Prostate-specific Antigen Decrease Research Articles

Pluvicto in the real world setting and timing to PSA50 as a predictive marker of treatment response.

e17026 Background: Prostate cancer, the leading cause of cancer mortality in men, has seen notable advances with PSMA-targeted therapies like 177Lu-PSMA-617 (Pluvicto), particularly in the metastatic castrate resistant setting. While prostate specific antigen (PSA) serves as a useful biomarker in newly diagnosed patients or those on androgen deprivation therapy, its efficacy in monitoring patients under PSMA-directed therapy remains unclear. This underscores a critical gap: the absence of established biomarkers for tracking response to these emerging treatments. Such biomarkers are vital for enhancing patient outcomes and evaluating therapeutic efficacy in early-stage trials. Methods: In this real-world, cohort study, we retrospectively followed adult patients with metastatic, castrate-resistant prostate cancer who are treated with Pluvicto at our institution beginning January 1, 2022 through November 2023. We assessed several potential biomarkers of response temporally throughout the treatment duration of Pluvicto, including serial blood counts, chemistry profiles, PSA levels, BMI, as well as their historical treatment patterns and demographics. All patients were heavily pre-treated prior to receiving Pluvicto. By using logistic regression, we identify factors associated with treatment response. Results: In our study, 21 patients qualified for enrolment. These patients received a median of 6 treatments prior to Pluvicto. Among them, 8 (38.1%) demonstrated at least PSA50 and showed response post-treatment. Of these, 6 (75%) completed all six Pluvicto treatments, while 2 (25%) are currently undergoing treatment. Remarkably, 7 of the 8 responders (87.5%) achieved a PSA50 response after two Pluvicto doses, with all 8 (100%) reaching this marker by the third dose. Furthermore, 6 of these 8 patients (75%) exhibited a PSA90 response after the fourth dose, though 2 patients (25%) did not attain PSA90. Conclusions: Our real-world study at Scripps Clinic provides valuable insights into the efficacy of Pluvicto in treating metastatic, castrate-resistant prostate cancer. Out of 21 patients treated with Pluvicto, 38.1% exhibited a significant PSA decrease during the treatment course. Notably, 87.5% of responders achieved PSA50 before their third dose, and all responders reached this benchmark prior to their fourth dose. These findings are crucial, especially as clinical trials are exploring Pluvicto's application in earlier treatment stages. Additionally, the use of PSA50 as a biomarker could guide clinicians in timely decision-making, allowing for quicker intervention and therapy adjustments, thus potentially mitigating disease progression. Updated data to be presented.

Does enzalutamide related PSMA upregulation affect outcomes of lutetium-177 PSMA radioligand therapy?

Enzalutamide is an antiandrogen drug used prior to lutetium-177 prostate specific membrane antigen (Lu-PSMA) radioligand therapy and has shown promising results for upregulating the PSMA expression on prostate cancer cells. In this study, we aim to compare prostate specific antigen (PSA) level changes in prostate cancer patients who received enzalutamide to those who did not. Prostate cancer patients who underwent Lu-PSMA between 2021 and 2023 were retrospectively included. Patients were grouped based on prior enzalutamide therapy: those who received enzalutamide (EZ+) for at least 14 days and those who did not (EZ-). PSA changes and F-18 DCFPyL SUV (Standardized Uptake Values) were compared. Thirty-seven patients were included, 18 EZ+ and 19 EZ-. The median age, Gleason score, and prior chemo/hormonal therapies were similar for EZ+ and EZ-, except for radium-223. Eleven patients (61%) in EZ+ and 13 patients (68%) in EZ- showed a decrease in PSA after the first cycle (p = 0.64). Four patients (22%) in EZ+ and seven patients (37%) in EZ- had more than 50% decrease in PSA after the first cycle (p = 0.33). The average percent decline at the end of the treatment was 23.3% in EZ+ and 50.4% in EZ- (p = 0.4). There was no difference in terms of lesion with highest SUVmax, mean SUV, total tumor volume or activity on pre-therapy PSMA imaging. Enzalutamide treatment prior to Lu-PSMA does not improve patient outcomes when applied remotely. Larger studies evaluating the combination therapies and the timing of enzalutamide are needed to assess its correlation with Lu-PSMA outcomes.

A phase 2, single-arm trial evaluating 131 I-PSMA-1095 targeted radioligand therapy for metastatic castration-resistant prostate cancer.

