Radiorecurrent Prostate Cancer Research Articles

Abstract 4205: Investigating micro-environmental changes in a syngeneic radio-recurrent prostate cancer model

Abstract Approximately 1 in 8 men in Canada will be diagnosed with prostate cancer (PCa) in their lifetime, with ~20% presenting with high-risk disease. A standard treatment is radiotherapy (RT) and while many patients respond well to RT, up to 40% of men with high-risk disease can recur, often within the prostate. It can be challenging to salvage prostate relapses due to the morbidity of re-irradiation and the high rate of subsequent progression. The tumor micro-environment (TME) is altered after radiotherapy with increased immune-suppressor and immune-stimulatory effects occurring concurrently. Therapies capitalizing on these changes in the TME might provide an advantage to tackling radiation-recurrent cancer. Identifying TME changes in radio-recurrent PCa is the first step; however, existing PCa animal models do not accurately model the TME. Our collaborator’s lab has created the DVL3 mouse model with a clinically relevant TME. It forms tumors with distinct glandular morphology and displays micro-environmental responses to RT like what is seen in high-risk PCa patients, making this model an innovative tool for investigating radio-recurrence. The objective of this study is to create a radio-recurrent DVL3 PCa cell line to explore changes in the TME both in vitro and in vivo via orthotopic injection. To generate the radio-recurrent model, the DVL3 Parental cells (DVL3-Par) underwent a conventionally fractionated RT schedule (78Gy/39fx), herein referred to as DVL3-CF cells. The first part of the project involves in vitro characterization. Radiation resistance was evaluated via clonogenic assay which demonstrated a significant increase in clonogenic survival in the DVL3-CF cells relative to DVL3-Par. Characterization of DVL3-CF cells demonstrates that they are more proliferative at baseline, they recover quicker following G2/M blocks, they have decreased senescence following high dose radiation, and they are more invasive in vitro. The second part of the project evaluates the radio-recurrent model in vivo using an orthotopic mouse model as this best emulates the TME and clinical tumor progression. Parental and CF cells will be injected orthotopically into the prostate of C57/BL-6 mice and monitored for growth by MRI which will provide information on tumor volume as well as vasculature. At the time of sacrifice, the prostate and draining lymph nodes will be cryo-preserved and formalin fixed for downstream histological analysis. Transcriptional analyses, MRI data, and histological analysis of the tumors and draining lymph nodes will be compared across the radio-recurrent model and its parental cell line to evaluate environmental changes and potentially implicated mechanisms. This study will elucidate some of the complex interactions that are occurring within the TME of radio-recurrent PCa, increasing our understanding of mechanisms of radio-recurrence. Citation Format: Stephanie D. White, Xiaoyong Huang, Ian Mills, Stanley K. Liu. Investigating micro-environmental changes in a syngeneic radio-recurrent prostate cancer model [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 4205.

Abstract 1353: Potentiating salvage radiotherapy in radiorecurrent prostate cancer through anti-CTLA4 therapy: Implications from a syngeneic model

Abstract Background: Advanced prostate cancer (PCa) is a leading cause in cancer death and can elicit significant morbidity and mortality. A common treatment modality for advanced PCa is radiation therapy (RT). Currently, salvage of local disease recurrence after RT is a major clinical problem. Emerging evidence indicates the importance of the immune system in governing RT response. In support of this, immune checkpoint inhibitors (ICIs), which enhance immune activation, have demonstrated clinical therapeutic promise in combination with RT in certain advanced cancers. Irradiation (IR) combined with ICIs may prime the immune system to recognize and target recurrent cancer. Purpose: Investigate the therapeutic efficacy of ICIs in combination with RT for radiorecurrent PCa in a syngeneic pre-clinical model. Methods: TRAMP-C2 cells were treated with 10 Gy of radiation over 5 fractions (similar to clinical hypofractionated (HF) schedule) to generate TRAMP-C2 HF cells. Immune-competent mice were transplanted subcutaneously with TRAMP-C2 HF cells. Once tumors reached palpable size, mice were administered either ICIs (anti-PDL1 or anti-CTLA4) alone or in combination with RT. Tumor volume was monitored to determine the treatment effect. Correlative studies on excised tumors and secondary lymphoid organs included flow cytometry and NanoString gene expression panel to evaluate immunological mechanisms that contribute to anti-tumor effects. Results: TRAMP-C2 HF cells were validated for radiation resistance and exhibited a more aggressive phenotype (reduction in senescence, increase in clonogenicity) similar to clinically recurrent PCa. Radiation resistance of TRAMP-C2 HF tumors was validated in vivo. Administration of anti-PDL1 and anti-CTLA4 as monotherapy or in combination did not achieve significant tumor growth delay compared to control. IR alone produced an observable tumor growth delay compared to ICIs alone. The combination of anti-PDL1 and IR did not yield additional growth delay compared to IR alone. Strikingly, significant tumor growth delay was seen with the combination of IR and anti-CTLA4 compared to IR alone, while also resulting in complete cure in a third of the mice. mice. Lymph nodes and tumors from mice treated with IR and anti-CTLA4 vs. IR and isotype control demonstrated differential expression of genes in T cell functions and enrichment in both CD4+ and CD8+ T cell populations. Conclusion: We generated the first syngeneic radiorecurrent PCa model and demonstrated that combining anti-CTLA4 and IR results in synergistic tumor response. Combined therapy resulted in augmented immune response, most notably enhancement of CD8 T cell activity. Significance: These findings contribute to our understanding of immunological events associated with RT and ICIs in the context of radiorecurrent PCa and support new avenues for salvage therapy in clinical trials. Citation Format: Hanzhi Wang, Linsey Gong, Xiaoyong Huang, Stephanie D. White, Hanz T. Chung, Danny Vesprini, Tera N. Petchiny, Emmanouil Fokas, Hansen He, Robert S. Kerbel, Stanley K. Liu. Potentiating salvage radiotherapy in radiorecurrent prostate cancer through anti-CTLA4 therapy: Implications from a syngeneic model [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 1353.

