PCa) is the most common cancer and the fifth leading cause of death in men worldwide. The treatment of PCa depends on the clinical stage of the disease, prostate-specific antigen (PSA) level, and histology. Lycopene is a bright red carotenoid found in tomatoes, which enhances apoptosis in prostate cells, but its effectiveness has not been studied in East African countries. This study aimed to determine the effectiveness of lycopene from tomato extracts in reducing PSA levels, disease progression, and apoptosis in the prostate glands of men with PCa in Tanzania. Methods This study will be a randomized phase III clinical trial of men diagnosed with PCa in Tanzania. In total, 400 men will be randomized in a 1:1 ratio to receive intervention (n=200) and control (n=200) and followed for 12 months. The intervention arm will receive tomato paste for daily use in addition to the standard treatment, whereas the control arm will only follow the standard of care. The primary endpoints will be a reduction in PSA levels, improved clinical status, and apoptosis of the prostate gland. Data analysis was performed based on the intention-to-treat principle. Descriptive statistics were used to compare average lycopene and PSA levels in the intervention group using T-test and Chi-squared tests. Generalized linear mixed models will be used to further assess the effect of lycopene on PCa progression, urinary symptoms, and PSA reduction. All statistical tests were two-sided at an alpha level of &lt;0.05. Discussion The study used a food supplement as a drug/intervention with minimal or no adverse reactions. However, there is a fear that the control group may not adhere to the protocol after learning the benefits of tomato paste. The study findings will promote the consumption of tomato paste in males diagnosed with PCa to improve the clinical status and reduce disease progression. Trial registration The study has been registered at the Pan African Clinical Trial Registry with registration No PACTR202405488763956.

Prospective observational study on the efficacy and tolerability of a complex of phytochemicals versus dutasteride in the treatment of Lower Urinary Tract Symptomps due to Benign Prostatic Hyperplasia.

The aim of our study was to treat 2 similar groups of patients suffering from BPH: one group with a complex based on phycocyanin, PEA and selenium; the other group with dutasteride. So the effectiveness of these treatments was checked, especially regarding the improvement of LUTS and the reduction of PSA and prostate volume. We included 104 patients in the study. All patients aged between 50 and 70 years, PSA values between 4 and 10 ng/ml, prostate volume calculated by transrectal ultrasound between 50 and 70 cc, flowmetry with maximum flow value greater than or equal to 10 ml/s, no suspicious nodules on DRE, no suspicious lesions on MRI (PI-RADS 1-2), negative previous prostatic biopsies or never bioptied, moreover absence of diabetes mellitus or chronic renal failure (blood creatinine >2 mg/dl). We considered: -Group A of 54 men who used the complex; -Group B of 50 patients treated with dutasteride. Then we controlled all patients 6 months after starting therapy, considering the following parameters: PSA, prostate volume, flowmetry. Our results showed that both dutasteride and complex decreased PSA levels (both had a p<0.0001), with a more significant contribution of dutasteride (mean decrease of -2.743 ng/ml vs -0.971 ng/ml). Uroflowmetry also improved with both ( p<0.0001) with a mean increase in maximum flow of urine of + 3.03 ml/min for the former and + 13.02 ml/min for the latter. Lastly, dutasteride proved to be highly effective on reducing the prostate volume on TRUS (- 22.14 ml, p<0.0001) compared to Ficoxpea, which showed a mean decrease of - 10.04 ml (p<0.0001). Moreover the consistent reduction in prostate volume obtained through the use of dutasteride proved to be more intense than the one obtained by using the complex even in statistical analysis (p<0.0001). Both Ficoxpea and Dutasteride showed reduction of PSA values after 6 months of treatment. The complex based on phycocyanin, PEA and selenium showed a statistically significant improvement in urinary flow, while dutasteride acts more on the volume of the prostate. However, the natural complex is a product with good efficacy on the phlogistic component and does not have the side effects of dutasteride (e.g. gynecomastia, reduced libido). Therefore, we believe it can be used by a large part of the population, in order to reduce LUTS and PSA and improve urinary flow, without side effects.

Correlation of PSA and survival in metastatic hormone-sensitive prostate cancer treated with rezvilutamide plus ADT in the CHART trial.

