High-risk Localized Prostate Cancer Research Articles

Proton therapy for high-risk prostate cancer: Results from the Proton Collaborative Group PCG 001-09 prospective registry trial.

Data for proton therapy in high-risk prostate cancer (HRPC) are limited. Using the Proton Collaborative Group prospective registry, we evaluated outcomes for HRPC patients treated with proton therapy. A totsl of 605 men with localized HRPC treated with proton therapy from 8/2009 to 3/2019 at nine institutions were selected. Outcomes examined included freedom from progression (FFP), metastasis free survival (MFS), overall survival (OS), and toxicity. Multivariable cox/binomial regression models were used to assess predictors of FFP and toxicity. Median age was 71 years. Gleason grade groups 4 (49.4%) and 5 (31.7%) were most common, as were clinical stage T1c (46.1%) and cT2 (41.3%). The median pretreatment prostate specific antigen (PSA) was 9.18 and median International Prostate Symptom Score (IPSS) was 6. Androgen deprivation therapy was given in 63.6%. Median dose was 79.2 GyE in 44 fractions. Pelvic lymph nodes were treated in 58.2% of cases. Pencil beam scanning was used in 54.5%, uniform scanning in 38.8%, and a rectal spacer in 14.2%. At a median followup of 22 months, the 3- and 5-year FFP were 90.7% and 81.4%, respectively. Five-year MFS and OS were 92.8% and 95.9%, respectively. Independent correlates of FFP included Gleason ≥8, PSA > 10, and cT2 (all p < 0.05). No grade 4 or 5 adverse events were reported. There were 23 (5%) grade 2 and 0 grade 3 gastrointestinal events. Prevalence of late grade 3, late grade 2, acute grade 3, and acute grade 2 genitourinary toxicity was 1.7%, 5.8%, 0%, and 21.8%, respectively. Prevalence of grade 2 and 3 erectile dysfunction at 2 years was 48.4% and 8.4%, respectively. In the largest series published to date, our results suggest early outcomes using proton therapy for HRPC are encouraging for both safety and efficacy. Further evaluation is needed to determine if an advantage exists to use protons over other radiation techniques in this population.

A Randomized Feasibility Trial of Stereotactic Prostate Radiation Therapy With or Without Elective Nodal Irradiation in High-Risk Localized Prostate Cancer (SPORT Trial)

To establish the feasibility of a randomised clinical trial comparing stereotactic ablative radiotherapy (SABR) to the prostate-only (P-SABR) or to prostate plus pelvic lymph nodes (PPN-SABR) in patients with unfavourable intermediate- or high-risk localised prostate cancer and explore potential toxicity biomarkers. Thirty adult men with at least one of the following features; clinical MRI stage T3a N0 M0, Gleason score ≥ 7 (4+3), PSA > 20 ng/mL were randomised 1:1 to P-SABR or PPN-SABR. P-SABR patients received 36.25Gy/5 fractions/29 days, PPN-SABR patients also received 25Gy/5 fractions to pelvic nodes with the final cohort receiving a boost to the dominant intraprostatic lesion of 45-50 Gy. γH2AX foci numbers, citrulline levels and circulating lymphocyte counts were quantified. Acute toxicity information (CTCAE v4.03) was collected weekly at each treatment and at six weeks and three months. Physician-reported late RTOG toxicity was recorded from 90 days to 36 months post-completion of SABR. Patient-reported quality of life (EPIC and IPSS) scores were recorded with each toxicity timepoint. The target recruitment was achieved and treatment successfully delivered in all patients.0% and 6.7% (P-SABR) and 6.7% and 20.0% (PPN-SABR) experienced acute grade ≥ 2 gastrointestinal (GI) and genitourinary (GU) toxicity respectively. At 3 years, 6.7% and 6.7% (P-SABR) and 13.3% and 33.3% (PPN-SABR) had experienced late grade ≥ 2 GI and GU toxicity respectively. One patient (PPN-SABR) had late grade 3 GU toxicity (cystitis and haematuria), no other grade ≥ 3 toxicity was observed. 33.3% and 60% (P-SABR) and 64.3% and 92.9% (PPN-SABR) experienced a minimally clinically important change (MCIC) in late EPIC bowel and urinary summary scores respectively. γH2AX foci numbers at 1 hour post-first fraction were significantly higher in PPN-SABR arm compared to P-SABR arm (p=0.04). Patients with late grade ≥ 1 GI toxicity had significantly larger falls in circulating lymphocytes (12 weeks post-radiotherapy, p=0.01), and a trend towards higher γH2AX foci numbers (p=0.09), than patients with no late toxicity. Patients with late grade ≥ 1 bowel toxicity and late diarrhoea experienced greater falls in citrulline levels (p=0.05). A randomised trial comparing P-SABR to PPN-SABR is feasible with acceptable toxicity. Correlations of γH2AX foci, lymphocyte counts and citrulline levels with irradiated volume and toxicity suggest potential as predictive biomarkers. This study has informed a multicentre UK randomised phase III clinical trial.

