Recurrence In Prostate Cancer Patients Research Articles

Abstract CT108: Phase I data from TENDU101, a first-in-human trial of a novel synthetic peptide conjugate cancer vaccine platform assessed in recurrent prostate cancer patients before salvage treatment

Abstract Synthetic peptides are explored in the clinic in cancer vaccine development for the purpose of inducing tumor-directed T cell responses. Their immunogenicity is dependent on the chosen adjuvant and target organ exposure (lymphoid organs). To improve peptide immunogenicity, we have developed a technology enabling cross-linking of endogenous, pre-existing circulating antibodies (Abs) by employing a three-dimensional chemistry design. Multiple identical tetanus toxin-derived B cell epitopes (MTTEs) are conjugated to synthetically made antigenic tumor peptides intended to induce T cell responses. Here we report the first clinical safety assessment of the vaccine platform in the trial TENDU101 (NCT04701021). The cancer vaccine candidate (TENDU) was designed to include longer synthetic peptides harboring prostate cancer derived epitopes (CD4 and CD8) from PAP and PSMA. The study was a 3+3 design and doses were 40, 400 and 960 microgram in patients with documented recurrent disease after radical prostatectomy. A tetanus toxoid (TTd) containing vaccine boost was followed by TENDU vaccination via subcutaneous injection in the abdomen (4 doses in total with a 2 week interval) in n=9 patients (gr 1, 2, 3.1). For group 3.2 (n=3) TENDU vaccination was administrated in the same arm as the TTd vaccination. Primary objective was safety and secondary objective assessment of immune responses and preliminary anti-tumor responses. A total of 52 adverse events (AEs) were reported, most mild and deemed unrelated to vaccination. Six treatment-related AEs were reported of which 50% were mild transient injection site reactions in a single patient (gr 3.1), and three events of increases in lipase levels in two patients (gr 2). No serious AEs was reported. T cell responses pre/post TENDU were assessed in a total of six patients of which five patients displayed increased response against vaccine-related CD8 and CD4 epitopes (ELISpot). The three patients with the greatest increase in T cell responses were found to display the highest anti-MTTE IgG responses. A trend towards decrease in circulating tumor cells from screening to the end of treatment visit was observed in the patients with the highest levels of anti-MTTE IgGs post TENDU vaccination. There were no trends for decrease in PSA and/or PAP at the end of treatment and follow-up measurements were affected by initiation of radiation and short-term androgen deprivation. The administration of TTd and TENDU to the same anatomical location although spaced in time appeared to negatively influence immune responses to TTd and TENDU. In conclusion, the novel synthetic peptide conjugate vaccine conjugate was found safe with no serious AEs reported and a positive correlation between anti-MTTE and T cell responses was noted in patients when TENDU was administrated in the abdomen. Citation Format: Wolfgang Lilleby, Anna Bergqvist, Aikaterini Nasi, Wenche Rasch, Sara Mangsbo. Phase I data from TENDU101, a first-in-human trial of a novel synthetic peptide conjugate cancer vaccine platform assessed in recurrent prostate cancer patients before salvage treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT108.

Abstract 1725: Role of PRMT5 in neuroendocrine prostate cancer development

Abstract Background: Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer responsible for an estimated 20-30% of castration resistant prostate cancer (CRPC) deaths. While NEPC can arise de novo, the majority of these cases emerge as treatment-induced NEPC (tNEPC). Our data establish PRMT5:MEP50 as a key epigenetic regulator in NEPC and provide a potential predictive biomarker for tNEPC. Methods: Here we generated an in vitro cell culture model and mouse model to mimic the clinical conditions in androgen signaling inhibitor (ASI) or androgen deprivation treatment (ADT) We developed an in vitro cell culture and in vivo model to mimic the clinical conditions in enzalutamide-resistant prostate cancer. Regulation and role of protein arginine methyltransferase 5 (PRMT5) and its cofactor methylosome protein 50 (MEP50) were determined by treating cells and mice tumors with doxycycline inducible-shRNAs and catalytic inhibitors followed by analysis of cell viability, neurite growth, and effects on neuroendocrine related gene transcription. Pro-NEPC development effects were analyzed by immunofluorescence, immunohistochemical analysis, and western blot. PRMT5:MEP50-dependent methyltransferase activity was further validated by observing histone deposition levels via western blot and ChIP-qPCR. For clinical correlation, PRMT5 and MEP50 expression levels were comprehensively analyzed in both CRPC and NEPC patient prostate tissue samples. Results: Our clinical and computational analyses have identified increased expression of PRMT5:MEP50 in NEPC. Overexpression of PRMT5 and MEP50 in prostate cancer cells is sufficient to induce neuroendocrine differentiation (NED) in prostate cancer cells. Gene depletion of PRMT5 and MEP50 prevented the NE phenotype induced by androgen receptor inhibition and resensitized the prostate cancer cells to ASI/ADT. PRMT5 and MEP50 facilitate chromatin modulation through the dimethylation of H4R3, which is highly correlated with the NED phenotype. Moreover, overexpression of PRMT5 and MEP50 in mouse prostate induces NEPC development, and gene downregulation can prevent NED in a xenograft mouse model. Elevated PRMT5 and MEP50 correlated with increased recurrence in prostate cancer patients receiving ADT and their recurrence probability after the treatment. Conclusion: Our data establish PRMT5:MEP50 as a key epigenetic regulator in NEPC and provide a potential predictive biomarker for tNEPC. Citation Format: Hye Seung Nam, Xuehong Deng, Chang-Deng Hu. Role of PRMT5 in neuroendocrine prostate cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1725.