Abstract 1274: Investigating PLOD2 as a therapeutic target to overcome metastasis in radiorecurrent prostate cancer

Abstract Prostate cancer (PCa) is the second most common cancer in males, with 1 in 8 men developing the disease in their lifetime. For PCa, a common treatment strategy is external beam radiation therapy to the prostate. However, when cancer recurs (radiorecurrent PCa), it often behaves aggressively by invading into surrounding organs or spreading distantly. Radiorecurrent PCa metastasis is therefore a significant cause of morbidity and mortality that must be overcome to improve survival of advanced PCa patients. Proteomic analysis revealed the procollagen enzyme Lysyl Hydroxylase 2 (PLOD2) to be upregulated in our radiorecurrent, and highly aggressive, conventionally fractionated DU145 (DU145-CF) PCa cell line. Given its established function as a mediator of invasion in various other cancers, we sought to characterize the role of PLOD2 in the aggressive phenotype of our radiorecurrent PCa cells. Bioinformatic analysis of clinical data revealed PLOD2 genomic amplification to be significantly associated with biochemical recurrence in PCa patients. Upon further examination in vitro, it was revealed that PLOD2 knockdown significantly reduces matrigel invasion and migration in our radiorecurrent DU145-CF cell line, in addition to numerous other PCa cell lines, including primary cells we derived directly from PCa patients. Using the in vivo chick Chorioallantoic Membrane (CAM) model, we confirmed that PLOD2 knockdown significantly reduces the ability of DU145-CF cells to extravasate from the CAM vasculature into the surrounding stroma, a critical step of the metastatic cascade. To explore mechanisms of metastatic cellular reprogramming downstream of PLOD2, RNA sequencing of DU145-CF cells was conducted; a total of 681 genes were discovered to be dysregulated by PLOD2 knockdown, with their functional analysis suggesting changes in cellular metabolism and respiration. Finally, since PLOD2 is known to be regulated by hypoxia-induced protein HIF1α, we explored whether PLOD2 expression could be inhibited by the HIF1α inhibitor, PX-478. Treatment with PX-478 reduced both HIF1α and PLOD2 protein expression, and significantly reduced invasion, migration, and in vivo extravasation in DU145-CF cells, thereby indicating its potential as a pharmacological inhibitor of HIF1α-associated PLOD2 in radiorecurrent PCa. Together, our results demonstrate for the first time the role of PLOD2 in radiorecurrent PCa invasiveness, and point towards its potential as a therapeutic target to reduce metastasis and improve survival outcomes in PCa patients. Citation Format: Gavin Frame, Hon Leong, Roni Haas, Xiaoyong Huang, Jessica Wright, Paul C. Boutros, Thomas Kislinger, Stanley K. Liu. Investigating PLOD2 as a therapeutic target to overcome metastasis in radiorecurrent prostate cancer [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 1274.

Evaluation of the safety and efficacy of high-dose rate brachytherapy for radiorecurrent prostate cancer: asystematic review and meta-analysis.

High-dose-rate brachytherapy (HDR-BT) plays an important role in the treatment of locally recurrent prostate cancer after definitive treatment. The objective of this study is to summarize the efficacy and toxicity of HDR-BT in these patients. We performed asystematic review of PubMed and EMBASE from inception to July 2023. The primary endpoint was relapse-free survival (RFS) in different subgroups, and the secondary endpoint was gastrointestinal (GI) and genitourinary (GU) toxicity. Asemi-automated tool (WebPlotDigitizer) and anew Shiny application combined with Rsoftware (R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria; https://www.R-project.org/ ) helped to reconstruct survival curves. Twenty-six studies met the inclusion criteria for quantitative analysis, including 1447 patients. Atotal of 761 patients from 13studies were included in survival reconstruction, and the median RFS time was 61.2 months (57.6-72.0months). The estimated 2‑, 3‑, and 5‑year rates were 75.9% (95% confidence interval [CI] 72.8 ~ 79.2%), 66.7% (95% CI 63.0 ~ 70.5%), and 52.3% (95% CI 47.5 ~ 57.4%), respectively. Whole-gland irradiation with multiple fractions (≥ 2F) resulted in better RFS compared with focal gland irradiation with fewer fractions (1F mostly; hazard ratio [HR]: 0.60, 95% CI 0.47-0.77, p < 0.0001). According to the different median time from primary treatment to salvage therapy (TRS) and median age at recurrence, short median TRS (56-67.2 months vs. 70-120 months; HR 0.52, 95% CI 0.68-0.40; p < 0.0001) and younger median age (60-70years vs. 71-75years; HR 0.58, 95% CI 0.46-0.74; p < 0.0001) were positive factors for RFS. The cumulative incidences estimated for grade ≥ 3 acute and late GU toxicities were 1% (95% CI 0 ~ 1%) and 5% (95% CI 4 ~ 7%), respectively. Three patients (3/992) experienced grade ≥ 3 late GI toxicity, and no cases of grade ≥ 3 acute GI toxicity were reported. HDR-BT has ahigh safety profile and good RFS benefit for salvage treatment of radiorecurrent prostate cancer. In terms of RFS, whole-gland irradiation with multiple fractions seems to be better than focal gland irradiation with fewer fractions, while short TRS and younger age are good prognostic factors. In view of the low level of evidence in the included studies and the large heterogeneity of each study, these conclusions still need to be confirmed by randomized controlled trials.