Evaluating Germline Testing Panels in Southern African Males With Advanced Prostate Cancer.

Germline testing for prostate cancer is on the increase, with clinical implications for risk assessment, treatment, and management. Regardless of family history, NCCN recommends germline testing for patients with metastatic, regional, very-high-risk localized, and high-risk localized prostate cancer. Although African ancestry is a significant risk factor for aggressive prostate cancer, due to a lack of available data no testing criteria have been established for ethnic minorities. Through deep sequencing, we interrogated the 20 most common germline testing panel genes in 113 Black South African males presenting with largely advanced prostate cancer. Bioinformatic tools were then used to identify the pathogenicity of the variants. After we identified 39 predicted deleterious variants (16 genes), further computational annotation classified 17 variants as potentially oncogenic (12 genes; 17.7% of patients). Rare pathogenic variants included CHEK2 Arg95Ter, BRCA2 Trp31Arg, ATM Arg3047Ter (2 patients), and TP53 Arg282Trp. Notable oncogenic variants of unknown pathogenicity included novel BRCA2 Leu3038Ile in a patient with early-onset disease, whereas patients with FANCA Arg504Cys and RAD51C Arg260Gln reported a family history of prostate cancer. Overall, rare pathogenic and early-onset or familial-associated oncogenic variants were identified in 6.9% (5/72) and 9.2% (8/87) of patients presenting with a Gleason score ≥8 or ≥4 + 3 prostate cancer, respectively. In this first-of-its-kind study of southern African males, we provide support of African inclusion for advanced, early-onset, and familial prostate cancer genetic testing, indicating clinical value for 30% of current gene panels. Recognizing current panel limitations highlights an urgent need to establish testing guidelines for men of African ancestry. We provide a rationale for considering lowering the pathologic diagnostic inclusion criteria and call for further genome-wide interrogation to ensure the best possible African-relevant prostate cancer gene panel.

Comparison of outcomes in high-risk prostate cancer patients treated with low-/high-dose-rate brachytherapy plus external beam radiotherapy.

Although brachytherapy is a standard treatment option for patients with high-risk prostate cancer, only a few studies have compared low-dose-rate brachytherapy (LDR-BT) and high-dose-rate brachytherapy (HDR-BT). We applied propensity score-based inverse probability treatment weighting (IPTW) to compare oncological outcomes for LDR-BT and HDR-BT. We retrospectively assessed prognosis in 392 patients with high-risk localized prostate cancer who had undergone brachytherapy plus external beam radiation. IPTW was applied to adjust the Kaplan-Meier survival analyses and Cox proportional hazards regression analyses, with the goal of minimizing bias from patient background. The IPTW-adjusted Kaplan-Meier survival analyses showed no statistically significant differences for time to biochemical recurrence, clinical progression, castration-resistant prostate cancer, or death from any cause. The IPTW-adjusted Cox regression analyses also showed that the modality of brachytherapy was not an independent factor in these oncological outcomes. Notably, the two groups differed regarding complications; LDR-BT was associated with a higher rate of acute grade ≥ 2 GU toxicity, and late grade 3 toxicity was noted only in HDR-BT. Our analysis of long-term outcomes in patients with high-risk localized prostate cancer shows no significant differences in oncological outcomes between LDR-BT and HDR-BT, but some differences in toxicity, and offers patients and clinicians useful information in deciding management strategies for high-risk localized prostate cancer.

Real-world clinical outcomes of patients with localized prostate cancer (LPC) treated with external beam radiation therapy (EBRT).