This exploratory analysis of the CHART trial (ClinicalTrials.gov: NCT03520478) investigated prostate-specific antigen (PSA) kinetics and the correlation between PSA and survival outcomes in high-volume, metastatic, hormone-sensitive prostate cancer (mHSPC). A total of 654 patients were randomized 1:1 to receive either rezvilutamide plus androgen deprivation therapy (ADT; n= 326) or bicalutamide plus ADT (n= 328). PSA kinetics were evaluated, and the correlation between survival and the achievement of undetectable PSA (≤0.2ng/mL) or ≥90% PSA reduction (PSA90) was assessed. The rezvilutamide group exhibited higher proportions of ≥50% PSA reduction (PSA50; 98.2% vs. 87.5%), PSA90 (88.7% vs. 63.1%), and undetectable PSA (38.3% vs. 17.7%) responses compared to the bicalutamide group by 3months. The rezvilutamide group demonstrated superior efficacy in delaying PSA progression compared to the bicalutamide group (hazard ratio [HR] 0.21, 95% confidence interval 0.16-0.27). The achievement of undetectable PSA and PSA90 by 6months in the rezvilutamide group was associated with prolonged overall survival (undetectable PSA, HR= 0.34; PSA90, HR= 0.22), radiographic progression-free survival (HR= 0.36, HR= 0.26), time to PSA progression (HR= 0.25, HR= 0.17), and time to castration resistance (HR= 0.34, HR= 0.23) compared to those who did not achieve these PSA milestones. Stratification by baseline PSA level revealed consistent survival improvements with rezvilutamide plus ADT across quartiles. PSA kinetics is a valuable prognostic factor in mHSPC treated with rezvilutamide plus ADT, and the achievement of undetectable PSA and PSA90 is associated with improved survival. These findings highlight the importance of monitoring PSA kinetics in the management of mHSPC. This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Bipolar androgen therapy for treatment of metastatic castration‐resistant prostate cancer: A case series

AbstractIntroductionAdvanced prostate cancer treatment has improved with androgen receptor signaling inhibitors (ARPI), yet many patients develop metastatic castration‐resistant prostate cancer (mCRPC), characterized by sustained androgen receptor (AR) signaling. Bipolar androgen therapy (BAT) introduces supraphysiologic testosterone levels to inhibit tumor growth, offering novel treatment for mCRPC by exploiting AR‐dependent mechanisms.Case PresentationsCase 1: A 53‐year‐old man with mCRPC, post multiple systemic therapies, initiated BAT and pembrolizumab, achieving PSA reduction and improved quality of life before progression. The patient exhibited AR amplification, which may have contributed to favorable response to BAT.Case 2: A 73‐year‐old man with recurrent prostate cancer, stable on ADT and abiraterone, experienced PSA decline with BAT to an undetectable level, maintaining stability post‐therapy discontinuation.Case 3: A 73‐year‐old man with metastatic prostate cancer, initially resistant to enzalutamide, achieved clinical benefit and disease control with BAT, although he did not meet PSA response criteria, patient had remarkable response upon enzalutamide rechallenge.Case 4: A 90‐year‐old man with localized prostate cancer, refractory to multiple treatments, experienced symptom relief and PSA reduction with BAT before progression.ConclusionBAT represents a promising treatment strategy for mCRPC. This case series underscores BAT's potential to induce significant clinical and biochemical responses, resensitize tumors to ARPIs, and improve patients' quality of life. Despite eventual progression in some cases, BAT offers a period of disease control. Further research is needed to optimize patient selection and understand the molecular determinants of BAT responsiveness.

Abstract C162: Prespecified interim analysis of the DARolutamide ObservationaL (DAROL) study in Black/African American patients with nonmetastatic castration-resistant prostate cancer (nmCRPC)

Abstract Introduction: Black/African American (B/AA) men are disproportionately affected by prostate cancer, having higher incidence and mortality rates compared with other ethnic/racial populations. Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor with low blood–brain barrier penetration and limited potential for drug–drug interactions. In ARAMIS (NCT02200614; phase 3), DARO significantly improved metastasis- free survival (MFS) by ∼2 years and reduced the risk of death by 31% vs placebo in patients with nmCRPC, with favorable tolerability. The DAROL study (NCT04122976) is assessing the real- world safety and effectiveness of DARO in patients with nmCRPC. Here we report a subgroup analysis of B/AA patients from the prespecified third interim analysis (IA3). Methods: DAROL is an ongoing, global, open-label, single-arm, non-interventional study in patients aged ≥18 years with nmCRPC for whom the decision to be treated with DARO was decided pre-enrollment. The primary endpoint is safety, including incidence and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints include MFS, overall survival (OS), prostate-specific antigen (PSA) progression, and PSA response. IA3 was conducted when 550 patients completed ≥6 months of treatment (data cut-off July 17, 2023). Results: Of 550 patients, 199 (36%)/191 (35%)/152 (28%)/8 (2%) were from Europe/North America/Asia Pacific/Latin America, respectively. All 23 B/AA patients were from North America and represented 12% of this cohort. At baseline, PSA levels (median 4.2 ng/mL vs 4.0 ng/mL) and PSA doubling time (median 5.9 months vs 5.3 months) were similar in the B/AA and overall DAROL population, whereas B/AA patients were generally younger than the overall population (median 74 [range 49–94] vs 79 [range 29–98] years, respectively) with proportionately fewer patients aged ≥75 yrs (12 [52%] vs 387 [70%]), fewer B/AA patients (33%) had a Gleason score ≥8 vs the overall population (53%), and proportionally more B/AA patients (94%) had ECOG PS 0 vs the overall population (64%). Consistent with the DAROL IA3 overall population, DARO showed a favorable safety profile in the B/AA subgroup, and TEAEs were mostly grade 1/2. In the DAROL IA3 overall population, the proportion of patients who achieved a 90% reduction in PSA from baseline was 54%, while MFS and OS rates at 2 years were 78% and 88%, respectively. Effectiveness and safety outcomes for the B/AA subgroup will be presented. Conclusion: Findings from the DAROL IA3 B/AA subgroup were similar to the overall population and consistent with the favorable efficacy and safety profile of DARO observed in the ARAMIS B/AA subgroup and overall population. Citation Format: Evan Y. Yu, Christopher Pieczonka, Hiroyoshi Suzuki, Alberto Briganti, Murilo Luz, Declan Murphy, Patrick Adorjan, Mercedeh Ghadessi, Frank Verholen, Andrew J. Armstrong. Prespecified interim analysis of the DARolutamide ObservationaL (DAROL) study in Black/African American patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C162.