Metastatic castration-resistant prostate cancer (mCRPC) remains uniformly lethal. Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in prostate cancer. 131 I-PSMA-1095 (also known as 131 I-MIP-1095) is a PSMA-targeted radioligand which selectively delivers therapeutic radiation to cancer cells and the tumor microenvironment. We conducted a single-arm, phase 2 trial to assess efficacy and tolerability of 131 I-PSMA-1095 in mCRPC patients who had exhausted all lines of approved therapy. All patients underwent 18 F-DCFPyL PET and 18 F-FDG PET to determine PSMA-positive tumor volume, and patients with >50% PSMA-positive tumor volume were treated with up to four doses of 131 I-PSMA-1095. The primary endpoint was the response rate of prostate specific antigen (PSA). Secondary endpoints included rates of radiographic response and adverse events. Overall and radiographic progression-free survival were also analyzed. Eleven patients were screened for inclusion and nine patients received 131 I-PSMA-1095. The median baseline PSA was 162 µg/l, and six patients demonstrated a >50% PSA decrease. One patient demonstrated a confirmed radiographic response. Median overall survival was 10.3 months, and median progression-free survival was 5.4 months. Four patients experienced adverse events of grade 3 or higher, the most frequent being thrombocytopenia and anemia. 131 I-PSMA-1095 is highly active against heavily-pretreated PSMA-positive mCRPC, significantly decreasing tumor burden as measured by PSA. Adverse events, mainly hematologic toxicity, were not infrequent, likely related to off-target irradiation. This hematologic toxicity, as well as a higher logistical burden associated with use, could represent relative disadvantages of 131 I-PSMA-1095 compared to 177 Lu-PSMA-617.

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

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

Three- and Seven-month Prostate-specific Antigen Levels as Prognostic Markers for Overall Survival in Metastatic Hormone-sensitive Prostate Cancer: Results from SWOG S1216, a Phase 3 Randomized Trial of Androgen Deprivation Plus Orteronel or Bicalutamide

BackgroundA robust decrease in prostate-specific antigen (PSA) in response to androgen deprivation therapy (ADT) has been evaluated as a prognostic factor in patients with metastatic hormone-sensitive prostate cancer (mHSPC) since 2006, but the treatment of mHSPC has since evolved to include intensified therapy. ObjectiveWe assessed the association of PSA levels at 3 (PSA-3mo) and 7 (PSA-7mo) mo with overall survival (OS) in patients with mHSPC treated with ADT combined with either bicalutamide or orteronel in the S1216 phase 3 clinical trial. Design, setting, and participantsPSA responses to treatment of patients in the S1216 trial were categorized as: complete response (CR) if PSA was ≤0.2 ng/ml, partial response if PSA was >0.2 and ≤4 ng/ml, and no response (NR) if PSA was >4 ng/ml. Outcome measurements and statistical analysisA Cox analysis (adjusted for treatment arm and three stratification factors: performance status, severity of disease, and early vs late induction) was used for OS association. While PSA-7mo association was a prespecified objective, PSA-3mo association was also evaluated. Results and limitationsA total of 1251 and 1231 patients from the S1216 study were evaluable for PSA-3mo and PSA-7mo, respectively. A PSA-7mo CR was associated with improved OS compared with NR (HR: 0.20; p < 0.0001). A PSA-3mo CR showed a similar association to NR (HR: 0.34; p < 0.0001). The association of a PSA response with survival did not differ by treatment arm at either time point. ConclusionsThe PSA-3mo and PSA-7mo responses were strongly associated with OS; taken with other emerging prognostic biomarkers, these markers may allow for early identification of patients at the highest risk of death, aid with counseling in clinical practice, and permit design of future clinical trials targeting these patients. Patient summaryA low prostate-specific antigen level at 3 or 7 mo after starting treatment for metastatic hormone-sensitive prostate cancer predicts longer survival regardless of the first treatment given with androgen deprivation therapy.

Early change in apparent diffusion coefficient as a predictor of response to neoadjuvant androgen deprivation and external beam radiation therapy for intermediate- to high-risk prostate cancer

To determine the role of serial apparent diffusion coefficient (ADC) as a biomarker for response to neoadjuvant androgen deprivation therapy (nADT) followed by external beam radiation therapy (EBRT) in intermediate- to high-risk prostate cancer (PCa) patients. This Health Insurance Portability and Accountability Act (HIPAA)-compliant, institutional review board (IRB)-approved prospective study included 12 patients with intermediate- to high-risk PCa patients prior to nADT and EBRT, who underwent serial serum prostate-specific antigen (PSA) and multiparametric prostate magnetic resonance imaging (mpMRI) at baseline (BL), 8-weeks after nADT initiation (time point [TP]1), 6-weeks into EBRT delivery (TP2), and 6-months after nADT initiation (TP3). Tumour volume (tVOL) and tumour and normal tissue ADC (tADC and nlADC) were determined at all TPs. tADC and nlADC dynamics were correlated with post-treatment PSA using Pearson's correlation coefficient. Paired t-tests compared pre/post-treatment ADC. There was a sequential decrease in PSA at all TPs, reaching their lowest values at TP3 post-treatment completion. Mean tADC increased significantly from baseline to TP1 (917.8±107.7×10-6 versus 1033.8±139.3×10-6 mm2/s; p<0.01), with no subsequent change at TP2 or TP3. Both percentage and absolute change in tADC from BL to TP1 correlated with post-treatment PSA (r=-0.666, r=-0.674; p=0.02). Post-treatment PSA in good responders (<0.1 ng/ml) versus poor responders (≥ 0.1 ng/ml) was associated with a greater increase in tADC from BL to TP1 (169.2±122.4×10-6 versus 22.9±75.5×10-6 mm2/s, p=0.03). This pilot study demonstrates the potential for early ADC metrics as a biomarker of response to nADT and EBRT in intermediate to high-risk PCA.

