High-risk Localized Prostate Cancer Research Articles

Differences in real-world outcomes by risk classification for localized prostate cancer patients after radiation therapy.

Limited real-world evidence exists on the long-term clinical outcomes of patients with localized prostate cancer (LPC) who received external beam radiation therapy (EBRT) as the initial treatment. This study evaluated clinical outcomes of US patients with high-risk LPC (HR-LPC) and low/intermediate-risk LPC (LIR-LPC) who received EBRT. This retrospective study using Surveillance, Epidemiology, and End Results-Medicare linked data from 2012 to 2019 included patients ≥ 65 years old who received EBRT as initial therapy. Baseline patient characteristics were summarized, metastasis-free survival (MFS), overall survival, and time to initiation of advanced prostate cancer treatment were compared using Kaplan-Meier (KM) and adjusted Cox proportional hazard (PH) models. 5-year survival probabilities stratified by race/ethnicity (non-Hispanic [NH] White, NH Black, NH Asian, and Hispanic) were assessed. Of 11,313 eligible patients, 41% (n = 4600) had HR-LPC and 59% (n = 6713) had LIR-LPC. Patient characteristics for both groups were comparable, with mean age at EBRT initiation > 70 years, 86% white, and mean follow-up time >40 months. More patients in the HR-LPC than LIR-LPC groups (78% vs 34%) had concurrent androgen deprivation therapy use and for a longer duration (median 10.4 months vs. 7.4 months). A higher proportion of HR-LPC patients developed metastasis, died, or received advanced prostate cancer treatment. Adjusted Cox PH survival analyses showed significantly (p < 0.0001) higher risk of mortality (hazard ratios[HR], 1.57 [1.38, 2.34]), metastasis or death (HR, 1.97 [1.78, 2.17]), and advanced prostate cancer therapy use (HR, 2.57 [2.11, 3.14]) for HR-LPC than LIR-LPC patients. Within 5 years after the initial EBRT treatment, 18%-26% of patients with HR-LPC are expected to have died or developed metastasis. The 5-year MFS rate in the HR-LPC group was lower than the LIR-LPC group across all racial/ethnic subgroups. NH Black patients with HR-LPC had the highest all-cause mortality rate and lowest rate of receiving advanced prostate cancer treatment, compared to other racial/ethnic subgroups. This real-world study of clinical outcomes in patients with LPC treated with EBRT suggests substantial disease burden in patients with HR-LPC and highlights the need for additional treatment strategies to improve clinical outcomes in patients with HR-LPC.

Long-Term Oncological Outcomes after Nerve-Sparing Robot-Assisted Radical Prostatectomy for High-Risk Localized Prostate Cancer: A Single-Center, Two-Arm Prospective Study.

To compare the oncological outcomes of patients with high-risk localized prostate cancer undergoing nerve-sparing and non-nerve-sparing robot-assisted radical prostatectomy (RARP). Between November 2002 and December 2018, we prospectively recorded the data of patients undergoing RARP for high-risk localized prostate cancer (PCa) at our tertiary referral center. NSS (nerve-sparing surgery) was carefully offered on the basis of the preoperative clinical characteristics of the patients and an intraoperative assessment. The patients were stratified into two groups: nerve-sparing and non-nerve-sparing groups (yes/no). Radical prostatectomies were performed by 10 surgeons with a robot-assisted technique using a daVinci® surgical system. The primary oncological outcome evaluated was biochemical recurrence (BCR). The secondary oncological outcomes assessed were positive surgical margins (PSMs) and cancer-specific survival (CSS). A total of 779 patients were included in the study: 429 (55.1%) underwent NSS while 350 (44.9%) underwent non-NSS. After a mean (±SD) follow-up of 192 (±14) months, 328 (42.1%) patients developed BCR; no significant difference was found between the NSS and non-NSS groups (156 vs. 172; p = 0.09). Both our univariable and multivariable analyses found that the nerve-sparing approach was not a predictor of BCR (p > 0.05). Kaplan-Mayer survival curves for BCR showed no significant difference among the non-NSS, unilateral NSS, and bilateral NSS groups (log rank test = 0.6). PSMs were reported after RARPs for 254 (32.6%) patients, with no significant difference between the NSS and non-NSS group (143 vs. 111; p = 0.5). In the subgroup of 15 patients who died during the follow-up period, mean (±SD) CSS was 70.5 (±26.1) months, with no significant difference between the NSS and non-NSS groups (mean CSS: 70.3 vs. 70.7 months). NSS does not appear to negatively impact the oncological outcomes of patients with high-risk PCa. Randomized clinical trials are needed to confirm our promising findings.