Long-term outcomes for patients with radiorecurrent prostate cancer treated with salvage combination IMRT and brachytherapy.

Long-term outcomes for patients with radiorecurrent prostate cancer treated with salvage combination IMRT and brachytherapy.

A Phase 1 Trial of Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer After Brachytherapy

NCT03253744 is a phase 1 trial with the primary objective to identify the maximum tolerated dose (MTD) of salvage stereotactic body radiation therapy (SBRT) in patients with local prostate cancer recurrence after brachytherapy. Additional objectives included biochemical control and imaging response. This trial was initially designed to test 3 therapeutic dose levels (DLs): 40 Gy (DL1), 42.5 Gy (DL2), and 45 Gy (DL3) in 5 fractions. Intensity modulation was used to deliver the prescription dose to the magnetic resonance imaging and prostate-specific membrane antigen-based positron emission tomography imaging-defined gross tumor volume while simultaneously delivering 30 Gy to an elective volume defined by the prostate gland. This phase 1 trial followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities were scored until trial completion at 2 years post-SBRT using Common Terminology Criteria for Adverse Events version 5.0. Escalation was halted if 2 dose limiting toxicities occurred, defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT or any grade ≥3 genitourinary (GU) or grade 4 gastrointestinal toxicity thereafter. Between August 2018 and January 2023, 9 patients underwent salvage SBRT and were observed for a median of 22 months (Q1-Q3, 20-43 months). No grade 3 to 5 adverse events related to study treatment were observed; thus, no dose limiting toxicities occurred during the observation period. Escalation was halted by amendment given excellent biochemical control in DL1 and DL2 in the setting of a high incidence of clinically significant late grade 2 GU toxicity. Therefore, the MTD was considered 42.5 Gy in 5 fractions (DL2). One- and 2-year biochemical progression-free survival were 100% and 86%, representing a single patient in the trial cohort with biochemical failure (prostate-specific antigen [PSA] nadir + 2.0) at 20 months posttreatment. The MTD of salvage SBRT for the treatment of intraprostatic radiorecurrence after brachytherapy was 42.5 Gy in 5 fractions producing an 86% 2-year biochemical progression-free survival rate, with 1 poststudy failure at 20 months. The most frequent clinically significant toxicity was late grade 2 GU toxicity.

Abstract A025: Combination of anti-CTLA4 and radiation induce synergistic tumor control in radiorecurrent prostate cancer

Abstract Background: Advanced prostate cancer (PCa) is a leading cause in cancer death and can elicit significant morbidity and mortality. A common treatment modality for advanced PCa is radiation therapy (RT). Currently, salvage of local disease recurrence after RT is a major clinical problem. Emerging evidence indicates the importance of the immune system in governing RT response. In support of this, immune checkpoint inhibitors (ICIs), which enhance immune activation, have demonstrated clinical therapeutic promise in combination with RT in certain advanced cancers. Irradiation (IR) combined with ICIs may prime the immune system to recognize and target recurrent cancer. Purpose: Investigate the therapeutic efficacy of ICIs in combination with RT for radiorecurrent PCa in a syngeneic pre-clinical model. Methods: TRAMP-C2 cells were treated with 10 Gy of radiation over 5 fractions (similar to clinical hypofractionated (HF) schedule) to generate TRAMP-C2 HF cells. Immune-competent mice were transplanted subcutaneously with TRAMP-C2 HF cells. Once tumors reached palpable size, mice were administered either ICIs (αPDL1 or αCTLA4) alone or in combination with RT. Tumor volume was monitored to determine the treatment effect. Correlative studies on excised tumors and secondary lymphoid organs included flow cytometry and NanoString gene expression panel to evaluate immunological mechanisms that contribute to anti-tumor effects[SL1]. Results: TRAMP-C2 HF cells were validated for radiation resistance and exhibited a more aggressive phenotype (reduction in senescence, increase in clonogenicity) similar to clinically recurrent PCa. Radiation resistance of TRAMP-C2 HF tumors was validated in vivo. Administration of αPDL1 and αCTLA4 as monotherapy or in combination did not achieve significant tumor growth delay compared to control. IR alone produced an observable tumor growth delay compared to ICIs alone. The combination of αPDL1 and IR did not yield additional growth delay compared to IR alone. Strikingly, significant tumor growth delay was seen with the combination of IR and αCTLA4 compared to IR alone, while also resulting in complete cure in a third of the mice. NanoString analysis of lymph nodes from mice treated with αCTLA4 and IR vs. IR alone demonstrated differential expression of genes regulating CD molecules, interleukins, and T-cell functions. Furthermore, enrichment of CD45 and CD8a RNA following αCTLA4 and IR was observed. Validation by flow cytometry is currently ongoing. Conclusion: We generated the first syngeneic radiorecurrent PCa model and demonstrated that combining αCTLA4 and IR results in synergistic tumor response. Combined therapy resulted in augmented immune response, most notably enhancement of CD8 T cell activity. Significance: These findings contribute to our understanding of immunological events associated with RT and ICIs in the context of radiorecurrent PCa and support new avenues for salvage therapy in clinical trials. Citation Format: Hanzhi Wang, Xiaoyong Huang, Stepahnie D White, Linsey Gong, Tera N Petchiny, Hans Chung, Emmanouil Fokas, Robert S Kerbel, Stanley K Liu. Combination of anti-CTLA4 and radiation induce synergistic tumor control in radiorecurrent prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A025.