The superior detection rate of total-body [68Ga]Ga-PSMA-11 PET/CT compared to short axial field-of-view [68Ga]Ga-PSMA-11 PET/CT for early recurrent prostate cancer patients with PSA 

[68Ga]Ga-PSMA PET imaging has been extensively utilized for the detection of biochemical recurrence (BCR) in prostate cancer. However, the detection rate declines to merely 10-40% when PSA levels are < 0.2ng/mL employing short axial field-of-view (SAFOV) PET. Prior studies exhibited superior detection rates with total-body [68Ga]Ga-PSMA-11 PET compared to SAFOV [68Ga]Ga-PSMA-11 PET in BCR patients with PSA > 0.2ng/mL. Nevertheless, the diagnostic utility of total-body [68Ga]Ga-PSMA-11 PET for BCR patients when PSA is < 0.2ng/mL remains unclear. This study aimed to assess whether total-body [68Ga]Ga-PSMA-11 PET/CT could improve the detection rate compared to SAFOV [68Ga]Ga-PSMA-11 PET/CT in BCR patients with PSA < 0.2ng/mL. Eighty BCR patients with PSA < 0.2ng/mL underwent total-body [68Ga]Ga-PSMA-11 PET/CT. These patients were matched by baseline qualities to another 80 patients who received SAFOV [68Ga]Ga-PSMA-11 PET/CT. The detection rates of total-body [68Ga]Ga-PSMA-11 PET/CT and SAFOV [68Ga]Ga-PSMA-11 PET/CT were compared utilizing a chi-square test and stratified analysis. Image quality of total-body [68Ga]Ga-PSMA PET/CT and SAFOV [68Ga]Ga-PSMA-11 PET/CT was assessed based on subjective scoring and objective parameters. The objective parameters measured were SUVmax, SUVmean, standard deviation (SD) of SUV, and signal-to-noise ratio (SNR) of liver and gluteus maximus. The image quality of total-body [68Ga]Ga-PSMA PET/CT was superior to that of SAFOV [68Ga]Ga-PSMA-11 PET/CT in both early and delayed scans. The detection rate of total-body [68Ga]Ga-PSMA PET/CT for BCR patients with PSA < 0.2ng/mL was significantly higher than that of SAFOV [68Ga]Ga-PSMA-11 PET/CT (73.75% vs. 43.75%, P < 0.001). Total-body [68Ga]Ga-PSMA PET/CT resulted in noteworthy modifications to the treatment regimen when contrasted with SAFOV [68Ga]Ga-PSMA-11 PET/CT. In BCR patients with PSA < 0.2ng/mL, total-body [68Ga]Ga-PSMA-11 PET/CT not only demonstrated a significantly higher detection rate compared to SAFOV [68Ga]Ga-PSMA-11 PET/CT but also led to significant alterations in treatment regimens.

Quantitative and Qualitative Assessment of Urinary Activity of 18F-Flotufolastat-PET/CT in Patients with Prostate Cancer: a Post Hoc Analysis of the LIGHTHOUSE and SPOTLIGHT Studies

PurposeTo evaluate the impact of urinary activity on interpretation of 18F-flotufolastat (18F-rhPSMA-7.3) PET/CT, we conducted a post hoc qualitative and quantitative analysis of scans acquired in two phase 3 studies of 18F-flotufolastat.ProceduresNewly diagnosed or recurrent prostate cancer patients enrolled in LIGHTHOUSE (NCT04186819) or SPOTLIGHT (NCT04186845), respectively, underwent PET/CT 50–70 min after intravenous administration of 296 MBq 18F-flotufolastat. For the present analysis, 718 18F-flotufolastat scans (352 from LIGHTHOUSE and 366 from SPOTLIGHT) were re-evaluated by three board-certified nuclear medicine physicians. Reader 1 performed a quantitative assessment (SUVmax and SUVmean) of bladder activity in a circular region-of-interest over the maximum diameter of bladder activity in the transverse plane. All three readers qualitatively assessed the impact of any urinary activity in the bladder on image interpretation using a three-point scale (0 = no/minimal visible urinary activity, 1 = urinary activity visible but distinction between urine and disease possible and 2 = assessment inhibited by urinary activity) and the presence/absence of ureteric activity and halo artifacts.ResultsIn total, 712/718 scans were evaluable. Reasons for exclusion were cystectomy, renal failure, or urinary catheter in situ (n = 2 each). The median bladder SUVmax and SUVmean were 17.1 and 12.5, respectively. By majority read, 682/712 (96%) patients had either no urinary activity (score = 0) or visible activity that could be distinguished from disease uptake (score = 1). In the minority of patients (24, 3.4%) where urinary activity did impact assessment (score = 2), the median bladder SUVmean was higher (20.5) than those scored 0 (3.8) or 1 (14.0). Ureteric activity was absent in 401 (56%) patients. Halo artifacts were observed in only two (0.3%) patients (majority read).Conclusions18F-Flotufolastat urinary activity did not influence disease assessment for the majority of patients. While this study was not designed as a head-to-head comparison, the median bladder SUVs are lower than previously reported values for other renally cleared PSMA-PET radiopharmaceuticals.

Prognostic value of Controlling Nutritional Status score for postoperative complications and biochemical recurrence in prostate cancer patients undergoing laparoscopic radical prostatectomy.