Abstract CT137: Efficacy and immunological outcomes of non-fucosylated anti-CTLA-4 (BMS-986218) + degarelix acetate vs. degarelix acetate alone in men with high-risk localized prostate cancer (Neo-Red-P)

Abstract Background: Men with high-risk localized prostate cancer are at significant risk for disease recurrence and there is currently no role for neoadjuvant therapy. Although androgen deprivation therapy (ADT) is immunomodulatory and can increase CD8 T cell infiltration, these effects are counterbalanced by the expansion of suppressive regulatory T cells (Tregs). We therefore designed a correlative-rich clinical trial for men with high-risk localized prostate cancer to test whether BMS-986218 - a novel afucosylated anti-CTLA-4 antibody optimized for antibody-dependent cell-mediated cytotoxicity (ADCC) - depletes Tregs and augments response to ADT. Methods: Neo-Red-P is a single-center, two-arm, open-label pilot study assessing degarelix (ADT) versus ADT + anti-CTLA-4-NF (BMS-986218) in patients with treatment naïve high-risk localized prostate cancer. Key eligibility criteria included histologically confirmed adenocarcinoma with Gleason sum of ≥4+3 and clinical stage T1c-T3bN0M0. All patients received degarelix (ADT; 240mg SQ) 2 weeks before radical prostatectomy (RP). Patients were randomized to Arm A (ADT only), or Arm B (ADT + BMS-986218 [20mg IV] 2 doses Q2w starting 3 weeks before RP). The primary endpoint was the safety and feasibility of neoadjuvant BMS-986218 in prostate cancer. Secondary endpoints included the pathologic complete response rate, rate of undetectable PSA at 12 months, PSA response rate (&amp;gt;50% decrease pre-RP), and time-to-PSA recurrence. Fresh tumor specimens were collected at RP for single-cell RNA-sequencing, cytometry by time-of-flight, next-generation sequencing, and multiplex immunofluorescence. A treatment naïve cohort of matching demographic and pathological characteristics was collected for comparative analysis (n=14). Results: Between February 26, 2020, and November 15, 2022, 24 patients were enrolled. Severe treatment-related adverse events (TRAE; Grade ≥ 3) were rare in both arms; 0% in the ADT alone arm and 4% in the combination arm, suggesting a tolerable safety profile with the addition of BMS-986218. In the combination arm, 54% of subjects achieved a 50% reduction in PSA versus 33% in the ADT alone arm. In the ADT alone arm, 80% of patients had an undetectable PSA at 12 months, with a median recurrence-free survival of 1.61 years (IQR: 1.50-1.99 years). In the combination group, 75% had an undetectable PSA at 12 months, with a median recurrence-free survival of 1.82 years (IQR: 0.89-2.07 years). The overall recurrence rate in patients treated with combination therapy was 25% (3 of 12 patients) versus 20% (2 of 10 patients) in the ADT alone arm. Correlative studies suggest that aCTLA4-NF mitigates ADT-induced Treg accumulation through enhanced Fc receptor activity and augmented CTL activation, indicating an enhanced anti-tumor response with combination therapy. Conclusions: The neoadjuvant combination of ADT + aCTLA-4-NF (BMS-986218) is feasible, well tolerated, and induces significant remodeling of the immune TME through enhanced Fc receptor and CTL activity. Rates of disease recurrence following surgery were low in this high-risk population, warranting further investigation of combination immuno-hormonal therapy in the neoadjuvant setting for high-risk prostate cancer. Clinical Trial Information: NCT04301414 Citation Format: Patrick J. McCann, Casey R. Ager, Aleksandar Z. Obradovic, Matthew G. Chaimowitz, Samuel Pan, Caroline J. Laplaca, Parin Shah, Renu K. Virk, Christopher B. Anderson, Catherine S. Spina, Karie D. Runcie, Mark N. Stein, Charles G. Drake, Matthew C. Dallos. Efficacy and immunological outcomes of non-fucosylated anti-CTLA-4 (BMS-986218) + degarelix acetate vs. degarelix acetate alone in men with high-risk localized prostate cancer (Neo-Red-P) [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 CT137.