Novel Treatment Strategies for Low-Risk Metastatic Castration-Sensitive Prostate Cancer.

The treatment strategy for metastatic castration-sensitive prostate cancer (mCSPC) has changed significantly in recent years. Based on various guidelines, an upfront androgen receptor signaling inhibitor (ARSI) is the first choice, but in patients of Asian descent, including Japanese patients, there are a certain number of cases in which androgen deprivation therapy (ADT) and CAB are more effective. If patients can be identified who show a marked response to ADT within 12 weeks after the initiation of ADT, which is the inclusion criterion for ARSI clinical trials targeting mCSPC, it would be valuable from an economic standpoint. A total of 218 patients with pure prostate adenocarcinoma and treated with ADT at the Kanazawa University Hospital between January 2000 and December 2020 were included in this study. As a risk classification for mCSPC, in addition to the LATITUDE and CHAARTED criteria, we used the castration-sensitive prostate cancer classification proposed by Kanazawa University (Canazawa), developed by the Department of Urology of Kanazawa University. The Canazawa classification was based on three factors: Gleason pattern 5, bone scan index (BSI) ≥ 1.5, and lactate dehydrogenase (LDH) ≥ 300 IU/L. It defined patients with one factor or less as low-risk and patients with two or three factors as high-risk. The overall survival (OS) and time to castration resistance (TTCR) were estimated retrospectively using the Kaplan-Meier method, and factors associated with TTCR were identified using univariate and multivariate analyses. The median follow-up period was 40.4 months, the median OS period was 85.2 months, and the median TTCR period was 16.4 months. The Canazawa risk classification provided the clearest distinction between the OS and TTCR in mCSPC patients. Multivariate analysis revealed a decrease in PSA levels of <95% at 12 weeks after ADT initiation and was a predictor of short TTCR in low-risk, low-volume patients across all risk classifications. The Canazawa classification differentiated the prognosis of mCSPC patients more clearly. A PSA reduction rate of <95% at 12 w after starting ADT in low-risk, low-volume patients of all risk classifications was significantly shorter than the TTCR. We propose a new treatment strategy, in which patients with low-risk mCSPC are treated with ADT and switched to ARSIs based on the rate of PSA reduction at 12 w.

Phase II trial of multi-kinase inhibitor ESK981 in patients with metastatic castration-resistant prostate cancer.

ESK981 is a potent tyrosine kinase and PIKfyve lipid kinase inhibitor. This phase II trial evaluated the efficacy of ESK981 as a single agent in patients with androgen receptor-positive (AR +) metastatic castration-resistant prostate cancer (mCRPC). Eligible patients had mCRPC with progression on AR-targeted agents and without prior chemotherapy treatment. Each patient received 160mg ESK981 once daily for 5days per week for 4weeks per cycle (except for an adverse event (AE) occurrence). The primary endpoints were a 50% reduction in prostate-specific antigen (PSA50), and safety. Secondary endpoints included the time and the duration of PSA response, PSA progression rates, PSA progression free survival (PFS) and overall survival (OS). Exploratory investigations included whole exome sequencing in patients before treatment, and morphological evaluation of biopsy samples pre- and post-treatment. PSA was evaluated in 13 patients. Only one patient (7.7% two-sided 95% Wilson CI (0.4%, 33.3%)) experienced a reduction in their PSA levels by 50% or more. The most common grade 3 treatment-related AEs were cardiac disorders, diarrhea, hypertension, alanine transaminase and aspartate transaminase elevations. No grade 4-5 events occurred. Median PFS was 1.8months, and median OS was 12.1months. Peripheral immune cells showed increased T cell activation and cytokine production in two patients who received 12-weeks of ESK981. Although relatively well tolerated, ESK981 alone showed no anti-tumor activity in patients with AR + mCRPC and its further evaluation as a single agent in AR + mCRPC is not warranted. (Trial registration: ClinicalTrials.gov, NCT03456804. Registration date: March 7, 2018).