330 Background: Patients (pts) with localized prostate cancer (LPC) or locally advanced prostate cancer (PC) have several treatment options, including external beam radiation therapy (EBRT) and radical prostatectomy, which can be curative in some pts. However, limited real-world evidence exists on the long-term clinical outcomes of these pts, particularly those with high-risk LPC (HRLPC). This study examines real-world clinical outcomes for HRLPC and low/intermediate risk LPC (LIRLPC) pts treated with EBRT in the US. Methods: A retrospective study using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked registry-claims data from 2012−2019 included LPC pts aged ≥65 treated with EBRT as initial definitive therapy. Baseline demographic and clinical characteristics were summarized for HRLPC and LIRLPC pts. Clinical outcomes of interest (overall survival, metastasis-free survival [MFS] and time to initiation of advanced PC treatment) were compared using Kaplan-Meier (KM) and Cox proportional hazards (PH) models. Results: Of 11,127 LPC pts treated with EBRT within 6 months of LPC diagnosis, ~40% (n=4,414) were HRLPC and ~60% (N=6,713) were LIRLPC. Patient characteristics for both groups appeared similar, with mean age at EBRT initiation &gt;70 years, 86% white, and mean follow-up time &gt;40 months. ADT was used with EBRT in 78% HRLPC and 34% LIRLPC. Median (IQR) duration of ADT therapy (via KM analysis) was 9.9 (5.8, 21.5) months for HRLPC and 7.2 (5.3, 9.8) months for LIRLPC. A higher proportion of HRLPC vs LIRLPC pts experienced metastasis, death, and progression to advanced PC therapies (medians were not reached). Unadjusted Cox PH survival analyses showed higher risk of mortality, metastasis, and advanced PC therapy use for HRLPC vs LIRLPC pts. Conclusions: This real-world study of clinical outcomes in pts with HRLPC and LIRLPC treated with EBRT suggested substantial additional disease burden in pts with HRLPC and highlights the need for additional strategies and treatments to improve clinical outcomes in pts with HRLPC. [Table: see text]

A randomized phase II trial of neoadjuvant chemokine modulation in patients with localized prostate cancer undergoing radical prostatectomy.

TPS406 Background: Most patients with high or very high risk localized prostate cancer (PCa) experience disease recurrence after radical prostatectomy (RP). Neoadjuvant androgen ablation has not improved high-risk pathological features or recurrence rates after RP.1 We reported the association between high intratumoral CD8+ T lymphocyte (CTL) density and improved survival post-RP, suggesting clinical benefit from neoadjuvant immunomodulation (NI).2 Analysis of the tumor immune microenvironment after NI may also provide key insights into potential therapeutic strategies in PCa. CTL/NK/Th1-recruiting chemokines (CCL5, CXCL9 and CXCL10) are downregulated while MDSC/Treg-attracting chemokines (CCL2, CCL22, and CXCL12) are upregulated in human PCa tissue.3 A large proportion of T cells in PCa are Tregs or dysfunctional CTLs and this immunosuppressive profile may be partly driven by COX-2 upregulation.4,5 A chemokine modulating regimen (CKM) of rintatolimod (TLR-3 ligand), aspirin (COX-2 inhibitor), and IFN-α favorably reprogrammed the chemokine profile and CTL/Treg ratio in human PCa explants.3 This combination has demonstrated safety in phase I/II trials across other tumor types, though it is unclear if IFN-α can be omitted without compromising efficacy.7-8 Methods: This is a three-arm, phase II trial where patients with localized PCa scheduled to undergo RP are randomized in 1:1:1 ratio to a 2-week regimen of neoadjuvant CKM triplet (rintatolimod + aspirin + IFN-α) vs CKM doublet (rintatolimod + aspirin) vs no CKM. Thirty patients will be enrolled to assess CD8+ T cell density in the RP specimen as the primary endpoint. Pathological and PSA responses, surgical margin positivity, and safety/toxicity of the CKM combinations will be secondary endpoints. Pre- and post-treatment density of various infiltrating T cell subtypes, MDSCs, chemokine and chemokine receptor profiles, immune checkpoint expression, immune-regulatory gene expression signatures, and peripheral blood immune cell landscape will be key exploratory endpoints. The trial is currently open with 11 patients enrolled. Clinical trial ID: NCT03899987 .

Neo-adjuvant PARP inhibition prior to prostatectomy: A phase II biomarker-driven trial for men with high-risk, localized prostate cancer and alterations in DNA repair genes.