The influence of Gleason score ≤ 6 histology on the outcome of high-risk localized prostate cancer after modern radiotherapy

We aimed to retrospectively review outcomes in patients with high-risk prostate cancer and a Gleason score ≤ 6 following modern radiotherapy. We analyzed the outcomes of 1374 patients who had undergone modern radiotherapy, comprising a high-risk low grade [HRLG] group (Gleason score ≤ 6; n = 94) and a high-risk high grade [HRHG] group (Gleason score ≥ 7, n = 1125). We included 955 patients who received brachytherapy with or without external beam radio-therapy (EBRT) and 264 who received modern EBRT (intensity-modulated radiotherapy [IMRT] or stereotactic body radiotherapy [SBRT]). At a median follow-up of 60 (2–177) months, actuarial 5-year biochemical failure-free survival rates were 97.8 and 91.8% (p = 0.017), respectively. The frequency of clinical failure in the HRLG group was less than that in the HRHG group (0% vs 5.4%, p = 0.012). The HRLG group had a better 5-year distant metastasis-free survival than the HRHG group (100% vs 96.0%, p = 0.035). As the HRLG group exhibited no clinical failure and better outcomes than the HRHG group, the HRLG group might potentially be classified as a lower-risk group.

Abstract 4570: Prostate-specific membrane antigen targeted chemo-photodynamic therapy for the treatment of prostate cancer

Abstract Introduction: Prostate cancer is the most prevalent cancer among men in the United States and is their second leading cause of cancer death. During initial screen, about 17-31% of patients are diagnosed with non-metastatic high-risk localized prostate cancer. These patients have an increased risk of treatment failure and oncological progression. The contemporary treatment paradigm of high risk localized prostate cancer is moving toward a multidisciplinary integrated approach of systemic and local therapy. In addition, incorporation of molecular biomarkers can also improve the risk stratification and treatment of prostate cancer. Among the biomarkers for prostate cancer, prostate specific membrane antigen (PSMA) has been proven to be an excellent target for diagnosis and treatment of prostate cancer. We have generated a PSMA-targeted photodynamic therapy (PDT) agent, PSMA-1-Pc413, and a PSMA-targeted chemotherapeutic agent, PSMA-1-MMAE. The objective of this study is to generate a new molecule that combines PDT and chemotherapy to achieve improved antitumor activity. Methods: Using a bifunctional PSMA ligand, a novel theranostic PSMA-targeting conjugate was synthesized, which integrated both the photosensitizer Pc413 and the microtubular inhibitor monomethyl auristatin E (MMAE) in one simple molecule, PSMA-1-MMAE-Pc413. This molecule was first tested for in vitro uptake and cytotoxicity studies using PSMA-positive PC3pip and PSMA-negative PC3flu cells. The conjugate was then tested for in vivo fluorescence imaging using mice bearing both PC3pip and PC3flu tumors. Finally, the antitumor activity of PSMA-1-MMAE-Pc413 was tested in mice with PC3pip tumors with and without light irradiation. Results: In in vitro uptake studies, the uptake of PSMA-1-MMAE-Pc413 in PC3pip tumor was about 3-fold higher than that in PC3flu cells. In in vitro cytotoxicity studies, when exposed to 5 J/cm2 of 672nm light, PSMA-1-MMAE-Pc413 demonstrated a synergistic effect leading to greater cytotoxicity for PC3pip cells (IC50=2.77nM) when compared to PSMA-1-Pc413 with light irradiation (IC50=372nM) or PSMA-1-MMAE-Pc413 without light irradiation (IC50=12.6nM). In in vivo imaging studies, PSMA-1-MMAE-Pc413 demonstrated selective uptake in PC3pip tumors. Further, antitumor activity studies showed that PSMA-1-MMAE-Pc413 with light irradiation significantly inhibited PC3pip tumor growth and prolonged survival time as compared to mice receiving equimolar amounts of PSMA-1-Pc413 with light irradiation or PSMA-1-MMAE-Pc413 without light irradiation. Conclusion: We have synthesized a new theranostic agent PSMA-1-MMAE-Pc413 that combines imaging, chemotherapy and PDT. The new molecule dramatically improves the treatment effect as compared to each single treatment alone. (The work is supported by NIH 1RO1CA255925-01A.) Citation Format: Xinning Wang, Aditi Shirke, Sriprada Chavali, Lifang Zhang, Ethan Walker, Gopolakrishnan Ramamurthy, James Basilion. Prostate-specific membrane antigen targeted chemo-photodynamic therapy for the treatment of 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 4570.