Comparison of salvage radical prostatectomy vs. salvage ablation therapy for biopsy-proven radio-recurrent localized prostate cancer.

Radiation therapy for prostate cancer is associated with a 15-20% five-year recurrence rate. Patients with recurrence in the prostate only are candidates for salvage local therapies; however, there is no consensus on modality. This study uses registries at Memorial Sloan Kettering Cancer Center (MSKCC) and University of Western Ontario (UWO) to compare the oncologic outcomes of salvage radical prostatectomy (SRP) and salvage ablation (SA). A total of 444 patients were available for analysis. Due to intergroup differences, propensity score methodology was used and identified 378 patients with more comparable pre-salvage prostate-specific antigen (PSA), Gleason score, and primary radiation treatment. Patients underwent SRP at MSKCC and SA at UWO. Of the 378 patients, 48 died of disease, with a 6.0-year median (interquartile range [IQR] 3.0, 9.7) followup among survivors; 88 developed metastases, with a median 4.6-year (IQR 2.3, 7.9) followup among metastasis-free survivors. There was a non-significantly higher rate of cancer-specific (hazard ratio [HR ] 1.02, 95% confidence interval [CI] 0.51, 2.06, p=0.9) and improved metastasis-free survival (HR 0.71, 95% CI 0.44, 1.13, p=0.15) among patients undergoing SA compared to patients undergoing SRP. There were 143 patients who received hormonal therapy, with higher rates of androgen deprivation therapy (ADT) in SA (HR 1.42, 95% CI 0.97, 2.08, p=0.068), although this did not meet conventional levels of significance. This propensity score analysis of salvage therapy for radio-recurrent prostate cancer identified no statistically significant differences in oncologic outcome between SRP and SA; however, there was evidence of a lower risk of ADT in the cohort undergoing SRP. Given they are both potentially curative therapies, these treatments are viable options for men with clinically localized, radio-recurrent prostate cancer rather than ADT alone. Future research may further elucidate subpopulations that may be more amenable to either SRP or SA.

Genomic Characterization of Locally Recurrent Prostate Cancer after Radiation Therapy.

Radiation therapy (RT) is a backbone of treatment for patients with prostate cancer (PCa). However, locally recurrent disease after definitive RT (i.e., radiorecurrent PCa) is not uncommon and is associated with a higher risk of distant metastases and death from PCa. While the genomic landscape of primary PCa is well-characterized, little is known regarding the genomic landscape of radiorecurrent PCa or how this compares to that of primary PCa. We hypothesized that the genomic landscape of radiorecurrent PCa differs significantly from primary PCa and that these differences have clinical relevance. We examined this hypothesis by performing whole exome sequencing (WES) of radiorecurrent PCa. We identified 25 patients with radiorecurrent PCa with available post-RT tissue obtained from biopsy or radical prostatectomy, as well as germline tissue. The tumor and germline tissue for 19 patients successfully underwent WES. We identified genomic variants including single nucleotide variants (SNVs), insertions/deletions, and copy number alterations. Furthermore, we estimated the tumor mutational burden (TMB; number of nonsynonymous mutations per megabase [Mb]) and contribution of individual mutational signatures. We compared our samples to a publicly available large cohort of primary PCa (n = 680) to define genomic alterations unique to radiorecurrent PCa. In the overall cohort of 25 patients, the RT modality included external beam RT (56%), brachytherapy (36%), and combination of both (8%). 40% of patients received upfront androgen deprivation therapy with RT. The median time to local recurrence was 6.5 years. For the 19 radiorecurrent patients with WES data, the median TMB was 2.7 mutations/Mb, which was significantly higher than the median TMB of 0.7 mutation/Mb for primary PCa (P = 0.002 after multivariable adjustment). Radiorecurrent PCa demonstrated an enrichment of short deletions, with a significantly higher deletion/SNV ratio compared to primary PCa (P = 0.006). TP53 was the most frequently mutated gene in radiorecurrent PCa (n = 6), and the TP53 mutation prevalence was significantly higher compared to primary PCa (32% vs 10%, P = 0.016 by Fisher's exact test). TP53 was also determined to be recurrently mutated using MutSigCV (Q = 0.0003). Additionally, 3 samples demonstrated evidence of whole genome doubling. Radiorecurrent PCa has a distinct genomic profile compared to primary PCa, characterized by a higher TMB with an enrichment of short deletions as part of the mutational composition, which may be a scar of nonhomologous end joining subsequent to RT-induced DNA double-stranded breaks. In addition, TP53 mutations may be of functional consequence in radiorecurrent PCa. Further efforts are underway to examine other genomic features apparent in WES data, as well as perform whole transcriptome sequencing to provide complementary insights into radiorecurrent PCa.

The Importance of Multi-Parametric MRI, PET/CT, and Biopsy for Identifying and Delineating the Extent of Locally Radiorecurrent Prostate Cancer: A Multi-institutional Analysis of the F-SHARP Clinical Trial.