TPS401 Background: Many men with localized prostate cancer will experience recurrence and progression after radical prostatectomy. While radiation therapy for high-risk prostate cancer is routinely given with systemic androgen therapy, peri-operative systemic therapy is not part of the standard of care with prostatectomy. Defective DNA repair pathways represent a non-hormonal target for PARP inhibitors which have proven efficacy in the metastatic, castrate resistant setting. We designed a novel biomarker driven neoadjuvant trial with niraparib prior to prostatectomy for men with clinically localized high risk prostate cancer and alterations in DNA repair genes (NCT04030559). Methods: We instituted a phase II trial for men with NCCN high and very high-risk prostate cancer. All men who met inclusion by clinical variables underwent targeted genomic sequencing for somatic and/or germline alterations in genes involved in DNA repair pathways. Enrolled patients are treated with oral Niraparib 300mg/day for 90 days before surgery. The primary endpoint is pathologic response at prostatectomy defined as complete response or minimal residual disease (&lt;0.5 cc3) of histological viable cancer. The secondary endpoint is biochemical free survival as well as molecular endpoints including disease responses stratified by mutational status. We have screened 37 men and 10 have met genomic criteria. We have enrolled 8 out of planned 30 men to date, 7 have undergone prostatectomy. Enrolled men have alterations in BRCA2 (germline), MSH6, ZMYM3, MUTYH, ATM, CDK12, ERCC3 and KMT2c. Clinical trial information: NCT04030559 .

DASL-HiCaP: A randomized, phase 3, double-blind trial of darolutamide with androgen-deprivation therapy and definitive or salvage radiation for localized very high-risk prostate cancer.

TPS396 Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone analogue (LHRHA), is a standard of care for patients with very high-risk localized prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of patients with very high-risk features. Darolutamide is a structurally distinct oral androgen receptor antagonist with low blood-brain-barrier penetration, a demonstrated favorable safety profile, and low potential for drug-drug interactions. Our aim is to determine the efficacy of adding darolutamide to ADT and RT used either as primary definitive therapy, or as salvage therapy, for very high-risk PC. Methods: This study is a randomized (1:1), phase 3, placebo-controlled, double-blind, international trial for patients planned for RT who have very high-risk localized PC on conventional imaging; or very high-risk features with PSA persistence or rise within one year following RP. The trial is stratified by previous RP; planned use of adjuvant docetaxel; clinical or pathological pelvic nodal involvement. 1100 participants will be randomized to receive darolutamide 600 mg or placebo twice daily for 96 weeks in combination with SOC (LHRHA for 96 weeks, plus RT starting week 8-24 from randomization). Participants are allowed nonsteroidal antiandrogen in addition to LHRHA for up to 90 days prior to randomization. Early treatment with up to 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival, with secondary endpoints of overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety, and resistance to study treatment. Clinical trial information: NCT04136353 .

Results of a multicenter, randomized, phase 3 trial of trimodality therapy with I-125 brachytherapy, external beam radiation therapy, and long- versus short-term androgen deprivation therapy for localized high-risk prostate cancer (TRIP/TRIGU0907).

305 Background: The TRIP trial was a multicenter, phase 3 randomized investigation designed to determine whether 30 months of androgen deprivation therapy (ADT) was superior to 6 months of ADT when combined with brachytherapy and external beam radiotherapy (EBRT) for localized high-risk prostate cancer. Methods: The trial was done in 37 hospitals in Japan. Men between 40 to 79 years old with stage T2c-3a, or a prostate-specific antigen (PSA) &gt;20 ng/ml or a Gleason score &gt;7 received 6 months of ADT combined with I-125 brachytherapy at a prescription dose of 110 Gy, followed by EBRT of 45 Gy. Patients were randomly assigned either no further treatment (short arm) or 24 months of adjuvant ADT (long arm) after stratification. The primary endpoint was biochemical progression-free survival using the Phoenix definition of failure. Secondary endpoints included clinical progression, metastasis, salvage treatment, disease-specific survival, overall survival, and grade 3 or higher of adverse events. An intention-to-treat analysis was conducted with survival estimates determined using competing risk analyses. Results: Of 332 patients, 165 were randomized to the short and 167 to the long arm. The median follow-up periods were 9.43 and 9.24 years, respectively. 24 patients have died in each arm. The cumulative incidence for biochemical progression in the short vs. long arm were 10.4% (95% confidence interval [CI] 6.62-16.42) vs 9.5% (5.85-15.46) at 9 years, respectively (p=0.647). The cumulative incidences for clinical progression, distant metastases, salvage treatment, and disease-specific mortality events were not significantly different between the two arms. The overall survival rates of the short arm vs long arm were 87.2% (82.13-92.63%) and 85.9% (80.41-91.77%) at 9 years, respectively (p=0.914). Endocrine-related grade 3 morbidity for short arm vs long arm was 0.6% vs 1.8% (p=0.623), and radiation-related grade 3 morbidity was 1.2% vs 0.6% (p=0.622). Conclusions: In localized high-risk prostate cancer, TRIP did not demonstrate the superiority of 30 months vs. 6 months of ADT when combined with brachytherapy and EBRT. These data suggest that ultra-high radiation doses can be combined with a shorter course of ADT without compromising survival. Clinical trial information: UMIN000003992 .