Controlling Nutritional Status (CONUT) score was used for screening the preoperative nutritional status. The correlation between the CONUT score and the prognosis of patients with prostate cancer (PCa) has yet to be elucidated. Herein, we analyzed the prognostic value of CONUT scores in patients with PCa who underwent laparoscopic radical prostatectomy. Data of 244 patients were retrospectively evaluated. Perioperative variables and follow-up data were analyzed. The patients were categorized into 2 groups according to their preoperative CONUT scores. Postoperative complication and incontinence rates were also compared. The Kaplan-Meier method was used to estimate the median biochemical recurrence-free survival (BCRFS) between the 2 groups. Univariate and multivariate Cox regression analyses were performed to identify the potential prognostic factors for BCRFS. Patients were categorized into the low-CONUT group (CONUT score <3, n = 207) and high-CONUT group (CONUT score ≥3, n = 37). The high-CONUT group had a higher overall complication rate (40.5% vs.19.3%, p = 0.004), a higher major complication rate (10.8% vs. 3.9%, p = 0.013), and longer postoperative length of stay (8 days vs. 7 days, p = 0.017). More fever, urinary infection, abdominal infection, scrotal edema, rash, and hemorrhagic events (all p values < 0.05) were observed in the high-CONUT group. A higher rate of urinary incontinence was observed in the high-CONUT group at 1 (34.4% vs. 13.2%, p = 0.030) and 3 months (24.1% vs. 8.2%, p = 0.023) postoperatively. The high-CONUT group had shorter medium BCRFS (23.8 months vs. 54.6 months, p = 0.029), and a CONUT score ≥3 was an independent risk factor for a shorter BCRFS (hazards ratio, 1.842; p = 0.026). The CONUT score is a useful predictive tool for higher postoperative complication rates and shorter BCRFS in patients with PCa who undergo laparoscopic radical prostatectomy.

ADT Use and Nodal Irradiation in Men Receiving Post-Prostatectomy Salvage Radiotherapy within a Statewide Radiation Oncology Quality Consortium.

For men with biochemical recurrence after radical prostatectomy, salvage radiotherapy (SRT) is a standard of care. Outcomes are improved when SRT is delivered at lower PSA levels, and there has been increased emphasis on more timely treatment. With early SRT, however, there remains uncertainty as to the optimal use and duration of androgen deprivation therapy (ADT) and pelvic lymph node radiation (PLNRT). Moreover, PET imaging and genomic classifiers have emerged as tools to guide treatment decisions, but their uptake in routine practice is unknown. To address these questions, we analyzed a contemporary cohort treated with SRT within the Michigan Radiation Oncology Quality Consortium (MROQC). We hypothesized that ADT and PLNRT practices would reflect recent trial results in this setting. Eligible patients receiving SRT at an MROQC center were enrolled from 06/09/20 to 11/04/22. Data was prospectively collected via patient-, physician-, and physicist-completed forms. Patients were matched to the Michigan Urological Surgery Improvement Collaborative (MUSIC) database for additional treatment- and patient-related data. Univariable (UVA) and multivariable analyses (MVA) were performed to test associations between patient/tumor factors and ADT or PLNRT use. A total of 191 patients across 26 centers were enrolled in the MROQC database. Of these, 116 were matched to the MUSIC database. Median time from RP to SRT was 17 months (IQR 8 - 33 months). The median post-RP PSA prior to SRT was 0.25 (IQR 0.16 - 0.60). Early SRT was defined as pre-SRT PSA ≤0.5, and 27% (n = 31/116) had a pre-SRT PSA >0.5. Twenty-eight were pT3b/T4, 97% were pN0/NX, and 51% had positive surgical margins. Fractionation was conventional (>28 fractions) in 58% and moderate hypofractionation (20-28 fractions) in 38%. Table 1 describes the patients receiving ADT and/or PLNRT. Median ADT duration was 6 mo (IQR 6 - 7 mo). MVA revealed pre-SRT PSA >0.5 (OR 5.05 [1.89 - 15.33]) and pT3b/T4 disease (OR 4.23 [1.40 - 14.56]) were significantly associated with ADT use (p <0.05), but not grade group (GG) or margin status. PLNRT was significantly associated with pre-SRT PSA >0.5 (OR 3.04 [1.21 - 8.42], p <0.05) but not pT stage, margin status, or GG. PET imaging was performed in 37% of men (52% negative, 21% prostate bed alone uptake, and 26% lymph node positivity) and genomic classifiers were performed in 24%. Nearly 75% of biochemically recurrent prostate cancer patients within MROQC received early SRT, and about half received ADT. A pre-SRT PSA >0.5 was strongly associated with ADT and PLNRT. With prostate bed SRT alone, very few received ADT. Given the considerable heterogeneity in treatment, additional studies may help identify patients who most benefit from ADT + PLNRT, and who may be spared potential added toxicity.

DCE-MRI-Based Atlas for Prostate Bed Recurrence after Radical Prostatectomy: Consistency of CTV Delineation with the Available Contouring Guidelines