Up to 50% of clinical recurrences after curative-intent radiation are intraprostatic local radiorecurrences (LRR), with improved detection through the recent incorporation of multi-parametric MRI and PET/CT in workup. Salvage local therapy (SLT) is increasingly being offered, particularly focal SLT to try to reduce toxicity due to prior radiation. Limited data exist on the incremental value of each imaging modality and biopsy in defining LRR. The objective of this study is to compare the findings of MRI, PET/CT and biopsy in patients with LRR prostate cancer, and the impact each modality has on identifying recurrence and defining the extent of prostate involvement. This is a secondary analysis of 58 patients enrolled on the ongoing F-SHARP phase I/II clinical trial of salvage HDR brachytherapy from 3 institutions who underwent PSMA or fluciclovine PET/CT, MRI, and biopsy prior to enrollment. Recurrent tumor was delineated on each imaging modality and by inclusion of involved regions on biopsy. Descriptive statistics were used to compare the imaging-defined tumor with biopsy findings to assess the congruence between the imaging modalities and generate the percentage of patients with disease involvement on biopsy outside of the image-defined targets. Initial therapy was conventional/moderately hypofractionated photons in 35 patients, LDR in 13, proton therapy in 7, SBRT in 2, and neutrons in 1. Recurrence Gleason grade groups included 1 (n = 3), 2 (17), 3 (12), 4 (8), 5 (9), and uninterpretable (9). MRI/TRUS sextant + fusion biopsy was performed in 40 patients, TRUS saturation biopsy in 4, and TRUS systematic biopsy in 14. The median number of cores involved and obtained were 6 and 14. The median number of discrete lesions on biopsy in different quadrants of the prostate was 3 (1-6). The median number of discrete lesions seen on MRI was 1 (0-4). MRI did not identity a discrete lesion in 4 patients. The sensitivity of MRI for detection of the LRR was 92.8%. The false negative rate for not detecting the focus of LRR on MRI was 7.2%. 68.4% of patients had biopsy-proven cancer outside of the MRI-defined target. Fluciclovine PET/CT was used in 45 patients, and 13 had PSMA PET/CT. The median number of lesions on PET/CT was 1 (0-2). PET/CT did not identify a discrete lesion in 8 patients. The pooled sensitivity of PET/CT in detecting the focus of LRR was 86.2% (Fluciclovine: 82.2%, PSMA: 100%). PET/CT false negative rate of PET/CT for not detecting the focus of LRR was 13.8% (Fluciclovine: 17.8%, PSMA 0%). 72.41% of patients had biopsy-proven cancer outside of the PET/CT-defined target (Fluciclovine: 77.8%, PSMA: 53.8%). Although mpMRI and PET/CT are valuable tools for identifying LRR and delineating the extent of prostate/SV involvement, a thorough biopsy is mandatory if pursuing focal SLT. Such treatment should optimally be performed on a clinical trial with robust integration of all imaging and histopathologic data.

A Phase I Trial of Focal Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer.

Locally recurrent prostate cancer after radiotherapy (RT) is an increasingly recognized entity with no standard management. NCT03253744 was a phase I trial with a primary objective of identifying the maximally tolerated dose (MTD) of a course of image-guided, focal, salvage stereotactic body radiotherapy (SBRT) for patients with local recurrence after prior definitive RT. Additional objectives included biochemical control and imaging response on mpMRI and 18F-DCFPyL (PSMA) PET/CT. SBRT was prescribed to three dose levels (DLs): 40Gy (DL1), 42.5Gy (DL2), and 45Gy (DL3) in 5 fractions. The prescription dose was delivered to a PTV defined by mpMRI and PSMA imaging and biopsy confirmed tumor volume. Dose escalation followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities above baseline were scored using CTCAE v5.0 criteria for two years after completion of SBRT. Escalation was halted if 2 dose limiting toxicities (DLTs) were observed. DLTs were defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT, and any grade 3 GU or grade 4 GI toxicity thereafter. Imaging response was compared between baseline and 6-months by the Wilcoxon signed rank test. Between 08/2018 and 05/2022, 8 patients underwent salvage SBRT to 11 intraprostatic lesions with a median follow-up of 27 months. No DLTs were observed on DL1. Two patients were enrolled on DL2 and both experienced grade 3 GU toxicities, prompting de-escalation and expansion (n = 6) on DL1, the MTD. The most common toxicities were grade 2 GU toxicities: acute urinary urgency/frequency, acute weak urinary stream, and noninfective cystitis. One patient at DL1 had a self-limited episode of grade 2 GI toxicity (proctitis). No grade 3 GI toxicities were observed. All but two patients achieved an undetectable PSA nadir. Only one of these experienced biochemical failure (nadir + 2.0) at 33 months with suspicion of distant metastatic failure on restaging PET/CT. Imaging response was demonstrated by MRI in all lesions with heterogeneity in volumetric response (6% to 100%). A significant (p<0.01) response on PSMA PET/CT was observed for all measured parameters (SUVMax, SUVMean, GTVPSMA, Total Lesion PSMA [SUVMean × GTVPSMA]). Of the 11 lesions, 1 (9%) demonstrated a complete response (CR) by MRI and 9 (82%) by PSMA PET/CT. A single lesion increased in volume by 0.06 cc (16%) at 6-month PSMA PET/CT compared to baseline in the only patient who did not achieve an undetectable PSA nadir and did not have imaging suggestive of distant failure. On this phase I dose escalation study of salvage SBRT for isolated intraprostatic local failure after definitive RT, the MTD was 40Gy in 5 fractions. producing a 100% 24-month bPFS, with one late failure at 33 months occurring after the 24-month study period. The most frequent clinically significant toxicity was late grade 2 GU toxicity. Imaging response was demonstrated in all lesions on MRI and PSMA PET/CT with exception of a single lesion.