Role of adenomatous polyposis coli (APC) gene in SPOP-mutant prostate cancer and clinical outcomes.

202 Background: Speckle-type POZ protein (SPOP) mutations are a frequent initiating event in prostate cancer (PC) and are associated with increased androgen receptor transcriptional output. While SPOP-Mutant (MT) PCs may be more sensitive to hormonal therapy, they are still common amongst castration-resistant PCs (CRPCs) and frequently lethal. It remains unknown which SPOPMT PCs will respond well to hormonal therapy, and which have the potential to develop early castration resistance and cause patient death. Methods: With IRB approval, we retrospectively analyzed NGS data obtained via Tempus|xT tissue assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth) and/or Tempus|xF liquid biopsy assay (ctDNA sequencing of 105 genes in peripheral blood samples at 5,000x depth) for germline and/or somatic mutations in 234 consecutive patients with high-risk localized, locally advanced or metastatic PC followed at Ben Taub Hospital (BTH), a public hospital serving a racially/ethnically diverse patient population (&gt;50% of PC patients are African American). For confirmation, we examined de-identified NGS data from a nationwide cohort of 8812 PC patients sequenced with xT and/or xF by Tempus Labs (Chicago, IL), as well as publicly available data from four additional PC cohorts (PMIDs: 26544944, 34667026, 31061129 and 26855148). Results: We found SPOP mutations in 31/234 BTH PC patients (13.2%). Eleven of these 31 patients (35.5%) also exhibited loss-of-function (LOF) mutations or deletions in the tumor suppressor gene Adenomatous polyposis coli (APC). APC LOF events were found only in 15/203 (7.4%) of the SPOP-wild type (WT) PCs, and the enrichment of SPOPMT PCs for APC LOF events was highly significant (Chi square with Yates correction: P&lt;0.00001). The co-mutation pattern between these two genes was observed even when the analysis was limited specifically to the tissue NGS (133 patients) or the liquid biopsy NGS subsets of the dataset, respectively. This enrichment was confirmed in the nationwide TEMPUS cohort and in the four publicly available clinical PC datasets (APC LOF found in 23.4, 27.0, 21.5, 32.0 and 30.8% of SPOPMT PCs, respectively; and only in 5.8, 2.4, 6.0, 6.7 and 1.0% of SPOP-Wild Type (WT) PCs, respectively (P&lt;0.001 in each cohort). In the BTH PC cohort, SPOPMT PCs harboring APC LOF mutations were more likely to present with metastatic disease (M1) at diagnosis and to develop castration-resistance within 1 year of first-line hormonal therapy than SPOPMT PCs with WT APC. Conclusions: In SPOPMT PCs, inactivation of APC is a common event and associated with more aggressive disease (higher metastatic potential and faster progression to castration resistance). This observation may help identify SPOPMT PC patients who are at higher risk for early castration resistance and could benefit from more intensive treatment.

Effect of neoadjuvant stereotactic body radiation therapy (SBRT) on the immune microenvironment of high-risk localized prostate cancer in paired transcriptomic analysis of pretreatment biopsy and irradiated prostatectomy specimens.

371 Background: SBRT is a treatment option for men with prostate cancer. PREPARE-SBRT (NCT03663218) is a clinical trial testing the safety of neoadjuvant MRI-guided SBRT for men with high-risk localized prostate cancer. We leveraged paired samples from pre-treatment biopsy (Bx) and irradiated prostatectomy (RP) specimens to evaluate immune-related transcriptomic changes in irradiated tumors at acute timepoints following neoadjuvant SBRT. Methods: Transcriptomic profiles were generated using Decipher GRID (Veracyte, Inc). Differences in transcriptional signatures were assessed between Bx samples taken before treatment and RP samples post-treatment using a paired T-Test. A control cohort of transcriptomic profiles of 803 untreated Bx samples and matching RP samples from the same patients were used to account for differential effects in tissue preservation between Bx and RP. Linear regression model with the interaction effect of cohort (SBRT vs control) and by treatment status (Bx vs RP) to select signatures significantly impacted by neoadjuvant SBRT. Signatures with interaction p-value &lt;0.01 and paired T-test value &lt;0.05 were considered statistically significant. Results: 10 patients with paired pre-treatment Bx and post-SBRT RP specimens (n=20 samples) were analyzed with a median interval from completion of SBRT to RP of 5 days. Neoadjuvant SBRT was associated with upregulation of the T-cell inflamed signature (p=0.028) and immune190 signature (p=0.0031) supported by enrichment of transcriptomic features associated with IFN-gamma response (p=0.022), TCR signaling (p=0.0052) and antigen presentation (p=0.0048). Increased gene expression associated with effector memory/activated CD4 T-cells (p=0.0005 and p=0.0013, respectively) and effector memory/activated CD8 T-cells (p=0.0015 and p=0.013, respectively) were paralleled by a significant reduction in immunosuppressive regulatory T-cell (Treg; p=0.0015) and myeloid derived suppressor cell (MDSC; p=0.005) signatures. Additionally, macrophage-specific signatures were significantly enriched among SBRT-irradiated samples including CD68 and CSF1 gene clusters (both p=0.0041) as well as a decreased expression of the M2-to-M1 ratio signature (p=0.0052). Interestingly, WNT/β-catenin signaling, a putative oncogenic mediator of immune exclusion, was significantly downregulated in irradiated RP samples relative to pre-treatment Bx (p=2.6x10-5). Conclusions: Neoadjuvant SBRT was associated with significant immune remodeling of the irradiated prostate microenvironment. Collectively, immune-related transcriptional signatures skewed towards immune activation, increased effector T-cell and macrophage signatures and a reduction in immunosuppressive transcriptomic features.