Fluorine-18 prostate-specific membrane antigen-1007-avid indeterminate bone lesions in prostate cancer: clinical and PET/CT features to predict outcomes and prognosis

To determine clinical and fluorine-18 prostate-specific membrane antigen-1007 (18F-PSMA-1007) integrated positron-emission tomography (PET)/computed tomography (CT) features that could be used to interpret indeterminate bone lesions (IBLs) and assess the prognosis of prostate cancer (PCa) in patients with IBLs. Consecutive patients who underwent PSMA PET/CT were analysed retrospectively. IBLs were identified as benign or malignant based on follow-up imaging and clinical management. Lesion- and patient-based assessments were performed to define features predictive of bone lesion results and determine clinical risk. Patients' prognosis was analysed based on clinical characteristics, including prostate-specific antigen (PSA) and alkaline phosphatase (ALP), respectively. A total of 105 patients (mean age ± SD, 72.1±8 years) were evaluated and 158 IBLs were identified. Fifty-three (33.5%), 36 (22.8%), and 69 (43.7%) IBLs were benign, malignant, and equivocal, respectively. Variables including location, maximum standard uptake value (SUVmax), and lymph node metastases (LNM) were related to the benignancy or malignancy of IBLs (p=0.046, p<0.001 and p<0.001, respectively). Regression analysis indicated that LNM, SUVmax, and location of IBLs could be predictors of lesion interpretation (p<0.001, p=0.002 and p=0.035). Patients with benign IBLs experienced the most considerable decreases in PSA and ALP levels. LNM, SUVmax, and location may contribute to IBL interpretation. A rapid decrease in PSA and ALP levels might suggest a better prognosis for patients with benign IBLs.

Angiotensin II Receptor Blockers Cause Changes in Prostate-specific Antigen Levels: A Retrospective Cohort Study.

We previously reported a decrease in prostate-specific antigen (PSA) levels in patients with castration-resistant prostate cancer treated with angiotensin II receptor blockers (ARBs). However, no studies have reported the effect of ARBs on PSA variability in patients without a history of prostate cancer. Therefore, we conducted a population-based, retrospective study to determine whether ARBs have an inhibitory effect on elevated PSA levels in Japanese patients without a history of prostate cancer. This study was conducted using a large-scale Japanese claim database, including male patients aged ≥60 years who had two or more PSA measurements with an interval between measurements of 3 months to 2 years between April 2008 and June 2019. Patients who had been prescribed ARBs were grouped into the ARB group, and those who were prescribed antihypertensive drugs other than ARBs were grouped into the non-ARB group. We compared the proportions of patients with second PSA levels greater than the first. The numbers of eligible patients in the ARB and non-ARB groups were 777 and 527, respectively. Multivariate logistic regression analysis revealed that the proportion of patients with elevated PSA levels was significantly lower in the ARB group than in the non-ARB group (adjusted odds ratio=0.80, 95% confidence interval=0.64-0.99, p=0.047). ARBs may suppress elevated PSA levels in patients without a history of prostate cancer. This contributes to the prevention of prostate cancer.

External beam radiotherapy in treatment of high-volume metastatic hormone-sensitive prostate cancer: clinical case

The standard treatment for metastatic hormone-sensitive prostate cancer does not include external beam radiotherapy (EBRT) and radionuclide therapy with radium-223.The article describes a clinical case of successful use of EBRT and radionuclide therapy with radium-223 in a patient with primary high-volume metastatic hormone-sensitive prostate cancer.The patient received diagnosis of prostate cancer сT3bN1M1b (Gleason score 8 (4 + 4)), stage IV (metastases in the bones, extraperitoneal and intrathoracic lymph nodes; prostate specific antigen (PSA) level was 4280 ng/mL). Between October of 2017 and January of 2018, the patient received 6 cycles of chemohormonal therapy (degarelix + docetaxel). Bilateral orchiectomy was performed on 05.02.2018, and the patient underwent palliative EBRT on cervical vertebrae between 04.10.2017 and 19.10.2017 with total dose of 32.6 Gy (equivalent to 38.5 Gy). The patient received systemic radiotherapy with one injection of samarium oxabifor (153Sm) 40 mCi (21.03.2018) and radium-223 (4 injections once a month (17.04.2018, 15.05.2018, 14.06.2018, 10.07.2018) + 2 injections 1 time per 3 months (October 2018, January 2019)). Partial response was achieved in the form of PSA decrease from 4280 ng/mL (September 2017) to 0.505 ng/mL (May 2019). Palliative EBRT for the prostate and pelvis was performed between 14.11.2018 and 19.12.2018 for total dose of 62.5 Gy (equivalent to 69 Gy). For 2 years remission was observed with PSA level of 0.3–0.5 ng/mL. In December of 2020, biochemical recurrence was diagnosed: PSA level increased from 0.61 ng/mL in October to 1.43 ng/mL on 28.12.2020. The second course of radionuclide therapy with radium-223 5,500 MBq/mL was performed (22.01.2021, 05.03.2021, 02.04.2021) with increase of PSA level to 1.92 ng/mL (May of 2021) and independent decrease to 0.542 ng/mL (June of 2022). In December of 2022, biochemical recurrence was observed with a small increase of PSA level to 1.67 ng/mL. Currently, the disease is stabilized.