The Role of Multiparametric MRI and MRI–targeted Biopsy in the Diagnosis of Radiorecurrent Prostate Cancer: An Analysis from the FORECAST Trial

BackgroundThe role of multiparametric magnetic resonance imaging (MRI) for detecting recurrent prostate cancer after radiotherapy is unclear. ObjectiveTo evaluate MRI and MRI-targeted biopsies for detecting intraprostatic cancer recurrence and planning for salvage focal ablation. Design, setting, and participantsFOcal RECurrent Assessment and Salvage Treatment (FORECAST; NCT01883128) was a prospective cohort diagnostic study that recruited 181 patients with suspected radiorecurrence at six UK centres (2014 to 2018); 144 were included here. InterventionAll patients underwent MRI with 5 mm transperineal template mapping biopsies; 84 had additional MRI-targeted biopsies. MRI scans with Likert scores of 3 to 5 were deemed suspicious. Outcome measurements and statistical analysisFirst, the diagnostic accuracy of MRI was calculated. Second, the pathological characteristics of MRI-detected and MRI-undetected tumours were compared using the Wilcoxon rank sum test and chi-square test for trend. Third, four biopsy strategies involving an MRI-targeted biopsy alone and with systematic biopsies of one to two other quadrants were studied. Fisher’s exact test was used to compare MRI-targeted biopsy alone with the best other strategy for the number of patients with missed cancer and the number of patients with cancer harbouring additional tumours in unsampled quadrants. Analyses focused primarily on detecting cancer of any grade or length. Last, eligibility for focal therapy was evaluated for men with localised (≤T3bN0M0) radiorecurrent disease. Results and limitationsOf 144 patients, 111 (77%) had cancer detected on biopsy. MRI sensitivity and specificity at the patient level were 0.95 (95% confidence interval [CI] 0.92 to 0.99) and 0.21 (95% CI 0.07 to 0.35), respectively. At the prostate quadrant level, 258/576 (45%) quadrants had cancer detected on biopsy. Sensitivity and specificity were 0.66 (95% CI 0.59 to 0.73) and 0.54 (95% CI 0.46 to 0.62), respectively. At the quadrant level, compared with MRI-undetected tumours, MRI-detected tumours had longer maximum cancer core length (median difference 3 mm [7 vs 4 mm]; 95% CI 1 to 4 mm, p < 0.001) and a higher grade group (p = 0.002). Of the 84 men who also underwent an MRI-targeted biopsy, 73 (87%) had recurrent cancer diagnosed. Performing an MRI-targeted biopsy alone missed cancer in 5/73 patients (7%; 95% CI 3 to 15%); with additional systematic sampling of the other ipsilateral and contralateral posterior quadrants (strategy 4), 2/73 patients (3%; 95% CI 0 to 10%) would have had cancer missed (difference 4%; 95% CI –3 to 11%, p = 0.4). If an MRI-targeted biopsy alone was performed, 43/73 (59%; 95% CI 47 to 69%) patients with cancer would have harboured undetected additional tumours in unsampled quadrants. This reduced but only to 7/73 patients (10%; 95% CI 4 to 19%) with strategy 4 (difference 49%; 95% CI 36 to 62%, p < 0.0001). Of 73 patients, 43 (59%; 95% CI 47 to 69%) had localised radiorecurrent cancer suitable for a form of focal ablation. ConclusionsFor patients with recurrent prostate cancer after radiotherapy, MRI and MRI-targeted biopsy, with or without perilesional sampling, will diagnose cancer in the majority where present. MRI-undetected cancers, defined as Likert scores of 1 to 2, were found to be smaller and of lower grade. However, if salvage focal ablation is planned, an MRI-targeted biopsy alone is insufficient for prostate mapping; approximately three of five patients with recurrent cancer found on an MRI-targeted biopsy alone harboured further tumours in unsampled quadrants. Systematic sampling of the whole gland should be considered in addition to an MRI-targeted biopsy to capture both MRI-detected and MRI-undetected disease. Patient summaryAfter radiotherapy, magnetic resonance imaging (MRI) is accurate for detecting recurrent prostate cancer, with missed cancer being smaller and of lower grade. Targeting a biopsy to suspicious areas on MRI results in a diagnosis of cancer in most patients. However, for every five men who have recurrent cancer, this targeted approach would miss cancers elsewhere in the prostate in three of these men. If further focal treatment of the prostate is planned, random biopsies covering the whole prostate in addition to targeted biopsies should be considered so that tumours are not missed.

A Canadian center's experience on whole-gland salvage therapy for radio-recurrent prostate cancer with various modalities.

Salvage radical prostatectomy for localized radio-recurrent prostate cancer has historically been associated with significant morbidity. Prospectively collected data long-term data on salvage whole-gland cryoablation and, to a lesser extent, high-intensity focused ultrasound (HIFU), have shown they are viable treatment alternatives. This article chronicles the experience (cryoablation, n=187; HIFU, n=81) in a high-volume Canadian center and reviews the literature on other salvage ablative therapies. Whole-gland salvage ablation has yielded oncologic results comparable to those of salvage prostatectomy, with cancer-specific survival and metastatic-free survival of approximately 80%, and biochemical disease-free survival of 35%. Freedom from androgen deprivation therapy was 49% at 12 years. Improved ablative technologies and functional diagnostic imaging modalities have rendered focal salvage ablation feasible in selected patients. Preliminary oncologic and functional results of focal salvage ablation using several new ablative technologies are also reviewed in this article.