Comparative transcriptomic analysis of DNA-damage response and androgen receptor pathway activity between biopsy and radical prostatectomy specimens before and after pre-operative real-time MRI-guided stereotactic body radiotherapy.

375 Background: Pre-Prostatectomy MRI-Guided Stereotactic Body Radiotherapy for High-Risk Prostate Cancer Trial (PREPARE SBRT; NCT03663218) is an ongoing clinical trial testing the safety of preoperative MRI-guided SBRT for men with clinically localized high-risk prostate cancer. We sought to compare transcriptomic profiles of biopsy (Bx) specimens to acutely irradiated radical prostatectomy (RP) specimens. Methods: Biopsy and post-irradiated RP specimens from 10 subjects were examined. The median interval between the end of RT and the date of RP was 5 days. Transcriptomic profiles were generated using Decipher GRID (Veracyte, Inc). Differences in transcriptional signatures were assessed between Bx samples taken before irradiation and RP samples post-irradiation using a paired T-Test. A control cohort of transcriptomic profiles of 803 untreated Bx samples and matching RP samples from the same patients were used to account for effects in tissue preservation from the procedure different of Bx vs RP. Linear regression model with the interaction effect of cohort (SBRT vs control) by procedure (Bx vs RP) to select signatures impacted by radiation treatment. Results: Transcriptomic signatures associated with Androgen Receptor (AR) activity were significantly downregulated (p=0.002) in irradiated RP specimens compared with pre-treatment biopsies. Analysis of DNA damage repair (DDR) pathways demonstrated that nucleotide excision repair (NER) and non-homologous end joining (NHEJ) signatures were increased (p=0.002 and p=0.02, respectively) after pre-operative RT whereas homologous recombination (p=0.06) and mismatch repair (p=0.08) were not significantly different between pre-treatment and irradiated tissues. Several metabolic-associated pathways were impacted by pre-operative RT including increased glycogen metabolism (p=0.008) and a NADH-NADPH conversion (p=0.001) signature indicative of RT-induced oxidative damage. Consistent upregulation of transcriptomic features associated with increased angiogenesis (p=0.0012) and stromal remodeling (p=0.0008) was observed in irradiated samples. Conclusions: Paired transcriptomic analysis following pre-operative RT demonstrated differential upregulation of specific DDR pathways including NHEJ and NER and metabolic alterations related to oxidative stress and glycogen metabolism. AR activity signatures were decreased in response to pre-operative RT.

Comparative analysis of contemporary and past PSMA PET/CT results for recurrent prostate cancer in a high-volume Brazilian center.

51 Background: PSMA PET/CT scan (68Ga-PSMA PET/CT) has emerged as a highly accurate tool when assessing disease staging both for newly diagnosed localized high-risk prostate cancer and for recurrent disease, with treatment plan modification in up to two-thirds of patients. PSMA PET/CT is commercially available in Brazil since last decade and growing experience with this test has led to a more accurate analysis of the results over the years. Methods: We retrospectively reviewed the PSMA PET/CT scans results of patients undergoing the exam in all disease stages in a single institution in Brasilia, Brazil, between October 2015 and July 2022 and analyzed the results correlated with clinicopathological information (when available) in two separated timeframes for those in the recurrent disease setting. Results: Overall, more than 2,500 PSMA PET-CT scans were performed since October 2015. Between 2015 and 2019, 351 exams were performed, of which 303 in the setting of recurrent disease, while 297 tests were executed between 2021 and 2022, with 283 of them being done in the recurrent disease setting. Any clinicopathological information was available for 648 patients, of whom 586 underwent the test in the setting of recurrent disease following treatment of primary disease. Conclusions: There was a similar positivity rate among the clinicopathological characteristics analyzed in an indirect comparison of the two timeframes. It is remarkable the increased positivity rate among patients with lower levels of PSA in the contemporary dataset, which may reflect the learning curve of this image method. Among patients selected by Gleason grade, no definitive information can be extracted given the distinct PSA levels between patients in the two selected timeframes. [Table: see text]