Abstract 4987: TREM2 is a radiation-induced target for immunomodulation of tumor-associated macrophages in the prostate cancer tumor microenvironment

Abstract Background: The prostate cancer (PCa) tumor microenvironment (TME) is characterized by a predominance of myeloid cells that may have a key role in immunosuppression and disease progression. Stereotactic Body Radiation Therapy (SBRT) is utilized for treatment of localized and metastatic PCa and promotes inflammatory remodeling of the TME. We analyzed human PCa specimens at acute post-SBRT timepoints to identify radiation-induced targets in the PCa TME and used in vitro and in vivo models to test and validate our findings. Methods: We performed 10X single-cell RNA sequencing (scRNA-seq) on prostatectomy specimens from men with high-risk localized PCa; 12,988 cells from 4 patients that underwent pre-operative SBRT and 47,314 cells from 6 patients that underwent prostatectomy alone. THP-1 monocytes polarized into macrophage (Mɸ) states [M0, M1, M2 and tumor-associated macrophages (TAM), were used to characterize TREM2 expression and immune responses to radiation or conditioned media (CM) derived from irradiated PC3 cells. In vivo studies with C57BL/6 mice inoculated with MC38 flank tumors or PTEN-/- SPOPmut CHD1del mouse prostate organoid line were used to analyze intratumoral myeloid populations in response to SBRT (37.5Gy in 5 fractions). Results: scRNA-seq analysis (Cell Ranger 7.1.0 pipelines; Seurat v5 R package) revealed enrichment of a cluster of myeloid cells defined by a damage-associated Mɸ gene signature (TREM2, APOE, SPP1, LGALS3, CD9) in response to SBRT compared with non-irradiated specimens (35.6% vs 5.7%). TREM2 expression was significantly upregulated in THP-1 cells polarized in M2 (p&amp;lt;0.001) and TAM (p&amp;lt;0.001) conditions, compared to M1 conditions. Irradiation (20Gy x1) of THP-1 cells significantly increased TREM2 expression in M0 (p&amp;lt;0.01), M1 (p&amp;lt;0.001), and TAM (p&amp;lt;0.01) conditions. Proliferation of PC3 cells exposed to CM from irradiated TAMs was significantly increased (p&amp;lt;0.0001) compared to CM from non-irradiated TAM. Alternatively, CM derived from irradiated PC3 cells significantly increased (p&amp;lt;0.05) TREM2 expression in M0-polarized Mɸ. In vivo studies, in MC38 and organoid models, noted a significant reduction (p&amp;lt;0.0001) in tumor volume at day 7 post-SBRT. Multi-parametric flow cytometry demonstrated robust myeloid infiltration in response to SBRT dominated by CD11b+F4/80+ TAMs in irradiated tumors. Among irradiated tumors, TREM2 expression was markedly elevated in TAMs (organoid and MC38, p&amp;lt;0.0001). Conclusion: Preliminary data in human irradiated PCa and validation studies in preclinical models suggest TREM2 expression on myeloid cells is a radiation-induced target. Further studies are underway to understand the functional and immunological implications of SBRT-induced TREM2 expression on TAMs and whether this can be therapeutically targeted to enhance anti-tumor immunity in PCa. Citation Format: Janny A. Villa-Pulgarin, Un In Chan, Francesca Khani, Fabio Socciarelli, Jiansheng Wu, Ryan Carelli, Jeffrey Kraynak, Silvia C. Formenti, Luigi Marchionni, Massimo Loda, Himanshu Nagar, Ariel E. Marciscano, Christopher E. Barbieri. TREM2 is a radiation-induced target for immunomodulation of tumor-associated macrophages in the prostate cancer tumor microenvironment [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 4987.

Hypofractionated radiation therapy combined with androgen deprivation therapy for high-risk localized prostate cancer.