The Efficacy of Cabazitaxel in Treating Prostate Cancer: A Systematic Review and Meta-Analysis.

Cabazitaxel, a second-generation taxane chemotherapy agent, has demonstrated efficacy in treating metastatic castration-resistant prostate cancer (mCRPC) in patients who have previously received docetaxel-based therapy. By targeting microtubule dynamics, cabazitaxel inhibits cancer cell division and induces apoptosis, thereby extending survival and delaying disease progression in this challenging patient population. A systematic review and meta-analysis were done by searching the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE (including MEDLINE InProcess; OvidSP), Web of Science, Embase (OvidSP), and Scopus databases. ROB2 Cochrane tools assessment for RCTs. In the analysis, we used RevMan Cochrane software. Our research reveals significantly improved outcomes in terms of patient survival rates, both progression-free survival (PFS) and overall survival (OS), for cabazitaxel over comparative treatment (PFS HR 0.77 [0.61, 0.97]) (OS HR 0.79 [0.70, 0.88]). The treatment response rates were also favorable for cabazitaxel, reported as PSA Reduction Response of more than 50% (PRR) (odds ratio (OR) = 1.59 [0.56, 4.52]) and tumor response rate (TRR) (OR = 2.34 [1.28, 4.28]). Cabazitaxel was associated with significantly more incidence of adverse events. The risk ratio (RR) for serious adverse events was 1.64 [1.14, 2.35] for cabazitaxel compared to the current regimen. A systematic review and meta-analysis were done by searching in the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE (including MEDLINE InProcess; OvidSP), Web of Science, Embase (OvidSP), and Scopus databases. ROB2 Cochrane tools assessment for RCTs. In the analysis, we used RevMan Cochrane software.

Correlation of [68Ga]Ga-PSMA PET/CT response and PSA decline in first-line enzalutamide for metastatic castration-resistant prostate cancer patients.

to assess the utility of response monitoring to enzalutamide by using [68Ga]Ga-PSMA PET in mCRPC patients treated with enzalutamide as first-line therapy. patients underwent [68Ga]Ga-PSMA PET less than 8 weeks before and 3 months after starting enzalutamide. On the basis of EAU/EANM criteria, patients were categorized as PSMA responders (PET-R) or PSMA non-responders (PET-NR), whilst, based on PSA, they were classified as biochemical responders (PSA-R) or non-responders (PSA-NR). Survival analysis was performed using the Cox regression hazard model and the Kaplan-Meier method. 69 patients were considered fully evaluable. We observed 47.8% of concordance between [68Ga]Ga-PSMA PET and PSA monitoring at 3 months after starting enzalutamide. For discordant cases, the PSA reduction has a weak impact on PFS and a significant impact on OS in PET-NR patients, whilst this change has no impact either for PFS and OS in PET-R ones. [68Ga]Ga-PSMA PET could be a useful imaging tool for monitoring response to enzalutamide in mCRPC patients, being more informative than PSA in this setting, and possibly better guiding clinicians in therapeutic decisions.

Circulating Tumor DNA Assessment for Treatment Monitoring Adds Value to PSA in Metastatic Castration-Resistant Prostate Cancer.

Enzalutamide after abiraterone progression is commonly used in metastatic castration-resistant prostate cancer despite a low rate of clinical benefit. Analyzing IMbassador250, a phase III trial assessing enzalutamide with or without atezolizumab after abiraterone, we hypothesized that baseline and early changes in circulating tumor DNA (ctDNA) tumor fraction (TF) may identify patients more likely to exhibit survival benefit from enzalutamide. ctDNA was quantified from plasma samples using a tissue-agnostic assay without buffy coat sequencing. Baseline ctDNA TF, changes in ctDNA TF from baseline to cycle 3 day 1 (C3D1), and detection at C3D1 alone were compared with overall response rate, radiographic progression-free survival (rPFS), median OS (mOS), and 50% reduction in PSA. ctDNA TF detection at baseline and/or C3D1 was associated with shorter rPFS and OS in 494 evaluable patients. Detection of ctDNA TF at C3D1, with or without detection at cycle 1 day 1, was associated with worse rPFS and mOS than lack of detection. When ctDNA TF and PSA response at C3D1 were discordant, patients with (ctDNA TF undetected/PSA not reduced) had more favorable outcomes than (ctDNA TF detected/PSA reduced; mOS 22.1 vs. 16 months; P < 0.001). In a large cohort of patients with metastatic castration-resistant prostate cancer receiving enzalutamide after abiraterone, we demonstrate the utility of a new tissue-agnostic assay for monitoring molecular response based on ctDNA TF detection and dynamics. ctDNA TF provides a minimally invasive, complementary biomarker to PSA testing and may refine personalized treatment approaches.