Updated experience on PSMA PET/CT for recurrent prostate cancer in a high-volume Brazilian center.

50 Background: PSMA PET/CT scan (68Ga-PSMA PET/CT) has emerged as a highly accurate tool when assessing disease staging both for newly diagnosed localized high-risk prostate cancer and for recurrent disease, with treatment plan modification in up to two-thirds of patients. Methods: We retrospectively reviewed the PSMA PET/CT scans results of patients undergoing the exam in all disease stages in a single institution in Brasilia, Brazil, between October 2015 and July 2022 and correlated clinicopathological information with test results for those in the recurrent disease setting. Results: Overall, more than 2,500 PSMA PET-CT scans were performed during the selected time interval. Any clinicopathological information was available for 648 patients, of whom 586 underwent the test in the setting of recurrent disease following treatment of primary disease. Positive results were found in 400 studies, with a median PSA level of 1.035 ng/mL (IQR 0.3–3.5) and most prevalent Gleason score of 7 (3+4). Metastatic disease was found in 26.2% of patients with a median PSA level of 4.61 ng/mL. Conclusions: A positive correlation between both PSA level and Gleason grade and the positivity rate of PSMA PET/CT was found in this large dataset, confirming the findings previously demonstrated in a prior presentation of our database. This result reinforces the importance of including more sensitive image methods when staging recurrent prostate cancer for the early detection of metastatic disease and adequate treatment planning. [Table: see text]

Salvage radical prostatectomy following 177Lu-PSMA-617 radioligand therapy in men with high-risk localized prostate cancer: Surgical aspects of the LuTectomy study

Salvage radical prostatectomy following 177Lu-PSMA-617 radioligand therapy in men with high-risk localized prostate cancer: Surgical aspects of the LuTectomy study

Prostate Specific Antigen response to neoadjuvant Lutetium-177-PSMA treatment in high-risk localized prostate cancer patients

Prostate Specific Antigen response to neoadjuvant Lutetium-177-PSMA treatment in high-risk localized prostate cancer patients

Cost-effectiveness analysis of ultra-hypofractionated radiotherapy and conventionally fractionated radiotherapy for intermediate- to high-risk localized prostate cancer.

Radiotherapy is an effective curative treatment option for intermediate- to high-risk localized prostate cancer. According to the HYPO-RT-PC trial (ISRCTN45905321), there was no significant difference in 5 years of follow-up in terms of failure-free survival, overall survival, urinary toxicity, and bowel toxicity, while erectile function decreased between ultra-hypofractionated radiotherapy with conventionally fractionated radiotherapy, except that the incidence of urinary toxicity in ultra-hypofractionated radiotherapy was higher at 1 year of follow-up. We evaluated the cost-effectiveness of ultra-hypofractionated radiotherapy and conventionally fractionated radiotherapy for intermediate- to high-risk localized prostate cancer from the Chinese payer's perspective. We developed a Markov model with a 15-year time horizon to compare the cost and effectiveness of ultra-hypofractionated radiotherapy with those of conventionally fractionated radiotherapy for localized intermediate- to high-risk prostate cancer. The outcomes were measured in quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), and willingness-to-pay (WTP). Univariable and probability sensitivity analyses were performed to evaluate the robustness of the Markov model. Based on the Markov model, conventionally fractionated radiotherapy yielded 2.32 QALYs compared with 2.14 QALYs in ultra-hypofractionated radiotherapy in China. The cost of ultra-hypofractionated radiotherapy was found to be decreased by about 14% folds ($4,251.04) in comparison with that of conventionally fractionated radiotherapy. The ICER of conventionally fractionated radiotherapy versus that of ultra-hypofractionated radiotherapy was $23,616.89 per QALY in China. The failure-free survival with grade 2 or worse urinary toxicity and the discount rate per annum were the most sensitive parameters utilized in ultra-hypofractionated radiotherapy. The cost-effectiveness acceptability curve showed that conventionally fractionated radiotherapy had 57.7% probability of being cost-effective under the Chinese WTP threshold. From the perspective of Chinese payers, ultra-hypofractionated radiotherapy was not a cost-effective strategy compared with conventionally fractionated radiotherapy for patients with localized intermediate- to high-risk prostate cancer. Nevertheless, reduction of the grade 2 or worse urinary toxicity of ultra-hypofractionated radiotherapy could alter the results.