To create a magnetic resonance image (MRI)-based atlas of prostate bed recurrence for prostate cancer patients undergoing salvage radiotherapy (sRT) after radical prostatectomy and to evaluate the consistency of contouring guidelines for the prostatic fossa clinical target volume (PF-CTV) delineation. Patients with biochemical recurrence and prostate bed lesions at MRI before sRT were included. A reference patient was identified and the lesion(s) of each patient was mapped by a deformable co-registration among T2 weighted (T2w) images. The structure sets were combined to create a 3D recurrence incidence map, overlapped on T2w reference set, then transferred to the planning CT. The volume and the location of the lesions were extracted. On the reference CT, 5 PF-CTV contouring strategies were implemented: Radiation Therapy Oncology Group (RTOG); European Organization for Research and Treatment of Cancer (EORTC); Francophone Group of Urological Radiotherapy (GFRU); Faculty of Radiation Oncology Genito-urinary Group (FROGG) and Princess Margaret Hospital (PMH). Coverage was assessed after identifying the centroid of each lesion: if the centroid was included in the PF-CTV, the coverage was considered complete (fully covered-FC), otherwise uncovered (UC). The coverage was evaluated for each contouring strategy and compared with the chi-squared test; the strength of the correlation was assessed with the phi coefficient. A total of 112 patients with 124 recurrences were identified. The lesions were located at the vesicourethral anastomosis (VUA), around the bladder neck (BN) and beyond the bladder (RV) in 63, 36 and 25 cases. Regardless the contouring strategy, 89.1% of the lesions were FC. Coverage was higher (p<0.001) for BN (95.6%) over RV (83.2%) and VUA (73.7%) lesions. FC/UC rates were 66.1%/33.9%, 83.9%/16.1%, 89.5%/10.5%, 83.1%/16.9%, 87.1%/12.9% for EORTC, FROGG, GFRU, RTOG and PMH, respectively. At pair-wise comparison, the EORTC definition had lower coverage (p<0.001) and was poorly correlated to the other strategies (phi values ranging 0.385-0.540, p <0.001). Conversely, the correlations between the other definitions were >0.700, the highest between PMH-FROG (0.812, p<0.001). After selecting VUA lesions only (N = 63), the probability of FC was 60.3%, 74.6%, 82.5%, 71.4% and 79.4% for EORTC, FROGG, GFRU, RTOG and PMH, respectively. The EORTC definition performed poorly than GFRU (p = 0.006) and PMH (p = 0.020). When considering lesions above the VUA (N = 61), the performance improved (FC: 72.1%, 93.4%, 96.7%, 95.1% and 95.1% for EORTC, FROGG, GFRU, RTOG and PMH, respectively) but the EORTC was significantly less covering and its correlation with the others was ≤ 0.1. According to the criterium of coverage our data do not support the use of the EORTC definition. Here we provide an MRI-based atlas of prostatic bed recurrence that can optimize sRT contours.

Clinical Usefulness of PSMA PET/CT Imaging in Patients with Suspected Recurrence of Prostate Cancer after Primary RT with PSA below the Phoenix Criteria Threshold: Systematic Review and Meta-Analysis

To assess the detection rate and the patterns of PSMA PET/CT uptake in patients with suspected prostate cancer recurrence after primary radiotherapy with serum PSA levels below the accepted Phoenix definition criteria for biochemical recurrence. The meta-analysis was performed according to the PRISMA statement. Studies providing data on patients with suspected prostate cancer recurrence after primary radiotherapy with serum PSA levels below the accepted Phoenix definition criteria were included. Atotal of 5 studies included a total of 1334 patients, of which 489 patients with suspected BCR and serum PSA levels below the Phoenix criteria were included. The PSMA PET/CT detection rate (DR) was 60% for PSA <0.5 ng/mL, 76% for PSA 0.5-1 ng/mL, 81.03% for PSA 1-2 ng/mL, and 89.5% for PSA>2. No significant differences were found in the locations of PSMA-PET/CT uptake among those with PSA ≤2 ng/mL, compared with those meeting the Phoenix criteria. The PSMA-PET/CT uptake of local-only recurrence was more likely in patients with PSA <2 ng/mL (local-only recurrence PSA >2 ng/mL [40.07%] vs PSA <2 ng/mL [58.10%]), RR: 0.718 (95% CI: 0.579-0.892). Lymph node, bone, and visceral metastasis detection rates could be extracted from 3 studies (432 patients). For lymph nodes, the DR was 46% (95% CI: 38-54) in patients outside the Phoenix criteria threshold, and 50% (95% CI: 39-62) in patients with PSA>2 ng/mL. The DR for bone metastases was 19% (95% CI: 12-28) in patients outside the Phoenix criteria threshold, and 25% (95% CI: 19-31) in patients with PSA>2 ng/mL. The DR for visceral metastases was 3% (95% CI: 0-7) in patients outside the Phoenix criteria threshold, and 2% (95% CI: 0-4) in patients with PSA>2 ng/mL. The potentially salvageable disease was considered when all evidence of avid disease could be safely treated with local therapy. This data could be extracted from two studies (343 patients). A higher proportion of disease potentially amenable to salvage therapy was reported in patients outside the Phoenix criteria threshold [salvageable disease: PSA ≤2 ng/mL: 69% (95% CI: 57-80), and PSA >2 ng/mL: 61% (95% CI: 55-66). The pooled risk ratio meta-analysis showed no statistically significant differences between the two previous groups RR: 0.91 (95% CI: 0.75-1.10). PSMAPET/CT can detect prostate cancer recurrence in patients with PSA levels below the Phoenix criteria threshold (reaching up to 80%). Local-only recurrence detection by PSMA PET/CT was more likely in patients with PSA <2 ng/mL. The data from the present meta-analysis shows that a critical review of the Phoenix criteria in the era of PSMA PET/CT might be warranted. Nevertheless, the lack of anatomopathological validation and the retrospective nature of the studies are some of our limitations.