PSMA PET/CT SUVmax as a prognostic biomarker in patients with metachronous metastatic hormone-sensitive prostate cancer (mHSPC).

Metastatic hormone-sensitive prostate cancer (mHSPC) is treatment-resistant and generally considered incurable. The development of prostate-specific membrane antigen positron emission-computed tomography (PSMA PET/CT) has generated immense expectations due to its diagnostic accuracy in prostate cancer (PCa). PSMA expression of the primary tumor, quantified by SUVmax, is a predictor of oncological outcomes. The role of PSMA-PET/CT SUVmax in metachronous mHSPC treated with ADT plus second-generation antiandrogens (ARSI) is unknown. The main aim of this study was to evaluate 68Ga-PSMA-11expression (SUVmax) as a potential prognostic biomarker in patients with metachronous mHSPC treated with ADT and first or second-generation antiandrogens. A second aim was to determine the association between PSMA SUVmax and PSA response to hormone therapy. Patients diagnosed with metachronous mHSPC between July 2017 and February 2023 who developed biochemical recurrence following radical surgery (with or without salvage radiotherapy and/or ADT) or external radiation therapy (with or without ADT) were included. All patients underwent 68Ga-PSMA-11 PET/CT imaging and the SUVmax value was determined for all measurable locations. The SUVmax value was used for the semiquantitative analysis. The Wilcoxon method was used to compare responders (PSA reduction ≥ 50%) to non-responders (PSA reduction < 50%). The SUVmax value and hormone therapy were evaluated as independent variables relative to the PSA response rate or PSA reduction using the linear regression method. A mixed-effects model (ANOVA) was used for the comparisons. A total of 82 patients were included. Median follow-up was 11.7 months. On the linear regression analysis, patients with a high SUVmax treated with ADT + ARSI showed a greater PSA response (p = 0.034) than those treated with ADT + first-generation antiandrogens. In the mixed-effects model, SUVmax was significant (p = 0.041). On the univariate analysis, PSA at recurrence (HR, 3.2; 95% CI: 1.07-13.6; p = 0.078) and the number of metastases (HR, 4.77; 95% CI 1.1-26.1: p = 0.002) were associated with the type of hormone therapy administered. PSMA-PET/CT SUVmax is a prognostic biomarker that can be used to predict a PSA response to ADT + ARSI in patients with metachronous mHSPC. However, these findings need to be confirmed in larger prospective studies.

Transperineal Laser Ablation for Focal Therapy of Localized Prostate Cancer: 12-Month Follow-up Outcomes from a Single Prospective Cohort Study.

To evaluate the oncological and functional outcomes of transperineal laser ablation (TPLA) as the focal therapy for localized prostate cancer (PCa) after a 12-month follow-up. Patients with low- and intermediate-risk localized PCa were prospectively treated with focal TPLA between July 2021 and December 2022. The inclusion criteria were the following: clinical stage < T2b; PSA < 20 ng/mL; International Society of Urological Pathology (ISUP) grade ≤ 2; MRI-fusion biopsy-confirmed lesion classified as PI-RADS v2.1 ≥ 3. Intra-, peri-, and post-operative data were collected. Variables including age, PSA, prostate volume (PVol), Charlson's Comorbidity Index (CCI), International Prostate Symptom Score (IPSS) with QoL score, International Index of Erectile Function (IIEF-5), International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), and Male Sexual Health Questionnaire-Ejaculatory Dysfunction Short Form (MSHQ-EjD) were collected at baseline and at 3, 6 and 12 months after TPLA. Post-operative mpMRI was performed at 3 and 12 months. Finally, all patients underwent prostatic re-biopsy under fusion guidance at 12 months. The success of this technique was defined as no recurrence in the target treated lesion at the 12-month follow up. Twenty-four patients underwent focal TPLA. Baseline features were age [median 67 years (IQR 12)], PSA [5.7 ng/mL (3.9)], PVol [49 mL (27)], CCI [0 (0)], IPSS [11 (9)], IPSS-QoL [2 (2)], IIEF-5 [21 (6)], ICIQ-SF [0 (7)], MSHQ-EjD ejaculation domain [14 (4)] and bother score [0 (2)]. Median operative time was 34 min (IQR 12). Median visual analogue scale (VAS) 6 h after TPLA was 0 (IQR 1). The post-operative course was regular for all patients, who were discharged on the second post-operative day and underwent catheter removal on the seventh post-operative day. No patient had incontinence at catheter removal. A significant reduction in PSA (p = 0.01) and an improvement in IPSS (p = 0.009), IPSS-QoL (p = 0.02) and ICIQ-SF scores (p = 0.04) compared to baseline were observed at the 3-month follow-up. Erectile and ejaculatory functions did not show any significant variation during the follow-up. No intra- and peri-operative complications were recorded. Three Clavien-Dindo post-operative complications were recorded (12%): grade 1 (two cases of urinary retention) and grade 2 (one case of urinary tract infection). At the 12-month follow-up, eight patients showed mpMRI images referable to suspicious recurrent disease (PIRADS v2.1 ≥ 3). After re-biopsy, 7/24 patients' (29%) results were histologically confirmed as PCa, 3 of which were recurrences in the treated lesion (12.5%). The success rate was 87.5%. The focal TPLA oncological and functional results seemed to be encouraging. TPLA is a safe, painless, and effective technique with a good preservation of continence and sexual outcomes. Recurrence rate at 12 months was about 12.5%.