A Phase 1 Trial of Focal Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer

NCT03253744 was a phase 1 trial to identify the maximum tolerated dose (MTD) of image-guided, focal, salvage stereotactic body radiation therapy (SBRT) for patients with locally radiorecurrent prostate cancer. Additional objectives included biochemical control and imaging response. The trial design included 3 dose levels (DLs): 40 Gy (DL1), 42.5 Gy (DL2), and 45 Gy (DL3) in 5 fractions delivered ≥48 hours apart. The prescription dose was delivered to the magnetic resonance- and prostate-specific membrane antigen imaging-defined tumor volume. Dose escalation followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities were scored until 2 years after completion of SBRT using Common Terminology Criteria for Adverse Events, version 5.0, criteria. Escalation was halted if 2 dose-limiting toxicities occurred, defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT and any grade 3 genitourinary (GU) or grade 4 gastrointestinal (GI) toxicity thereafter. Between August 2018 and May 2022, 8 patients underwent salvage focal SBRT, with a median follow-up of 35 months. No dose-limiting toxic effects were observed on DL1. Two patients were enrolled in DL2 and experienced grade 3 GU toxicities, prompting de-escalation and expansion (n=6) at the MTD (DL1). The most common toxicities observed were grade ≥2 GU toxicities, with only a single grade 2 GI toxicity and no grade ≥3 GI toxicities. One patient experienced biochemical failure (prostate-specific antigen nadir+2.0) at 33 months. The MTD for focal salvage SBRT for isolated intraprostatic radiorecurrence was 40 Gy in 5 fractions, producing a 100% 24-month biochemical progression free survival, with 1 poststudy failure at 33 months. The most frequent clinically significant toxicity was late grade ≥2 GU toxicity.

External validation of a risk model predicting failure of salvage focal ablation for prostate cancer.

To externally validate a published model predicting failure within 2 years after salvage focal ablation in men with localised radiorecurrent prostate cancer using a prospective, UK multicentre dataset. Patients with biopsy-confirmed ≤T3bN0M0 cancer after previous external beam radiotherapy or brachytherapy were included from the FOcal RECurrent Assessment and Salvage Treatment (FORECAST) trial (NCT01883128; 2014-2018; six centres), and from the high-intensity focussed ultrasound (HIFU) Evaluation and Assessment of Treatment (HEAT) and International Cryotherapy Evaluation (ICE) UK-based registries (2006-2022; nine centres). Eligible patients underwent either salvage focal HIFU or cryotherapy, with the choice based predominantly on anatomical factors. Per the original multivariable Cox regression model, the predicted outcome was a composite failure outcome. Model performance was assessed at 2 years post-salvage with discrimination (concordance index [C-index]), calibration (calibration curve and slope), and decision curve analysis. For the latter, two clinically-reasonable risk threshold ranges of 0.14-0.52 and 0.26-0.36 were considered, corresponding to previously published pooled 2-year recurrence-free survival rates for salvage local treatments. A total of 168 patients were included, of whom 84/168 (50%) experienced the primary outcome in all follow-ups, and 72/168 (43%) within 2 years. The C-index was 0.65 (95% confidence interval 0.58-0.71). On graphical inspection, there was close agreement between predicted and observed failure. The calibration slope was 1.01. In decision curve analysis, there was incremental net benefit vs a 'treat all' strategy at risk thresholds of ≥0.23. The net benefit was therefore higher across the majority of the 0.14-0.52 risk threshold range, and all of the 0.26-0.36 range. In external validation using prospective, multicentre data, this model demonstrated modest discrimination but good calibration and clinical utility for predicting failure of salvage focal ablation within 2 years. This model could be reasonably used to improve selection of appropriate treatment candidates for salvage focal ablation, and its use should be considered when discussing salvage options with patients. Further validation in larger, international cohorts with longer follow-up is recommended.

Genomic characterization of locally recurrent prostate cancer after radiation therapy.

e17002 Background: Radiation therapy (RT) is a backbone of treatment for patients with prostate cancer (PCa). However, locally recurrent disease after definitive RT (i.e. radiorecurrent PCa) is not uncommon and is associated with a higher risk of distant metastases and death from PCa. While the genomic landscape of primary PCa is well-characterized, little is known regarding the genomic landscape of radiorecurrent PCa or how this compares to that of primary PCa. We hypothesized that the genomic landscape of radiorecurrent PCa differs significantly from primary PCa and that these differences have clinical relevance. We examined this hypothesis by performing whole exome sequencing (WES) of radiorecurrent PCa. Methods: We identified 25 patients with radiorecurrent PCa with available post-RT tissue obtained from biopsy or radical prostatectomy, as well as germline tissue. The tumor and germline tissue for 19 patients successfully underwent WES. We identified genomic variants including single nucleotide variants (SNVs), insertions/deletions, and copy number alterations. Furthermore, we estimated the tumor mutational burden (TMB; number of nonsynonymous mutations per megabase [Mb]) and contribution of individual mutational signatures. We compared our samples to a publicly available large cohort of primary PCa (n = 680) to define genomic alterations unique to radiorecurrent PCa. Results: In the overall cohort of 25 patients, the RT modality included external beam RT (56%), brachytherapy (36%), and combination of both (8%). 40% of patients received upfront androgen deprivation therapy with RT. The median time to local recurrence was 6.5 years. For the 19 radiorecurrent patients with WES data, the median TMB was 2.7 mutations/Mb, which was significantly higher than the median TMB of 0.7 mutation/Mb for primary PCa ( P= 0.002 after multivariable adjustment). Radiorecurrent PCa demonstrated an enrichment of short deletions, with a significantly higher deletion/SNV ratio compared to primary PCa ( P= 0.006). TP53 was the most frequently mutated gene in radiorecurrent PCa (n = 6), and the TP53 mutation prevalence was significantly higher compared to primary PCa (32% vs 10%, P= 0.016 by Fisher’s exact test). TP53 was also determined to be recurrently mutated using MutSigCV (Q = 0.0003). Additionally, 3 samples demonstrated evidence of whole genome doubling. Conclusions: Radiorecurrent PCa has a distinct genomic profile compared to primary PCa, characterized by a higher TMB with an enrichment of short deletions as part of the mutational composition, which may be a scar of nonhomologous end joining subsequent to RT-induced DNA double-stranded breaks. In addition, TP53 mutations may be of functional consequence in radiorecurrent PCa. Further efforts are underway to examine other genomic features apparent in WES data, as well as perform whole transcriptome sequencing to provide complementary insights into radiorecurrent PCa.