Feasibility of apalutamide combined with androgen deprivation therapy and short-course low-dose prednisone in treating metastatic hormone-sensitive prostate cancer: a pilot randomized controlled trial.

The role of prednisone in the prevention of androgen receptor antagonist-related rash and treatment for metastatic hormone-sensitive prostate cancer (mHSPC) is unclear. This pilot trial (ChiCTR2200060388) aimed to investigate the feasibility of apalutamide combined with androgen deprivation therapy (ADT) and short-course low-dose prednisone in the treatment of mHSPC. All patients received apalutamide and ADT and were randomly divided into two groups based on the administration of oral prednisone or not (control group). The primary endpoint was the incidence of rash. The secondary endpoint included the proportions of patients with a decline in PSA ≥50% from baseline, PSA ≥90% from baseline, and decreased to PSA ≤0.2 ng/mL. Between June 2021 and March 2022, a total of 83 patients were enrolled (41 in the prednisone group and 42 in the control group). During the 6-month follow-up, the incidence of rash was significantly lower in the prednisone group compared with the control group (17.1% vs. 38.1%, P=0.049). There were no significant differences in the incidence of other adverse events, the number of patients who required dose adjustment (reduction, interruption, or discontinuation) of apalutamide due to rash, the number of patients with prostate-specific antigen (PSA) decreased by ≥50%, the number of patients with PSA decrease ≥90%, and the number of patients with PSA ≤0.2 ng/mL between the two groups. All patients with diabetes had stable glycemic control with no glucose-related adverse events. In patients with mHSPC, the addition of short-course low-dose prednisolone to apalutamide plus ADT can reduce the incidence of rash without risk of other adverse events.

Prevalence and Prognostic Implications of PSA Flares during Radium-223 Treatment among Men with Metastatic Castration Resistant Prostate Cancer.

Radium-223 (Ra233) prolongs the survival of men with symptomatic bone-predominant metastatic castration-resistant prostate cancer (mCRPC). However, prostate-specific antigen (PSA) response patterns are not closely associated with Ra223 therapy outcomes. Herein, we sought to analyze the impact of Ra223-induced PSA flares on patient outcome. Using a retrospective cohort study of Ra223 treatment in four Ontario/Canada cancer centres, we identified 134 patients grouped into sub-cohorts according to distinct PSA response patterns: (i) initial PSA flare followed by eventual PSA decline; (ii) PSA response (≥30% PSA decrease within 12 weeks of treatment); and (iii) PSA non-response. We analyzed patient characteristics and outcome measures, including overall survival (OS), using the Kaplan-Meier method and log-rank testing. PSA flares were observed in 27 (20.2%), PSA responses in 11 (8.2%), and PSA non-responses in 96 (71.6%) patients. Amongst PSA flare patients, 12 presented with post-flare PSA decreases below baseline and 15 with PSA decreases below the flare peak but above baseline. Although only six flare patients achieved ≥30% PSA decreases below baseline, the median OS of all flare patients (16.8 months, 95% CI 14.9-18.7) was comparable to that of PSA responders and non-responders (p = 0.349). In summary, around 20% of mCRPC patients experience Ra223-induced PSA flares, whose outcome is similar to that of men with or without PSA responses. Further studies are needed regarding suitable biochemical surrogate markers of response to Ra223.