Real-life Data on First- and Second-Line Treatment of Metastatic Castration-Resistant Prostate Cancer With Abiraterone, Enzalutamide and Cabazitaxel – A multicentric Study From Portugal

Introduction and objectivesNew drugs for metastatic castrate resistant prostate cancer (mCRPC) were approved, first in the pos-docetaxel and then in the pre-docetaxel setting. We aim to assess the real daily practice benefit of abiraterone (Abi), enzalutamide (Enz) and cabazitaxel (Cab) in patients with mCRPC, compare it with RCT results and compare Abi vs Enz. Materials and methodsWe retrospectively collected the data of all consecutive mCRPC patients treated with Abi, Enz or Cab in the six major oncological hospitals in the north of Portugal until December 2020. ResultsA total of 470 treatments pre-docetaxel (163 Abi and 307 Enz) and 373 pos-docetaxel (160 Abi, 148 Enz and 59 Cab) were included, with median follow-up time of 35 months. Mean age was 73.1, 84.4% had ECOG status < 2, ISUP grade was ≥ 4 in 59% and 28.0% had oligometastatic disease. In first line, for Abi and for Enz respectively, the proportion of patients with PSA reduction > 50% was 64.4% and 80.4% (P < .001), the mean duration of treatment (DT) was 10 and 14 months (P = .037) and the median overall survival (OS) was 25 months and 30 months (P = .17). In second line the results for Abi, Enz and Cab were respectively: proportion of patients with PSA reduction > 50% was 40.4%, 57.4% and 24.6% (p for Abi vs Enz=0.004); DT was 7, 8, and 3 months (p for Abi vs Enz = 0.27); OS was 17, 22 and 10 months (p for Abi vs. Enz = 0,07). ConclusionThese drugs have good efficacy in real-world evidence, similar to those reported in randomized clinical trials, with the expected exception of lower OS due to the inclusion of a broader sample of patients. Our results add to the evidence that Enz might have better efficacy in this setting compared with Abi.

Clinical Outcomes and Risk Stratification in Patients With Metastatic Hormone-Sensitive Prostate Cancer Treated With New-Generation Androgen Receptor Signaling Inhibitors

BackgroundOptimal drug selection for metastatic hormone-sensitive prostate cancer (mHSPC) remains unclear. We therefore assessed the clinical outcomes of mHSPC treated with new-generation androgen receptor pathway inhibitors (ARSIs) and identified risk factors associated with the prognosis of mHSPC. MethodsWe retrospectively reviewed 324 patients with mHSPC who were treated with ARSIs, including abiraterone acetate, enzalutamide, and apalutamide, between January 2018 and December 2022. In addition to assessing the prostate-specific antigen (PSA) response and overall survival (OS) during ARSI treatment, we investigated several potential risk factors for a poor OS in patients with mHSPC. ResultsPatients with a ≥ 90% PSA reduction (hazard ratio [HR]: 0.24, 95% confidence interval [CI], 0.10-0.58; P = .002) and those whose PSA declined to ≤ 0.2 ng/mL (HR: 0.22, 95% CI, 0.08-0.63; P = .005) showed significantly better OS than other patients. Gleason grade group 5 (GG5), presence of liver metastasis, and an LDH ≥ 250 U/L were identified as prognostic factors significantly associated with a poor OS, with HRs of 2.31 (95% CI, 1.02-5.20; P = .044), 7.87 (95% CI, 2.61-23.8; P < .001) and 3.21 (95% CI, 1.43-7.23; P = .005). ConclusionWe identified GG5, the presence of liver metastasis, and elevated LDH at the diagnosis as significant factors predicting the OS of mHSPC, but the choice of ARSIs did not affect the prognosis. The potential prognostic impact of these markers requires further investigation.