Concurrent Radiation and Deep Hyperthermia Therapy for the Treatment of Recurrent Prostate Cancer

Robustpreclinical and clinical data have established hyperthermia as an effective radiosensitizer which can be used in the setting of recurrent disease to enhance the therapeutic window. We present a single institution experience examining outcomes in recurrent prostate cancer (RPCA) patients treated with concurrent deep hyperthermia (DHT) and radiation (RT). We hypothesized that concurrent DHT and RT would be well tolerated and would provide durable local control without unexpected toxicity. Consecutive RPCA patients treated with concurrent DHT and pelvic RT were retrospectively analyzed. Patients received twice weekly DHT treatments in addition to daily or twice daily (BID) RT. DHT was delivered using a concentric ring radiofrequency phased array system to a target temperature of 40-43°C. Acute and late treatment associated toxicities, graded per Common Terminology Criteria for Adverse Events (CTCAE) v5.0, were evaluated. Survival and control outcomes were evaluated using the Kaplan-Meier method. Eighteen patients were included for analysis. Median patient age was 69 yrs (64-82 yrs). Fifteen (83%) patients had received prior RT and 12 (67%) patients had undergone radical prostatectomy. At time of treatment, two patients had RPCA which had dedifferentiated to a small cell phenotype. Eight (44%) patients had extra-pelvic disease at time of treatment. Seventeen (94%) patients received proton RT, while 1 (6%) received photon RT. Median RT dose was 49 Gy (range 30-73.8 Gy). Five (28%) patients received BID RT. Fifteen (83%) patients also received sequential or concurrent systemic therapy including androgen deprivation therapy or chemotherapy. A total of 142 DHT treatments were administered (median of 7.5 treatments). Fourteen (78%) patients completed ≥ 75% of planned DHT treatments. Reasons for inability to complete treatment included discomfort and abnormal vital signs during DHT. Only one patient reported Grade 2 pain and pruritus attributed to concurrent RT and DHT. One acute Grade 3 RT toxicity (diarrhea) was reported. No late Grade 3+ toxicities occurred. Of ten patients (56%) treated with curative intent, 8 (44%) had no reported failures at 2-year follow up while two had distant failure and biochemical failure respectively. Three (17%) patients were treated with palliative intent for disease related pain; two reported partial relief and one reported complete pain relief. With a median follow-up of 27 months (1-46 months), 2-year failure free survival was 41.4% (95% CI: 27.8-55%), local control was 76.5% (95% CI 66.2-86.8%) and overall survival was 70.9% (95% CI 58.4-83.3%). Our results suggest that concurrent RT and DHT is well tolerated and allows for safe escalation of local therapy for RPCA, providing patients with durable local control and palliation with an acceptable toxicity profile. Prospective validation is warranted.

Conditional Prostate Cancer-Specific Survival Probabilities in Recurrent Prostate Cancer Patients Receiving Radiation ± Antiandrogen Therapy: Secondary Analysis of a Randomized Clinical Trial

Salvage radiation therapy (SRT) and androgen-deprivation therapy (ADT) are routinely used in patients with elevated prostate-specific antigen (PSA) levels after radical prostatectomy (RP) for prostate cancer (PCa). Although prostate cancer-specific survival (PCSS) following SRT is useful when counseling patients at the time of treatment, the utility of this data from time of diagnosis diminishes over time. Conditional survival (CS) can provide more relevant estimates, especially given long-term PCa survivorship. The primary aim of this study was to analyze CS estimates for recurrent PCa patients undergoing SRT ± ADT. The secondary objective was to determine if factors prognostic of PCSS at diagnosis remain relevant in survivorship. We analyzed data from 760 post-RP patients enrolled in NRG/RTOG 9601 (1998-2003). Eligible patients included men who had undergone prior RP and had pT2/T3 disease without nodal involvement and detectable PSA levels of 0.2-4.0 ng/mL. Patients were randomly assigned to undergo SRT and receive either 24 mo of ADT or placebo. OS was calculated (Kaplan-Meier), cumulative incidence was used to estimate PCSS rates, and prognostic factors associated with PCSS were analyzed by multivariable Cox proportional hazards modeling (MVA). Patients were followed for a median of 13 y. The 5- and 10-y PCSS estimates from diagnosis were 98.52% and 92.7%, respectively. At 1- (n = 755), 3- (n = 727), 5- (n = 680), and 8-y (n = 602) survivorship, chances of PCSS at an additional 5-y were 97.41%, 95.29%, 93.76%, and 91.04%, respectively. On MVA at diagnosis, omission of ADT (HR 2.156, P = 0.0003), increasing age (HR 1.833, P = 0.03), Gleason score (GS) 7 (HR 2.356, P = 0.0057), and GS 8-10 (HR 4.841, P < 0.0001) were associated with PCa-specific mortality. For those who achieved survivorship at 1-, 3-, 5-, and 8-y, all variables remained prognostic of PCa-specific mortality on MVA. Conditional risk of death from PCa for patients treated with SRT increases over time. The initial risk of dying from PCa over a given period, however, is higher than if already having survived a portion of that period. ADT, younger age, and lower GS continue to confer a reduced risk of PCa-specific mortality for long-term survivors. This data can be used to inform survivorship care planning, giving patients more relevant prognostic information during continued surveillance after completion of treatment.

148 Impact of Statin Use on Biochemical Recurrence in Prostate Cancer Patients Treated with Radiation Therapy

148 Impact of Statin Use on Biochemical Recurrence in Prostate Cancer Patients Treated with Radiation Therapy

Total-body [68Ga]Ga-PSMA-11 PET/CT improves detection rate compared with conventional [68Ga]Ga-PSMA-11 PET/CT in patients with biochemical recurrent prostate cancer.