Real-world Outcomes and Predictive Biomarkers for 177Lutetium Prostate-specific Membrane Antigen Ligand Treatment in Metastatic Castration-resistant Prostate Cancer: A European Association of Urology Young Academic Urologists Prostate Cancer Working Group Multi-institutional Observational Study

BackgroundThe European Association of Urology guidelines include the lutetium-177 (177Lu) PSMA-617 prostate-specific membrane antigen (PSMA) ligand as a therapy option for metastatic castration-resistant prostate cancer (mCRPC). A major challenge in clinical practice is to pursue a personalized treatment approach based on robust predictive biomarkers. ObjectiveTo assess the performance of 177Lu PSMA in real-world practice and to elaborate clinical biomarkers for evaluating treatment responses. Design, setting, and participantsWe conducted a retrospective observational study including 233 patients with mCRPC treated with 177Lu PSMA in eight high-volume European centers. Outcome measurements and statistical analysisBaseline characteristics and clinical parameters during and after 177Lu PSMA treatment were documented. Correlations to treatment response were analyzed using χ2 and log-rank tests, with differences between groups with and without disease progression calculated using a Mann-Whitney U test. Univariate and multivariate-adjusted hazard ratios (HRs) were measured using Cox proportional hazards models. Results and limitationsA prostate-specific antigen (PSA) decrease of ≥30% was observed in 41.7%, 63.5%, and 77.8% of patients after the first, second, and third treatment cycle, respectively. Restaging performed via PSMA positron emission tomography-computed tomography revealed that 33.7% of patients had an imaging-based response, including two patients with a complete response, while 13.4% had stable disease. The median time to progression was 5 mo and the median time until the start of a consecutive antineoplastic therapy was 8.5 mo. Of importance, a PSA decrease ≥30% after the first two cycles of 177Lu PSMA (1 cycle: p = 0.0003; 2 cycles: p = 0.004), absolute PSA after the first three cycles (1 cycle: p = 0.011; 2 cycles: p = 0.0005; 3 cycles: p = 0.002), and a PSA doubling time >6 mo (p = 0.009) were significantly correlated to treatment response. Furthermore, gamma-glutamyl transferase ≤31 U/L at the start of 177Lu PSMA therapy was correlated with 1.5 times higher risk of progression for patients without but not with visceral metastases (p = 0.046). Conclusions177Lu PSMA is an effective treatment option in mCRPC in the real-world setting. A PSA decrease ≥30% after the first two cycles is an early marker of response that can be easily implemented in clinical practice. Patient summary177Lu PSMA is a radioactive agent approved for treatment of advanced prostate cancer. We reviewed its use outside of clinical trials for patients treated at eight European centers. We found that 177Lu PSMA is an effective treatment option in real-world practice. A PSA (prostate-specific antigen) decrease of ≥30% after the first two therapy cycles is an early indicator of response to treatment and can be used in personalizing treatments for patients.

A phase 1, multi-center, open-label, dose-escalation and dose expansion study of CBP-1018, a bi-ligand-drug conjugate, in patients with heavily treated advanced solid tumors.

e15007 Kaiwen Li and Junyan Wu contributed equally to this work. Yehui Shi and Hai Huang are the corresponding authors. Background: Prostate-specific membrane antigen (PSMA) or folate hydrolase 1 (FOLH1) is highly expressed on prostate cancer and folate receptor α (FRα) overexpressed in various malignant tissues which both related to tumor invasiveness. CBP-1018 is a first-in-class bi-ligand-drug conjugate targeting both PSMA and FRα with monomethyl auristatin E (MMAE) as payload. Methods: This phase 1 study included both a dose-escalation and expansion stage. In the dose-escalation stage, an accelerated titration was conducted in single patient at 0.03mg/kg followed by an i3+3 design for dose levels (DLs) ≥ 0.06 mg/kg, Q2W in a 4-week cycle. This stage mainly enrolled patients (pts) with metastatic castration resistant prostate cancer (mCRPC) received a median 3.5 prior lines of treatment. The primary objectives were to evaluate the safety and tolerability, determine dose limiting toxicity (DLT) and maximum tolerated dose (MTD). Additionally, pharmacokinetics (PK) and preliminary efficacy will also be evaluated. Results: As of 24 Nov 2022, 14 pts (12 mCRPC, 1 bladder cancer and 1 ureteral carcinoma) were enrolled at 5 DLs (1 pt at 0.03 mg/kg, 3 pts each at 0.06, 0.08, 0.10 mg/kg, 4 pts at 0.12 mg/kg). No DLTs or drug-related deaths were observed. For 9 pts (64.3%) experienced treatment-related adverse events (TRAEs) ≥ grade 3, most common were neutrophil decrease (35.7%), WBC decrease (28.6%), lymphocyte decrease (14.3%), elevated GGT (14.3%) and hypertriglyceridaemia (14.3%). Among 10 efficacy evaluable pts with mCRPC, 3 SD were observed at DLs of 0.08, 0.10, and 0.12mg/kg, 4 non-PD at 0.06, 0.10, and 0.12 mg/kg, and 3 PD at 0.06 and 0.08 mg/kg. Decrease of prostate-specific antigen (PSA) was detected in 3 pts at 0.10 mg/kg. Overall median PFS was 7.2 months (95%CI, 1.7-9.3) and not reached in mCRPC pts. For PK profile of CBP-1018 and free MMAE, t1/2z was ranged 0.54-1.15 h and 40.28-57.27 h, respectively, no accumulation of both substances after multiple doses. Conclusions: CBP-1018 was well-tolerated at DLs of 0.03-0.12 mg/kg Q2W with no DLTs. Multiple SD were observed at DLs of 0.08-0.12 mg/kg, conferred a promising preliminary antitumor activity in pts with mCRPC. MTD was not reached and dose-escalation to establish the RP2D is continuing. Clinical trial information: NCT04928612 .