Utidelone for heavily pretreated metastatic castration-resistant prostate cancer after failing docetaxel treatment: An open-label, single-arm, phase II trial.

e17036 Background: The appropriate chemotherapy for metastatic castration-resistant prostate cancer (mCRPC) that progressed after docetaxel treatment remains unmet medical needs. Utidelone (UTD1) is a genetically engineered epothilone analog with antitumor activity in taxane-resistant cancers. UTD1 was approved for advanced breast cancer in 2021. This study was designed to evaluate the safety and efficacy of UTD1 in mCRPC. Methods: In this perspective, phase II clinical trial, men with progressive mCRPC after docetaxel and abiraterone, and/or enzalutamide, and/or apalutamide received UTD1 monotherapy treatment at a total dose of 150 mg/m2 for five days intravenous, every three weeks until disease progression, or intolerable toxicity, or death. We reported the preliminary results for potential benefits in this new treatment. The primary endpoint was prostate specific antigen (PSA) response rate, defined as a 50% or greater reduction in serum PSA. The secondary endpoint included investigators-assessed objective response rate (ORR) and disease control rate (DCR) according to RECIST v1.1, radiographic progression-free survival (rPFS) according to PCWG3 criteria, overall survival (OS), and safety. The trial was registered at Chinese Clinical Trial Registry (No. ChiCTR2200061635). Results: By January 31st, 2024, twenty-five mCRPC patients with a median age of 67 years were enrolled in this study at Sun Yat-sen University Cancer Center since March 23rd, 2022. Patients received an average of 4.2 lines of prior anticancer treatments: 100% of them received docetaxel, 96.0% of them received abiraterone, and 80.0% progressed after enzalutamide, and/or apalutamide. 28.0% of patients had visceral metastases, and 88.0% patients had bone metastases. At of the cut-off date, the PSA response rate was 16.0%. The median rPFS and OS were 4.9 months and 7.1 months, respectively. One patient had a durable response for 19.2 months and had been remaining on study treatment to date. One PR and four SD were observed in ten patients with measurable lesions, resulting in an overall ORR and DCR of 10.0% and 50.0%, respectively. The most common treatment-related adverse events (TRAEs) including peripheral sensory neuropathy (76.0%), dyspepsia (72.0%), anemia (64.0%), constipation (60.0%), fatigue (64.0%), nausea (36.0%), leukocytopenia (32.0%), arthralgia (32.0%), dizziness (32.0%), vomiting (20.0%), and diarrhea (20.0%) were manageable. The 3/4 grade TRAEs included anemia (16.0%), and diarrhea (4%). No treatment-related death occurred. Conclusions: UTD1 has demonstrated promising efficacy and favorable tolerance in heavily pretreated mCRPC patients after progression on docetaxel in the preliminary analyses. Additional randomized trials are warranted for this new regimen. Clinical trial information: ChiCTR2200061635.

Circulating tumour DNA fraction as a predictor of treatment efficacy in a randomized phase 2 trial of [177Lu]Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel (TheraP ANZUP 1603).

5055 Background: The TheraP trial showed that for patients with PSMA-positive, non-FDG-discordant mCRPC progressing after docetaxel, LuPSMA significantly improved biochemical and objective response rates, progression-free survival (PFS), and quality of life compared to cabazitaxel. While subsequent studies nominated high PSMA SUVmean to inform patient prioritization for LuPSMA, limited genomic data exists to guide optimal selection of these two life-prolonging therapies. We present an exploratory analysis of ctDNA fraction (ctDNA%) in baseline samples from the TheraP trial. Methods: We analyzed 180 baseline blood samples from participants who received ≥1 cycle of protocol-assigned treatment. Plasma cell-free DNA and matched white blood cell DNA underwent targeted sequencing to estimate ctDNA%. Prespecified ctDNA% categories (&lt;2%, 2-30%, and &gt;30%) were associated with previously validated imaging thresholds (PSMA SUVmean ≥10 and FDG metabolic tumor volume [MTV] ≥200mL), rate of PSA reduction ≥50% (PSA50-RR), and PFS, using chi-square test, logistic regression and Cox regression, respectively. Results: ctDNA% was evaluable in 178 (99%) participants, with ctDNA ≥2% in 85%. Median ctDNA% was 28% in ctDNA≥2% samples, and balanced across treatment arms. The odds of a PSA50 response to LuPSMA vs cabazitaxel were significantly higher for men with ctDNA &lt;2% (OR infinite, p=0.0067; PSA50-RR 100% vs 58%), with no difference at ctDNA &gt;30% (OR 1.1, p=1.0; PSA50-RR 46% vs 44%). Higher ctDNA% was associated with shorter PFS in LuPSMA- but not cabazitaxel-treated patients (LuPSMA: HR 5.0, p&lt;0.001 for ctDNA &lt;2% vs &gt;30%; cabazitaxel: HR 1.4, p=0.35 for ctDNA &lt;2% vs &gt;30%; interaction p=0.035). The predictive potential of ctDNA% was additive to PSMA SUVmean in LuPSMA-treated patients. Higher ctDNA% categories were enriched for patients with high FDG MTV and low PSMA SUVmean disease (Table). Conclusions: ctDNA% is a candidate predictive and prognostic biomarker for differential response to LuPSMA versus taxane chemotherapy in patients with molecular imaging-selected mCRPC progressing after docetaxel. Clinical trial information: NCT03392428 . [Table: see text]