Local salvage of radiorecurrent prostate cancer.

Locally recurrent prostate cancer following primary external beam radiotherapy without distant metastasis is a challenging problem, with no current consensus on the optimal management of these patients. Traditional whole-gland salvage treatments offered up to a 50% 5-year disease-free survival rate but with troubling levels of risk for significant complications. Recent progress in advanced imaging techniques has allowed a more accurate selection of patients with local-only recurrence and a selection of patients that may be suitable for newer partial-gland salvage treatments that may reduce late complications. This article reviews advances in patient selection and provides an overview of whole- and partial-gland salvage results from selected recent meta-analyses, multi-institutional series, and studies from centers of excellence for these treatment approaches. Salvage radical prostatectomy produces 5-year relapse-free survival (RFS) rates in the 50%-60% range with severe gastrointestinal (GI) toxicity in < 2% but severe genitourinary (GU) toxicity in 15%-23% of patients. The whole-gland options of high and low dose rate brachytherapy and stereotactic body radiation therapy appear to offer similar 5-year control rates, with low severe GU and GI toxicity rates of 4%-8% and <2%, respectively. Cryotherapy and high-intensity focused ultrasound (HIFU) offer similar 5-year RFS rates but carry significant risks for severe GU and GI toxicity in the range of 10%-27% and <2%, respectively. Early results of partial-gland salvage techniques in selected patients appear promising, with 3-year RFS rates of 48%-72% and rare grade 3 toxicity. It is important to understand the relative effectiveness and risks of the various treatment options to effectively counsel patients who face this distressing clinical situation. Whole-gland salvage options offer the possibility of long-term control but with significant risks of severe toxicity. Emerging data for the partial-gland salvage options in appropriately selected patients may offer hope of reasonable control rates with reduced severe toxicity.

Salvage prostate brachytherapy in radiorecurrent prostate cancer: An international Delphi consensus study

Background and PurposeLocal recurrences after previous radiotherapy (RT) are increasingly being identified in biochemically recurrent prostate cancer. Salvage prostate brachytherapy (BT) is an effective and well tolerated treatment option. We sought to generate international consensus statements on the use and preferred technical considerations for salvage prostate BT. Materials and MethodsInternational experts in salvage prostate BT were invited (n = 34) to participate. A three-round modified Delphi technique was utilized, with questions focused on patient- and cancer-specific criteria, type and technique of BT, and follow-up. An a priori threshold for consensus of ≥ 75% was set, with a majority opinion being ≥ 50%. ResultsThirty international experts agreed to participate. Consensus was achieved for 56% (18/32) of statements. Consensus was achieved in several areas of patient selection: 1) A minimum of 2–3 years from initial RT to salvage BT; 2) MRI and PSMA PET should be obtained; and 3) Both targeted and systematic biopsies should be performed. Several areas did not reach consensus: 1) Maximum T stage/PSA at time of salvage; 2) Utilization/duration of ADT; 3) Appropriateness of combining local salvage with SABR for oligometastatic disease and 4) Repeating a second course of salvage BT. A majority opinion preferred High Dose-Rate salvage BT, and indicated that both focal and whole gland techniques could be appropriate. There was no single preferred dose/fractionation. ConclusionAreas of consensus within our Delphi study may serve as practical advice for salvage prostate BT. Future research in salvage BT should address areas of controversy identified in our study.

MP44-06 TUMOR CHARACTERISTICS OF MULTIPARAMETRIC MRI-DETECTED AND -UNDETECTED LESIONS IN PATIENTS WITH SUSPECTED RADIORECURRENT PROSTATE CANCER: AN ANALYSIS FROM THE FOCAL RECURRENT ASSESSMENT AND SALVAGE TREATMENT (FORECAST) TRIAL

MP44-06 TUMOR CHARACTERISTICS OF MULTIPARAMETRIC MRI-DETECTED AND -UNDETECTED LESIONS IN PATIENTS WITH SUSPECTED RADIORECURRENT PROSTATE CANCER: AN ANALYSIS FROM THE FOCAL RECURRENT ASSESSMENT AND SALVAGE TREATMENT (FORECAST) TRIAL

MP73-04 EXTERNAL VALIDATION OF A RISK SCORE PREDICTING FAILURE AFTER SALVAGE FOCAL THERAPY FOR LOCALIZED RADIORECURRENT PROSTATE CANCER: AN ANALYSIS FROM THE FOCAL RECURRENT ASSESSMENT AND SALVAGE TREATMENT (FORECAST) TRIAL

MP73-04 EXTERNAL VALIDATION OF A RISK SCORE PREDICTING FAILURE AFTER SALVAGE FOCAL THERAPY FOR LOCALIZED RADIORECURRENT PROSTATE CANCER: AN ANALYSIS FROM THE FOCAL RECURRENT ASSESSMENT AND SALVAGE TREATMENT (FORECAST) TRIAL