Combined treatment of high and very high risk prostate cancer: results of neoadjuvant treatment

Purpose of the study. Assessment of safety and short‑term effectiveness of high and very high‑risk prostate cancer neoadjuvant chemo‑ hormonal treatment without distant metastases.Patients and methods. Combined hormone chemo‑ radiation treatment of 33 patients with prostate cancer of high and very high risk of progression without distant metastases was performed. Metastases to regional lymph nodes were found in 9 patients according to the examination data (MRI, MSCT), no metastases were detected in 24 patients. All patients underwent combined chemohormonal therapy in the amount of 4 courses of docetaxel intravenously at a dose of 75 mg/m2 every 3 weeks as the first stage of treatment. in combination with androgen deprivation therapy with agonists or antagonists of GnRH before performing radical radiation therapy (combined or remote). All patients underwent neoadjuvant hormone therapy: 16 patients – with the use of GnRH antagonists (Degarelix), 17 – with the use of GnRH agonists (Gozerelin/Leuprorelin/Triptorelin). The toxicity of the presented treatment regimen and its immediate effectiveness – the effect on the level of prostate‑s pecific antigen (PSA), prostate volume, and the quality of urination – were evaluated.Results. Treatment regimen was highly effective concerning PSA decrease (from initial median level 79,67 ng/ml to 1,45 ng/ml after neoadjuvant treatment), all subjects responded well, no non‑responders observed. Median prostate volume decreased from 44 cm3 to 25 cm3 after treatment, which guaranteed availability and safety of further radical radiation treatment. Urinary function was restored in all subject with initial urinary retention.Conclusion. Neoadjuvant chemo‑h ormonal treatment was highly effective in PSA level, prostate volume decrease and functional results improvement which secured further radical radiation treatment in one of its types. Toxicity was acceptable, adverse events did not exceed grade II in most cases and did not lead to treatment discontinuation in any cases, while quality of life remained high enough.

Androgen receptor signaling mechanism in prostate cancer: resistance to antiandrogen therapy and association with DNA repair genes

Background. Metastatic castration-resistant prostate cancer remains a complex problem due to patients' previous treatments and limited selection of subsequent therapies. While 2nd generation antiandrogens are initially effective, resistance to them is not an exceptional event. Mechanisms depending on androgen receptor and independent of it have been described. A special focus is on mutations in DNA repair genes, particularly genes involved in homologous recombination repair (HRR) as a possible cause of somatic genetic abnormalities specifically in progressive metastatic disease. However, data on the effect of the HRR defect on the effectiveness of antiandrogen therapy for prostate cancer are very limited, which requires additional clinical studies.Aim. To evaluate the effect of clinical, morphological, molecular and genetic factors on the effectiveness of enzalutamide antiandrogen therapy in patients with prostate cancer and known mutations in DNA repair genes involved in HRR and mismatch repair.Materials and methods. The study was performed at the Clinical Oncological Dispensary No. 1 (Krasnodar). Retrospective analysis of clinical and morphological parameters of 54 patients with prostate cancer who received enzalutamide antiandrogen therapy and with known status of germ line and somatic mutations of HRR DNA repair genes (BRCA1, BRCA2, ATM, BARD, BRIP1, CDK12, CHEK1, CHEK2, PALB2, RAD51B, RAD51C, RAD54L, FANCL) and microsatellite instability in immunohistochemical determination of mismatch repair deficit was performed. Statistical analysis was performed using IBM SPSS Statistics v.22 software.Results and conclusion. In 17 of 54 patients, pathogenic germline and somatic mutations of HRR genes were detected: 7 mutations in BRCA2 gene, 4 - in CHEK2, 2 - in BRCA1, 2 - in CDK12, 1 - in BRIP1 and 1 - in ATM. It was shown that in the group of patients with metastatic castration-resistant prostate cancer, histological grade per the International Society of Urological Pathology (ISUP) G2 (total Gleason score 7 (3 + 4)) is significantly associated with the absence of HRR mutation, and grade G3 (total Gleason score 7 (4 + 3)) was associated with HRR mutations (р &lt;0.05). Increase in prostate-specific antigen (PSA) level/biochemical progression 12-16 weeks after enzalutamide therapy start was significantly associated with metastatic castration-resistant prostate cancer without HRR mutations (р &lt;0.05). In case of tumor response to enzalutamide therapy, decrease in PSA level did not depend on the age of disease onset, differentiation grade, primary advancement, previous docetaxel treatment, and presence of HRR mutation. Cox multivariate regression test showed that prescription of docetaxel before enzalutamide increased the risk of PSA-progression (hazard ratio (HR) 5.160; 95 % confidence interval (CI) 1.549-17.189; р = 0.008) and radiographic progression (HR 5.161; 95 % CI 1.550-17.187; р = 0.008). Progression risk decreased with increased level of PSA decrease 12-16 weeks after enzalutamide therapy start: for PSA decrease &gt;30 % HR 0.150; 95 % CI 0.040-0.570; р = 0.005; for PSA decrease &gt;50 % HR 0.039; 95 % CI 0.006-0.280; р = 0.001; for PSA decrease &gt;90 % HR 0.116; 95 % CI 0.036-0.375; р = 0.000. Presence of HRR mutation, age &lt;58 years, primary metastatic disease and poorly differentiated morphology did not affect duration without PSA-progression (p &gt;0.05). Kaplan-Meier curves showed a trend towards increased time to development of castration resistance in the group of primary early cancer (Breslow р = 0.06; Tarone-Ware р = 0.062). Subgroup analysis showed that in the cohort of patients with castration-resistant prostate cancer (n = 48), absence of HRR mutation in patients who previously received docetaxel therapy increases time to PSA-progression compared to patients with mutations (log-rank р &lt;0.05).