The purpose of this study was to assess whether total-body [68Ga]Ga-PSMA-11 PET/CT could improve the detection rate compared with conventional [68Ga]Ga-PSMA-11 PET/CT in patients with biochemical recurrent prostate cancer. Two hundred biochemical recurrent prostate cancer patients with similar clinicopathological characteristics were included, of whom 100 patients underwent early total-body [68Ga]Ga-PSMA-11 PET/CT and diuretic-delayed total-body [68Ga]Ga-PSMA-11 PET/CT, and the other 100 patients received early conventional [68Ga]Ga-PSMA-11 PET/CT and diuretic-delayed conventional [68Ga]Ga-PSMA-11 PET/CT. The detection rates of total-body [68Ga]Ga-PSMA-11 PET/CT and conventional [68Ga]Ga-PSMA-11 PET/CT were compared using a chi-square test and stratified analysis. The image quality of total-body [68Ga]Ga-PSMA PET/CT and conventional [68Ga]Ga-PSMA-11 PET/CT was compared based on subjective scoring and objective parameters. Subjective scoring was conducted from background noise and lesion prominence using a 5-point scale. Objective parameters were evaluated by SUVmax, SUVmean, the standard deviation (SD) of SUV, and the signal-to-noise ratio (SNR) of liver and gluteus maximus. The SUVmax of the recurrent lesions was also measured. The liver SD of the total-body [68Ga]Ga-PSMA-11 PET/CT was significantly lower than that of conventional [68Ga]Ga-PSMA-11 PET/CT, the SNR was significantly higher than that of conventional [68Ga]Ga-PSMA-11 PET/CT, and the subjective evaluation was significantly better than that of conventional [68Ga]Ga-PSMA-11 PET/CT. The detection rate of total-body [68Ga]Ga-PSMA PET/CT for biochemical recurrence of prostate cancer was significantly higher than that of conventional [68Ga]Ga-PSMA-11 PET/CT (91.0% vs. 74.0%, P = 0.003). Total-body [68Ga]Ga-PSMA-11 PET/CT had better detection efficiency for patients with a Gleason score ≤ 8 or PSA ≤ 2ng/ml. The advantages of diuretic-delayed total-body [68Ga]Ga-PSMA-11 PET/CT were more obvious. Total-body [68Ga]Ga-PSMA-11 PET/CT could significantly improve the detection rate compared with conventional [68Ga]Ga-PSMA-11 PET/CT in patients with biochemical recurrent prostate cancer.

Prognostic utility of RECIP 1.0 with manual and AI-based segmentations in biochemically recurrent prostate cancer from [68Ga]Ga-PSMA-11 PET images

PurposeThis study aimed to (i) validate the Response Evaluation Criteria in PSMA (RECIP 1.0) criteria in a cohort of biochemically recurrent (BCR) prostate cancer (PCa) patients and (ii) determine if this classification could be performed fully automatically using a trained artificial intelligence (AI) model.MethodsOne hundred ninety-nine patients were imaged with [68Ga]Ga-PSMA-11 PET/CT once at the time of biochemical recurrence and then a second time a median of 6.0 months later to assess disease progression. Standard-of-care treatments were administered to patients in the interim. Whole-body tumour volume was quantified semi-automatically (TTVman) in all patients and using a novel AI method (TTVAI) in a subset (n = 74, the remainder were used in the training process of the model). Patients were classified as having progressive disease (RECIP-PD), or non-progressive disease (non RECIP-PD). Association of RECIP classifications with patient overall survival (OS) was assessed using the Kaplan-Meier method with the log rank test and univariate Cox regression analysis with derivation of hazard ratios (HRs). Concordance of manual and AI response classifications was evaluated using the Cohen’s kappa statistic.ResultsTwenty-six patients (26/199 = 13.1%) presented with RECIP-PD according to semi-automated delineations, which was associated with a significantly lower survival probability (log rank p < 0.005) and higher risk of death (HR = 3.78 (1.96–7.28), p < 0.005). Twelve patients (12/74 = 16.2%) presented with RECIP-PD according to AI-based segmentations, which was also associated with a significantly lower survival (log rank p = 0.013) and higher risk of death (HR = 3.75 (1.23–11.47), p = 0.02). Overall, semi-automated and AI-based RECIP classifications were in fair agreement (Cohen’s k = 0.31).ConclusionRECIP 1.0 was demonstrated to be prognostic in a BCR PCa population and is robust to two different segmentation methods, including a novel AI-based method. RECIP 1.0 can be used to assess disease progression in PCa patients with less advanced disease.This study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000608561) on 11 June 2015.

A novel, AI-generated morphologic biomarker to predict prostate cancer recurrence in patients with intermediate risk of progression.

e17097 Background: About half of the prostate cancer (PCa) patients within an intermediate-risk group return to the clinic with disease progression after the first line of therapy. While these patients can be stratified into Gleason Grades (GG) 3+4 and 4+3, studies indicate that high-risk patients can still be found in both groups. Using our AI platform, we have developed a morphometric biomarker by analyzing digitized H&amp;E slide images (WSIs), which can accurately predict early biochemical recurrence (within 36 months post-surgery) and the risk of metastatic disease more accurately than GG, TNM staging, and genomic tools. Methods: 125 intermediate-risk (n = 67, 3+4; n = 58, 4+3) samples were collected from the Icahn School of Medicine at Mount Sinai (ISSMS) to form a held-out test set. Seventy-eight patients within the test set had an associated genomic score. A series of deep learning models trained using data from ISMMS, the University of Wisconsin-Madison, and TCGA generated a high dimensional vector for each WSI to provide a numerical representation of observed morphologies, which is then converted into a single score to predict biochemical recurrence within 36 months (BCR) and rank risk of metastasis (MET). Area-under-the-receiver operating characteristic (AROC) was used to measure the accuracy of BCR, and the concordance index (CI) was used to measure the performance of MET. The high and low-risk groups' hazard ratios (HR) for patients within grades 3+4 and 4+3 show that our model can further stratify GG. Results: Our method was significantly better at predicting BCR (AROC: 0.801) and ranking MET (CI: 0.764) relative to GG, TNM, and genomic tool (Table 1). We further sub-stratified the patients into GG 3+4 and 4+3 and identified high-risk patients within each GG. Patients in GG 3+4 with high PATHOMIQ scores had a significantly higher risk of BCR (HR 3.3; 95% CI 1.44 – 7.56; p &lt; 0.005) compared to the low PATHOMIQ score patients. A similar trend was seen in the GG 4+3 group (HR 3.0; 95% CI 1.32 – 6.83; p &lt; 0.01). Conclusions: Our histopathology-based prognostic biomarker significantly improves over standard clinical markers in stratifying patients with intermediate-risk PCa for BCR and MET. Our method overcomes several limitations of genomic testing: We only need digitized WSIs. Our method is non-destructive and preserves the tissue for further interrogation. Moreover, our turn-around time is a few hours. Thus, the PATHOMIQ scoring method may strongly impact the management of intermediate-risk PCa patients and clinical trial patient selection for the successful development of new therapies for early-stage PCa. [Table: see text]