This study aimed to analyse the treatment outcomes of moderately hypofractionated radiation therapy (RT) combined with androgen deprivation therapy (ADT) and the prognostic implications of prostate-specific antigen (PSA) kinetics in high-risk localized prostate cancer. The medical records of 140 patients who underwent definitive RT (70 Gy in 28 fractions) combined with ADT were retrospectively reviewed. ADT consists of a gonadotropin-releasing hormone agonist and an anti-androgen. Clinical outcomes included the biochemical failure rate (BFR), clinical failure rate (CFR), overall survival (OS) and prostate cancer-specific survival (PCSS). The BFR and CFR were stratified by the PSA nadir and the time to the PSA nadir, respectively. Acute and late genitourinary and gastrointestinal adverse events were also recorded. The 5-year BFR, CFR, OS and PCSS rates were 9.8%, 4.5%, 90.2% and 98.7%, respectively. Ninety-five (67.9%) patients achieved a PSA nadir of 0.01 ng/mL. Patients with a PSA nadir >0.01 ng/mL had a significantly higher BFR and CFR (BFR, P = 0.001; CFR, P = 0.027), even after adjusting for other prognostic factors [per 0.1 ng/mL; BFR, hazard ratio (HR) 4.440, P < 0.001; CFR, HR 4.338, P = 0.001]. However, the time to the PSA nadir and pre-RT PSA were not significantly associated with the BFR and CFR. Six patients (4.3%) reported grade 3 late adverse events, mostly haematuria and haematochezia. Definitive RT with moderate hypofractionation combined with long-term ADT showed good efficacy for high-risk localized prostate cancer. The lowest PSA nadir was significantly associated with a low recurrence rate, indicating the importance of PSA follow-up.

Simultaneous Focal Boost With Stereotactic Radiation Therapy for Localized Intermediate- to High-Risk Prostate Cancer: Primary Outcomes of the SPARC Phase 2 Trial

Purpose: Dose escalated radiotherapy is associated with better biochemical control at the expense of toxicity. Stereotactic body radiotherapy (SBRT) with dose escalation to the dominant intraprostatic lesion (DIL) provides a logical approach to improve outcomes in high-risk disease whilst limiting toxicity. This study evaluated the toxicity and quality of life (QOL) with CyberKnife-based SBRT and simultaneous integrated boost in localised prostate cancer. Methods and Materials: Eligible participants included newly diagnosed, biopsy-proven unfavourable intermediate to high risk localised prostate cancer (at least one of the following: Gleason ≥ 4+3, MRI defined T3a N0, PSA ≥ 20) with up to two MRI-identified DILs. Participants received 36.25Gy in 5 fractions on alternative days with a simultaneous boost to DIL up to 47.5Gy as allowed by organs at risk constraints delivered by CyberKnife. All participants received androgen deprivation therapy. The primary outcome measure was acute grade 2 + genitourinary toxicity. Acute and late genitourinary and gastrointestinal toxicity using RTOG scoring, biochemical parameters, IPSS, IIEF5, EQ5D QOL outcomes were assessed. Results: Between 2013 and 2023, 20 participants were enrolled with a median follow-up of 30 months. The median D95 dose to DIL was 47.43Gy. Cumulative acute grade 2 + genitourinary and gastrointestinal toxicity was 25% and 30%, respectively. One patient developed acute grade 3 genitourinary toxicity (5%). There is no late grade 3 genitourinary or gastrointestinal toxicity to date. IPSS score and urinary QOL scores recovered to baseline by 6months. Patient-reported outcomes showed no significant change in EQ-5D QOL scores at 12 weeks and 1 year. There are no cases of biochemical relapse reported to date. Conclusions: CyberKnife SBRT delivered dose of 36.25Gy to the prostate with a simultaneous integrated boost up to 47.5Gy is well tolerated. Acute and late GU and GI toxicity rates are comparable to other contemporary SBRT trials and series with focal boost.