A Phase I Dose Escalation and Expansion Study of Epidiolex (Cannabidiol) in Patients with Biochemically Recurrent Prostate Cancer.

Cannabinoids (CBD) have anti-tumor activity against prostate cancer (PCa). Preclinical studies have demonstrated a significant decrease in prostate specific antigen (PSA) protein expression and reduced tumor growth in xenografts of LNCaP and DU-145 cells in athymic mice when treated with CBD. Over-the-counter CBD products may vary in activity without clear standardization, and Epidiolex is a standardized FDA-approved oral CBD solution for treatment of certain types of seizures. We aimed to assess the safety and preliminary anti-tumor activity of Epidiolex in patients with biochemically recurrent (BCR) PCa. This was an open-label, single center, phase I dose escalation study followed by a dose expansion in BCR patients after primary definitive local therapy (prostatectomy +/- salvage radiotherapy or primary definitive radiotherapy). Eligible patients were screened for urine tetrahydrocannabinol prior to enrollment. The starting dose level of Epidiolex was 600 mg by mouth once daily and escalated to 800 mg daily with the use of a Bayesian optimal interval design. All patients were treated for 90 days followed by a 10-day taper. The primary endpoints were safety and tolerability. Changes in PSA, testosterone levels, and patient-reported health-related quality of life were studied as secondary endpoints. Seven patients were enrolled into the dose escalation cohort. There were no dose-limiting toxicities at the first two dose levels (600 mg and 800 mg). An additional 14 patients were enrolled at the 800 mg dose level into the dose expansion cohort. The most common adverse events were 55% diarrhea (grade 1-2), 25% nausea (grade 1-2), and 20% fatigue (grade 1-2). The mean PSA at baseline was 2.9 ng/mL. At the 12-week landmark time-point, 16 out of 18 (88%) had stable biochemical disease, one (5%) had partial biochemical response with the greatest measurable decline being 41%, and one (5%) had PSA progression. No statistically significant changes were observed in patient-reported outcomes (PROs), but PROs changed in the direction of supporting the tolerability of Epidiolex (e.g., emotional functioning improved). Epidiolex at a dose of 800 mg daily appears to be safe and tolerable in patients with BCR prostate cancer supporting a safe dose for future studies.

MP11-16 PROSTATE-SPECIFIC ANTIGEN ANALYSES IN PROPEL: ABIRATERONE AND OLAPARIB VERSUS ABIRATERONE AND PLACEBO AS FIRST-LINE THERAPY FOR METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

MP11-16 PROSTATE-SPECIFIC ANTIGEN ANALYSES IN PROPEL: ABIRATERONE AND OLAPARIB VERSUS ABIRATERONE AND PLACEBO AS FIRST-LINE THERAPY FOR METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

Outcome of patients with biochemical recurrence of prostate cancer after PSMA PET/CT-directed radiotherapy or surgery without systemic therapy