PSMA-PET Guided Treatment in Prostate Cancer Patients with Oligorecurrent Progression after Previous Salvage Treatment

Prostate Specific Membrane Antigen-Positron Emission Tomography (PSMA-PET) is used to select recurrent prostate cancer (PCa) patients for metastases-directed therapy (MDT). We aimed to evaluate the oncologic outcomes of second-line PSMA-guided MDT in oligo-recurrent PCa patients. we performed a retrospective analysis of 113 recurrent PCa after previous radical prostatectomy and salvage therapies with oligorecurrent disease at PSMA-PET (≤3 lesions in N1/M1a-b) in three high-volume European centres. Patients underwent second-line salvage treatments: MDT targeted to PSMA (including surgery and/or radiotherapy), and the conventional approach (observation or Androgen Deprivation Therapy [ADT]). Patients were stratified according to treatments (MDT vs. conventional approach). Patients who underwent MDT were stratified according to stage in PSMA-PET (N1 vs. M1a-b). The primary outcome of the study was Progression-free survival (PFS). Secondary outcomes were Metastases-free survival (MFS) and Castration Resistant PCa free survival (CRPC-FS). Kaplan-Meier analyses assessed PFS, MFS and CRPC-FS. Multivariable Cox regression models identified predictors of progression and metastatic disease. Overall, 91 (80%) and 22 (20%) patients were treated with MDT and the conventional approach, respectively. The median follow-up after PSMA-PET was 31 months. Patients who underwent MDT had a similar PFS compared to the conventional approach (p = 0.3). Individuals referred to MDT had significantly higher MFS and CRPC-FS compared to those who were treated with the conventional approach (73.5% and 94.7% vs. 30.5% and 79.5%; all p ≤ 0.001). In patients undergoing MDT, no significant differences were found for PFS and MFS according to N1 vs. M1a-b disease, while CRPC-FS estimates were significantly higher in patients with N1 vs. M1a-b (100% vs. 86.1%; p = 0.02). At multivariable analyses, age (HR = 0.96) and ADT during second line salvage treatment (HR = 0.5) were independent predictors of PFS; MDT (HR 0.27) was the only independent predictor of MFS (all p ≤ 0.04) Conclusion: Patients who underwent second-line PSMA-guided MDT experienced higher MFS and CRPC-FS compared to men who received conventional management.

68Ga-PSMA PET/CT-Based Atlas for Prostate Bed Recurrence After Radical Prostatectomy: Clinical Implications for Salvage Radiation Therapy Contouring Guidelines.

The aim of this study was to analyze the patterns of prostate bed (PB) recurrence in prostate cancer patients experiencing prostate-specific antigen (PSA) persistence (BCP) or biochemical recurrence (BCR) after radical prostatectomy using 68Ga-PSMA-11 PET/CT (68Ga-PSMA PET) in relation to the Radiation Therapy Oncology Group (RTOG) clinical target volumes (CTVs). Methods: This single-center, retrospective analysis included patients with BCP or BCR after radical prostatectomy and PB recurrence on 68Ga-PSMA PET. The PB recurrences were delineated by nuclear medicine physicians, the CTVs by radiation oncologists contouring guidelines on the 68Ga-PSMA PET, respectively, masked from each other. The coverage of the 68Ga-PSMA PET recurrence was categorized as PSMA recurrence completely covered, partially covered, or not covered by the RTOG-based CTV. Further, we evaluated the differences in PSMA recurrence patterns among patients with different 68Ga-PSMA PET staging (miTNM). Mann-Whitney U tests, the chi-square test, and Spearman (ρ) correlation analysis were used to investigate associations between CTV coverage and 68Ga-PSMA PET-based tumor volume, serum PSA levels, miTNM, and rectal/bladder involvement. Results: A total of 226 patients were included in the analysis; 127 patients had PSMA recurrence limited to the PB (miTrN0M0), 30 had pelvic nodal disease (miTrN1M0), 32 had extrapelvic disease (miTrN0M1), and 37 had both pelvic nodal disease and extrapelvic disease (miTrN1M1). In the miTrN0M0 cohort, the recurrence involved the rectal and bladder walls in 12 of 127 (9%) and 4 of 127 (3%), respectively. The PSMA-positive PB recurrences were completely covered by the CTV in 68 of 127 patients (53%), partially covered in 43 of 127 (34%), and not covered in 16 of 127 (13%). Full coverage was associated with a smaller tumor volume (P = 0.043), a lack of rectal/bladder wall involvement (P = 0.03), and lower miTNM staging (P = 0.035) but not with lower serum PSA levels (P = 0.979). Conclusion: Our study suggests that 68Ga-PSMA PET can be a valuable tool for guiding salvage radiation therapy (SRT) planning directed to the PB in the setting of postoperative BCR or BCP. These data should be incorporated into the redefinition of PB contouring guidelines.