Outcomes following HDR Brachytherapy Boost for High Risk Localised Prostate Cancer: Data from a UK Centre

Purpose: Clinical trials have shown improvements in local control with the addition of a high dose rate brachytherapy boost to external beam radiotherapy in the treatment of higher risk prostate cancer [1,2]. We reviewed the 5-year outcomes of a cohort of patients treated within a single UK centre to examine biochemical progression free survival, overall survival and toxicity.

How to Improve the Quality of Life of Patients with Prostate Cancer Treated with Hormone Therapy?

Prostate cancer (PC) is a hormone-sensitive tumor. Androgen deprivation therapy (ADT) is the cornerstone of systemic therapy for patients with intermediate or high-risk localized, recurrent, and metastatic prostate cancer. Although generally well tolerated, ADT can lead to short- and long-term adverse events that can worsen the quality of life of patients with PC. In the last decade, the introduction of novel generation androgen receptor pathway inhibitors (ARPI) has resulted in an improvement in the prognosis of patients with metastatic PC when used in combination with ADT. The use of ARPI in increasingly early stages of the disease determines a longer exposure of patients to these treatments. Although ARPIs are normally well-tolerated drugs, they generally cause an increase in toxicity compared to ADT alone, being able to worsen some adverse events already induced by ADT or leading to the development of specific side effects. Although there are no specific treatments for all the adverse events induced by hormonal therapies, it is essential to know the possible toxicities induced by the different treatments and to start procedures to prevent and/or recognize and consequently treat them early in order to not compromise the quality of life of the patients with PC. The aim of this review is to describe the adverse events induced by hormonal therapies. We will first describe the side effects induced by both ADT and ARPI and then the specific adverse events of the different ARPIs. Furthermore, we will try to highlight the possible therapeutic options to prevent or mitigate the toxicity induced by hormone therapies in order to improve the quality of life of the patients with PC.

Adjusting the duration of androgen deprivation therapy (ADT) based on nadir PSA for high risk localized prostate cancer patients treated with definitive external beam radiation therapy and ADT

BackgroundA nadir Prostate-Specific Antigen (nPSA) of 0.06 ng/mL has been shown to be a strong independent predictor of biochemical recurrence-free survival (bRFS) in patients with intermediate or high-risk (HR) prostate cancer treated with definitive external beam radiation therapy (RT) and androgen deprivation therapy (ADT). We aimed to examine the association between the duration of ADT and bRFS in HR localized prostate cancer, based on nPSA.MethodsBetween 1998 and 2015, 204 patients with HR localized prostate cancer were identified. Of them, 157 patients (77.0%) reached the desired nPSA of < 0.06 ng/mL (favorable group), while 47 (23.0%) did not (unfavorable group). Duration of ADT varied among patients depending on physician preference, patient tolerance, and/or compliance. Survival outcomes were calculated using Kaplan–Meier methods and predictors of outcomes using multi-variable cox regression model.ResultsIn the favorable group, ADT for at least 12 months lead to superior bRFS compared to ≤ 9 months of ADT (P = 0.036). However, no significant difference was seen when examining the value of receiving ADT beyond 12, 18, or 24 months, respectively. On univariate analysis for bRFS, the use of ADT for at least 12 months was significant (P = 0.012) as well as time to nadir PSA (tnPSA), (≤ 6 vs > 6 months); (P = 0.043). The presenting T stage was borderline significant (HR 3.074; 95% CI 0.972–9.719; P = 0.056), while PSA at presentation, Gleason Score and age were not. On multivariate analysis, the use of ADT for 12 months (P = 0.012) and tnPSA (P = 0.037) remained significant. In the unfavorable group, receiving ADT beyond 9 and 12 months was associated with improved bRFS (P = 0.044 and 0.019, respectively). However, beyond 18 months, there was no significant difference.ConclusionIn HR localized prostate cancer patients treated with definitive RT and ADT, the total duration of ADT may be adjusted according to treatment response using nPSA. In patients reaching a nPSA below 0.06 ng/mL, a total of 12 months of ADT may be sufficient, while in those not reaching a nPSA below 0.06 ng/mL, a total duration of 18 months is required.