Evaluating Immune Checkpoint Blockade in Metastatic Castration-Resistant Prostate Cancers with Deleterious CDK12 Alterations in the Phase 2 IMPACT Trial.

CDK12 inactivation in metastatic castration-resistant prostate cancer (mCRPC) may predict immunotherapy responses. This phase 2 trial evaluated the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with CDK12-altered mCRPC. Eligible patients had mCRPC with deleterious CDK12 alterations and any prior therapies except ICI. Cohort A received ipilimumab (1 mg/kg) with nivolumab (3 mg/kg) every 3 weeks for up to four cycles, followed by nivolumab 480 mg every 4 weeks. Cohort C received nivolumab alone 480 mg every 4 weeks. Patients with CDK12-altered nonprostate tumors were enrolled in cohort B and not reported. The primary endpoint was a 50% reduction in PSA (PSA50). Key secondary endpoints included PSA progression-free survival, overall survival, objective response rate, and safety. PSA was evaluable in 23 patients in cohort A and 14 in cohort C. Median lines of prior therapy were two in cohorts A and C, including any prior novel hormonal agent (74% and 79%) and chemotherapy (57% and 36%). The PSA50 rate was 9% [95% confidence interval (CI), 1%-28%] in cohort A with two responders; neither had microsatellite instability or a tumor mutational burden >10 mutations/megabase. No PSA50 responses occurred in cohort C. Median PSA progression-free survival was 7.0 months (95% CI, 3.6-11.4) in cohort A and 4.5 months (95% CI, 3.4-13.8) in cohort C. Median overall survival was 9.0 months (95% CI, 6.2-12.3) in cohort A and 13.8 months (95% CI, 3.6-not reached) in cohort C. There was minimal activity with ICI therapy in patients with CDK12-altered mCRPC.

Assessment of PSA responses and changes in the rate of tumor growth (g-rate) with immune checkpoint inhibitors in US Veterans with prostate cancer

We examined data from US Veterans with prostate cancer (PC) to assess disease response to immune checkpoint inhibitors (ICI) as monotherapy or combined with abiraterone or enzalutamide to assess ICI efficacy in the real-world. We queried the VA corporate data warehouse (CDW) to identify Veterans with a diagnosis of PC who received ICI for any malignancy and had ≥1 PSA measurement while receiving ICI. To evaluate ICI monotherapy, we restricted analysis to Veterans who had not received LHRH agonists/antagonists, PC-directed medical therapy, or radiation/extirpative surgery of the bladder/prostate within and preceding the duration of ICI administration. For ICI combination analysis, we identified Veterans who received abiraterone or enzalutamide for PC while on ICI. We calculated rates of tumor (PSA) growth (g-rates), comparing them to a 1:2 matched reference cohort. We identified 787 Veterans with PC and ≥1 PSA measurement while receiving an ICI. Median duration of ICI therapy was 155 days. 223 Veterans received ICI monotherapy, with only 17(8%) having a reduction in PSA (median decline = 43%). 12 (5%) had PSA declines >30% (PSA30) which included 6 (3%) who had PSA reductions greater than 50% (PSA50). Median g-rates for ICI plus abiraterone (n = 20) or enzalutamide (n = 31) were 0.000689/d-1 and 0.002819/d-1, respectively, and were statistically insignificant compared to g-rates of matched cohorts receiving abiraterone (g = 0.000925/d-1, P = 0.73) or enzalutamide (g = 0.001929/d-1, P = 0.58) alone. Our data align with clinical trial data in PC, demonstrating limited benefit from ICI monotherapy and predicting no survival benefit from simultaneous abiraterone or enzalutamide with an ICI using g-rate.