Comprehensive analysis of fatty acid metabolism-related gene signatures for predicting prognosis in patients with prostate cancer.

Fatty acid metabolism (FAM) is an important factor in tumorigenesis and development. However, whether fatty acid metabolism (FAM)-related genes are associated with prostate cancer (PCa) prognosis is not known. Therefore, we established a novel prognostic model based on FAM-related genes to predict biochemical recurrence in PCa patients. First, PCa sequencing data were acquired from TCGA as the training cohort and GSE21032 as the validation cohort. Second, a prostate cancer prognostic model containing 10 FAM-related genes was constructed using univariate Cox and LASSO. Principal component analysis and t-distributed stochastic neighbour embedding analysis showed that the model was highly effective. Third, PCa patients were divided into high- and low-risk groups according to the model risk score. Survival analysis, ROC curve analysis, and independent prognostic analysis showed that the high-risk group had short recurrence-free survival (RFS), and the risk score was an independent diagnostic factor with diagnostic value in PCa patients. External validation using GSE21032 also showed that the prognostic model had high reliability. A nomogram based on a prognostic model was constructed for clinical use. Fourth, tumor immune correlation analyses, such as the ESTIMATE, CIBERSORT algorithm, and ssGSEA, showed that the high-risk group had higher immune cell infiltration, lower tumour purity, and worse RFS. Various immune checkpoints were expressed at higher levels in high-risk patients. In summary, this prognostic model is a promising prognostic biomarker for PCa that should improve the prognosis of PCa patients. These data provide new ideas for antitumour immunotherapy and have good potential value for the development of targeted drugs.

Construction of DNA methylation-based nomogram for predicting biochemical-recurrence-free survival in prostate cancer.

This study aimed to develop a DNA methylation-based nomogram for predicting biochemical recurrence in patients with prostate cancer. A DNA methylation signature was obtained via univariate, lasso, and stepwise multivariate Cox regression models. A 11-DNA methylation signature yielded a high evaluative performance for biochemical-recurrence-free survival. Cox regression analysis indicated that 11-DNA methylation signature and Gleason score served as independent risk factors. A nomogram was constructed based on the 11-DNA methylation signature and Gleason score, and C-index as well as the calibration plots demonstrated good performance and clinical application of the nomogram. A DNA methylation-associated nomogram serve as a prognosis stratification tool to predict the biochemical recurrence of prostate cancer patients after radical prostatectomy.

Nomograms for predicting local recurrence in prostate cancer patients with a positive resection margin

Background. Prostate cancer patients with a positive resection margin after radical prostatectomy are at risk of developing local recurrence. This risk should be carefully estimated in order to choose an optimal management strategy.Aim. To develop a nomogram to predict the risk of local recurrence in patients with a positive resection margin using the data on patients who have undergone surgery.Materials and methods. Routine pathomorphological examination of surgical specimens from 2255 patients with clinically significant local and locally advanced prostate cancer revealed 364 cases of positive resection margin. Statistical analysis allowed us to identify the most significant prognostic factors. Using selected preoperative factors and a mathematical model, we created a nomogram to predict local recurrence in patients with a positive resection margin.Results. Our nomogram had an accuracy of 93% (area under the ROC curve (AUC) 0.9392; p &lt;0.005), sensitivity of 0.99438, and specificity of 0.94545. The most significant prognostic factors included proportion of positive biopsy specimens, Gleason score (International Society of Urological Pathology (ISUP) grade estimated at routine pathomorphological examination), and presence and length of positive resection margin.Conclusion. Our mathematical model and the nomogram based on it are highly accurate for predicting local recurrence and can therefore be used for choosing an optimal management strategy.

68Ga-PSMA PET/CT in early relapsed prostate cancer patients after radical therapy

Biochemical recurrence (BCR) of prostate cancer (PCa) occurs in about 25% of patients treated with radical prostatectomy (RP) and up to 45% in patients who receive external beam radiotherapy (RT). Early diagnosis of PCa recurrence is of high importance for successful salvage therapy. The aim of the present study is to analyze the efficacy of 68 Ga-PSMA PET/CT in detecting the presence of local and/or systemic disease in patients with a history of PCa who have BCR. A total of 52 PCa patients with BCR referred for 68 Ga-PSMA PET/CT were recruited from the American University of Beirut Medical Center between November 2017 and December 2019. We compared the performance of PSMA PET/CT to the results and clinical factors based on follow up: PSA, PSA kinetics, primary treatment, and Gleason score. The relationship between the PET/CT findings and clinical indicators of disease were assessed by univariate and multivariate logistic regression. From a total of 52 patients, 34 (65.4%) had positive PSMA-PET/CT scans. Among those, 8/34 (23.5%) received primary RT. For all patients with a positive PSMA-PET: the detection rate was 2/4 (50%) for PSA < 0.2, 5/10 (50%) for PSA 0.2–0.49, 3/6 (50%) for PSA 0.5–0.99, 6/12 (50%) for PSA 1–1.99, 8/9 (88.9%) for PSA 2–3.99, and 10/11 (90.9%) for PSA 4–10.PSMA-PET/CT positivity was significantly associated with PSA level at time of PET scan, PSA doubling time, Gleason score and TNM staging. However, it did not show a significant correlation with radiotherapy as primary treatment, ongoing androgen deprivation therapy (ADT), time to relapse, and initial PSA before therapy. In our single center prospective trial, 68 Ga-PSMA PET/CT successfully detected the recurrence of PCa in patients with BCR. Scan positivity was significantly associated with PSA level at time of PET scan, PSA doubling time, Gleason score, and TNM staging. PSMA- PET/CT is a highly promising modality in the work up of patients with PCa in the setting of BCR for earlier detection of disease recurrence.