One-year clinical outcomes of MR-guided stereotactic body radiation therapy with rectal spacer for patients with localized prostate cancer

Background and purposeThis prospective study aimed to investigate adaptive magnetic resonance (MR)-guided stereotactic body radiation therapy (MRgSBRT) with rectal spacer for localized prostate cancer (PC) and report 1-year clinical outcomes.Materials and methodsThirty-four consecutive patients with low- to high-risk localized PC that underwent 5-fraction adaptive MRgSBRT with rectal spacer were enrolled. The dosimetric comparison was performed on a risk- and age-matched cohort treated with MRgSBRT but without a spacer at a similar timepoint. Clinician-reported outcomes were based on Common Terminology Criteria for Adverse Events. Patient-reported outcomes were based on the Expanded Prostate Cancer Index Composite (EPIC) questionnaire at baseline, acute (1–3 months), subacute (4–12 months), and late (> 12 months) phases.ResultsThe median follow-up was 390 days (range 28–823) and the median age was 70 years (range 58–82). One patient experienced rectal bleeding soon after spacer insertion that subsided before MRgSBRT. The median distance between the midline of the prostate midgland and the rectum after spacer insertion measured 7.8 mm (range 2.6–15.3), and the median length of the spacer was 45.9 mm (range 16.8–62.9) based on T2-weighted MR imaging. The use of spacer resulted in significant improvements in target coverage (V100% > 95% = 98.6% [range 93.4–99.8] for spacer vs. 97.8% [range 69.6–99.7] for non-spacer) and rectal sparing (V95% < 3 cc = 0.7 cc [range 0–4.6] for spacer vs. 4.9 cc [range 0–12.5] for non-spacer). Nine patients (26.5%) experienced grade 1 gastrointestinal toxicities, and no grade ≥ 2 toxicities were observed. During the 1-year follow-up period, EPIC scores for the bowel domain remained stable and were the highest among all other domains.ConclusionsMRgSBRT with rectal spacer for localized PC showed exceptional tolerability with minimal gastrointestinal toxicities and satisfactory patient-reported outcomes. Improvements in dosimetry, rectal sparing, and target coverage were achieved with a rectal spacer. Randomized trials are warranted for further validation.

Hypofractionated versus conventional fractionation external beam radiotherapy in intermediate and high risk localized prostate cancer

BackgroundProstate cancer is the second most common malignancy in men, and its incidence is increasing which is attributed to increased screening programs. The treatment options of intermediate and high risk prostate cancer include radical prostatectomy, radiotherapy and androgen deprivation therapy. Hypofractionated radiotherapy is becoming more popular lately due to better understanding of the radiobiology of prostate cancer and favorable logistics.ObjectiveTo compare the toxicity and efficacy of hypofractionated versus conventional fractionation external beam radiotherapy in patients with intermediate and high risk localized prostate cancer treated in Shaukat Khanum Memorial Hospital and Research Center, Lahore (SKMCH & RC).MethodologyWe retrospectively conducted this study on histopathologically confirmed 114 patients with prostate adenocarcinoma who underwent treatment from January 2013 till December 2018. These patients were treated with radical radiotherapy along with hormonal therapy as per indication. Data was collected from electronic hospital system and analyzed by SPSS version 23.Results114 patients were selected according to the inclusion criteria. Mean age was 68 years (61–75). 88% of patients had stage III-IVA disease at the time of diagnosis. Mean PSA and GS was 33 ± 39 SD and 7 ± 0.9 SD respectively. 89% (n = 102) received radiotherapy with 69% of patients receiving dose of 60 Gy in 20 fractions. Among patients who received hypofractionated dose, 86% (n = 61) of them were categorized as high risk and 14% (n = 10) were intermediate risk, whereas among conventional group 90% (n = 28) were high risk patients and 10% (n = 3) were of intermediate risk. In hypofractionated dose group, 14% (n = 10) developed grade 2 proctitis and 8% (n = 6) developed grade 2 cystitis, in contrast to conventional dose group in which only 3 patients (5%) developed grade 2 GI toxicity and 2 patients (2.9%) had grade 2 GU toxicity. However, these toxicities and their grade were clinically insignificant when compared with the dose groups (p = 0.11). 5 year overall survival for hypofractionated radiotherapy versus conventional dose was 100% and 90% respectively with 95% Cl and p value of 0.3 (clinically insignificant), whereas 5 year disease free survival was 100% and 75% for hypofractionation versus conventional EBRT respectively with 95% CI and p value of 0.04 (clinically significant).ConclusionHypofractionated radiotherapy in patients with intermediate and high risk localized prostate cancer has better disease free survival at the expense of higher risk for proctitis and cystitis but no difference in overall survival as compared to conventional dose of radiation.