BackgroundRadiotherapy (RT) and surgery are potential treatment options in patients with biochemical recurrence (BCR) following primary prostate cancer treatment. This study examines the value of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-informed surgery and RT in patients with BCR treated without systemic therapy.MethodsThis is a post-hoc subgroup analysis of a prospective clinical trial. Inclusion criteria were: histologically proven prostate cancer at initial curative-intent treatment, BCR after primary treatment with curative intent, having five or fewer lesions identified on [18F]DCFPyL PET/CT, and treatment with either PET/CT-directed RT or surgery without systemic therapy. The biochemical progression-free survival after PSMA ligand PET/CT-directed RT and surgery was determined. Uni- and multivariate Cox regression analyses were performed for the association of patients’ characteristics, tumor-specific variables, and PSMA PET/CT imaging results with biochemical progression at the last follow-up.ResultsFifty-eight patients (30 in surgery and 28 in radiotherapy groups) met the inclusion criteria. A total of 87 PSMA-positive lesions were detected: 16 local recurrences (18.4%), 54 regional lymph nodes (62.1%), 6 distant lymph nodes (6,8%), and 11 osseous lesions (12.7%). A total of 85.7% (24 of 28) and 70.0% (21 of 30) of patients showed a ≥ 50% decrease in prostate-specific antigen (PSA) levels after RT and surgery, respectively. At a median follow-up time of 21 months (range, 6–32 months), the median biochemical progression-free survival was 19 months (range, 4 to 23 months) in the radiotherapy group, as compared with 16.5 months (range, 4 to 28 months) in the surgery group. On multivariate Cox regression analysis, the number of PSMA positive lesions (2–5 lesions compared to one lesion), and the anatomic location of the detected lesions (distant metastasis vs. local relapse and pelvic nodal relapse) significantly correlated with biochemical progression at the last follow-up, whereas other clinical, tumor-specific, and imaging parameters did not.ConclusionsThis study suggests that RT or surgery based on [18F]DCFPyL PET/CT are associated with high PSA response rates. The number and site of lesions detected on the PSMA PET/CT were predictive of biochemical progression on follow-up. Further studies are needed to assess the impact of targeting these sites on patient relevant outcomes.Trial registrationRegistered September 14, 2016; NCT02899312; https://clinicaltrials.gov/ct2/show/NCT02899312

225Ac-PSMA-617 radioligand therapy of de novo metastatic hormone-sensitive prostate carcinoma (mHSPC): preliminary clinical findings

Purpose225Ac-PSMA-617 has demonstrated good anti-tumor effect as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients. No study has previously assessed treatment outcome and survival following 225Ac-PSMA-617 treatment of de novo metastatic hormone-sensitive prostate carcinoma (mHSPC) patients. Based on the potential side effects that are known and explained to the patients by the oncologist, some of the patients refused the standard treatment and are seeking alternative therapies. Thus, we report our preliminary findings in a retrospective series of 21 mHSPC patients that refused standard treatment options and were treated with 225Ac-PSMA-617.MethodsWe retrospectively reviewed patients with histologically confirmed de novo treatment-naïve bone ± visceral mHSPC that were treated with 225Ac-PSMA-617 radioligand therapy (RLT). Inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, treatment-naive bone ± visceral mHSPC, and patients refusal for ADT ± docetaxel, abiraterone acetate, or enzalutamide. We evaluated the response to treatment using prostate-specific antigen (PSA) response and the progression-free survival (PFS) and overall survival (OS) as well as the toxicities.ResultsTwenty-one mHSPC patients were included in this preliminary work. Following treatment, twenty patients (95%) had any decline in PSA and eighteen patients (86%) presented with a PSA decline of ≥ 50% including 4 patients in whom PSA became undetectable. A lower percentage decrease in PSA following treatment was associated with increased mortality and shorter progression-free survival. Overall, administration of 225Ac-PSMA-617 was well tolerated. The commonest toxicity seen was grade I/II dry mouth observed in 94% of patients.ConclusionsGiven these favorable results, randomized prospective multicenter trials assessing the clinical value of 225Ac-PSMA-617 as a therapeutic agent for mHSPC administered either as monotherapy or administered concomitant with ADT are of interest.

Prostate-specific antigen kinetics contributes to decision making for biopsy referral: the predictive implication for PSA retest in patients with elevated PSA levels.

It is common to repeat prostate-specific antigen (PSA) measurements for men with PSA elevation before prostate biopsy. In this scenario, they may have considerable psychological distress in fear of the presence of cancer until retests. We assessed possible clinical factors causing transient PSA rise and explored the parameters predictive of subsequent PSA change. As interfering conditions, the history of ejaculation, bicycling, and any types of infections were assessed using the questionnaire. The pattern of PSA change was compared in association with the various clinical factors. Predictive significance of PSA kinetics such as coefficient of variation (CV) and PSA velocity (PSAV) for PSA values at retest was evaluated. The rate of reversion to the normal range was 38.3% at retest. The rate of 12.8% of men showed a large increase by ≥20%, whereas 38.2% of men showed a large decline by ≥20% from the baseline. Men with younger age (≤60 years), small prostate (<20cc), and prior history of ejaculation or infections showed significantly larger PSA decrease than their counterparts. Those with large CV or PSAV before the baseline more frequently showed PSA decrease below the age-specific cutoff or decline by ≥10% from the baseline at retest. These parameters associated with PSA kinetics had independent predictive values for relevant PSA change at retest. Ejaculation and any types of infections should be avoided before PSA tests. Men with large PSA fluctuation before the baseline are likely to show a significant PSA decrease at retest. This predictive information may help both physicians to determine whether to proceed to an immediate biopsy and patients to reduce their psychological burden.