Neoadjuvant pamiparib plus abiraterone and ADT for high-risk/very high-risk localized prostate cancer: Results of a prospective study.

Neoadjuvant pamiparib plus abiraterone and ADT for high-risk/very high-risk localized prostate cancer: Results of a prospective study.

Impact of a rash management guide on incidence and severity of rash with apalutamide: Experience from the Apa-RP study in high-risk localized prostate cancer.

Impact of a rash management guide on incidence and severity of rash with apalutamide: Experience from the Apa-RP study in high-risk localized prostate cancer.

Neoadjuvant darolutamide plus androgen deprivation therapy for high-risk/very high-risk localized prostate cancer: A multicenter, open-labeled, single-arm phase II trial.

Neoadjuvant darolutamide plus androgen deprivation therapy for high-risk/very high-risk localized prostate cancer: A multicenter, open-labeled, single-arm phase II trial.

Post radical prostatectomy (RP) PSA outcomes following 6 versus 18 months of perioperative androgen receptor signaling inhibitors (ARSI) in men with localized high-risk prostate cancer: Results of Part 2 of a randomized phase 2 trial.

326 Background: Patients with localized high-risk prostate cancer have an increased risk of relapse following RP. We previously reported on Part 1 of a phase 2 trial testing neoadjuvant apalutamide, abiraterone acetate, prednisone, plus leuprolide (AAPL) or abiraterone, prednisone, and leuprolide (APL) for 6 months followed by RP. We demonstrated favorable pathologic responses (tumor ≤5 mm) in 20.3% of patients (n=24/118). Herein, we report the results of Part 2 testing adjuvant AAPL. Methods: At Part 2, patients were randomized 1:1 to AAPL for 12 months (Arm 2A) or observation (Arm 2B), stratified by neoadjuvant therapy and pathologic T stage (&lt;ypT3 or ≥ypT3). The primary endpoint was biochemical progression-free survival (bPFS) at 3 years post-RP. Secondary endpoints included safety and time to testosterone recovery (&gt;200 ng/dL). Results: Overall, 69% (n=82/118) of patients enrolled to Part 1 were randomized to Part 2, of whom 58.5% (n=48) had ≥ ypT3 disease at RP. Patient preference was the main reason for non-randomization in Part 2. Of patients not randomized to Part 2, 32.3% (n=10) had a pathologic complete response or minimum residual disease (tumor ≤5 mm) at RP. In the intent-to-treat analysis, 3-year bPFS was 81% for Arm 2A and 72% for Arm 2B; the difference was not statistically significant (HR 0.81 90% CI 0.43-1.49). In a post-hoc per-protocol analysis, the 3-year bPFS was 83% for AAPL treated patients and 69% for patients on observation (HR 0.50 90% CI 0.26-0.97). Of patients randomized to Part 2, 81% of patients had testosterone recovery in the AAPL treated group compared to 95% in the observation group with median to recovery of 8.7 months compared to 4.0 months, respectively. Of the 37 patients receiving AAPL on Arm 2A, 28 (75.7%) experienced any grade treatment-related adverse event (TRAE) and 4 (10.8%) had grade 3-4 TRAE. The most common any grade TRAE were fatigue (27%) and hypertension (16%). Conclusions: Neoadjuvant ADT in localized high-risk prostate cancer resulted in favorable pathologic responses and 3-year bPFS in a subset of patients. As 30% of patients declined an additional 12 months of adjuvant treatment, Part B of the study was underpowered to detect a difference between treatment arms. Subsequent studies will evaluate clinical and molecular predictors of bPFS. Clinical trial information: NCT02903368 .

Phase II study of pembrolizumab in combination with radiation with or without olaparib in localized high-risk prostate cancer.

TPS351 Background: Definitive radiation therapy (DRT) combined with androgen deprivation therapy (ADT) remains the standard of care in patients with high-risk prostate cancer (HRPC) who do not want surgery. However, up to 50% experience biochemical recurrence (BCR) within 5 years. A phase 3 NCIC group reported the 10-year biochemical recurrence free survival was 63% in ADT plus DRT vs. 27% in ADT alone. There is an urgent need for effective novel combination strategies. We hypothesize combined immune sensitizing effects of PARPi and radiation will result in significant activity of immunotherapy in men with HRPC. Methods: This is a multicenter phase II randomized study to assess biochemical response rates, safety and tolerability of combined therapy in pts with localized HRPC who elected for concurrent DRT. A total of 64 pts will be randomized 1:1 to receive either pembrolizumab (P) combined with olaparib or single agent P in addition to the standard of care ADT with DRT. Hypofractionated IMRT (2.4 to 4 Gy per fraction over 4-6 weeks) will be delivered and all pts will receive adjuvant P for one year and ADT for at least 18 months. All pts will undergo germline testing. Key eligible criteria include biopsy confirmed prostate adenocarcinoma who meets at least one of the four high-risk features: 1) clinical T3a, T3b or T4, 2) N1, 3) Gleason grade group 4 or 5, and 4) PSA &gt;20 ng/ml. Patients with less than 2 cm pelvic nodes and received ADT therapy within 3months prior to study enrollment are allowed. PSA &gt;150 ng/ml and patients with distant metastases will be excluded. The primary endpoint is to assess the proportion of patients who achieve a PSA nadir level of ≤ 0.06 ng/ml within six months after completion of radiation therapy in each arm. The secondary objectives include safety/tolerability, BCR and metastasis-free survival at 3 years. BCR is defined by the Phoenix definition. The study is designed to detect a 15% improvement in PSA nadir ≤ 0.06 ng/mL within 6 months after completion of the combined therapy versus historical control group data Geara FB et al., 2017. Enrollment began in August 2023. Clinical trial information: NCT05568550 .

Approach to Patients with High-Risk Localized Prostate Cancer: Radiation Oncology Perspective.

High-risk localized prostate cancer is a challenging clinical entity to treat, with heterogeneous responses to an evolving array of multidisciplinary treatment approaches. In addition, this disease state is growing in incidence due to a variety of factors, including shifting recommendations that discouraged routine prostate cancer screening. Current guidelines now incorporate an informed decision-making process for prostate cancer screening and evaluation. More work is underway to improve targeted screening for certain at-risk populations and to implement greater personalization in the use of diagnostic tools. Once diagnosed with high-risk localized disease, a multimodality treatment paradigm is warranted. Radiation-in its various forms and combinations-plays a large and continually evolving role in the management of high-risk prostate cancer, yet treatment outcomes are still suboptimal. There is a growing need to improve upon current treatment approaches, and better personalize a particular treatment recommendation based on both tumor and patient characteristics, as well as patient preference and goals of therapy. Given that treatment generally requires more than one therapy, there are notable implications on long-term quality of life, especially with respect to overlapping and cumulative side effects of local and systemic therapies, respectively. The desire for aggressive therapy to optimize cancer control outcomes must be weighed against the risk of morbidities and overtreatment and discussed with each patient so that an informed decision about treatment and care can be determined. High-level evidence to support treatment recommendations, where available, is critical for a data-driven and tailored approach to address all goals of care.

Surgical Management and Considerations for Patients with Localized High-Risk Prostate Cancer.

Localized high-risk (HR) prostate cancer (PCa) is a heterogenous disease state with a wide range of presentations and outcomes. Historically, non-surgical management with radiotherapy and androgen deprivation therapy was the treatment option of choice. However, surgical resection with radical prostatectomy (RP) and pelvic lymph node dissection (PLND) is increasingly utilized as a primary treatment modality for patients with HRPCa. Recent studies have demonstrated that surgery is an equivalent treatment option in select patients with the potential to avoid the side effects from androgen deprivation therapy and radiotherapy combined. Advances in imaging techniques and biomarkers have also improved staging and patient selection for surgical resection. Advances in robotic surgical technology grant surgeons various techniques to perform RP, even in patients with HR disease, which can reduce the morbidity of the procedure without sacrificing oncologic outcomes. Clinical trials are not only being performed to assess the safety and oncologic outcomes of these surgical techniques, but to also evaluate the role of surgical resection as a part of a multimodal treatment plan. Further research is needed to determine the ideal role of surgery to potentially provide a more personalized and tailored treatment plan for patients with localized HR PCa.

Diagnostic capability of 18F-PSMA PET-MRI and pelvic MRI plus bone scan in treatment-naive prostate cancer: a single-center paired validating confirmatory study.

Radical prostatectomy with pelvic lymph node dissection for the treatment of high-risk localized prostate cancer (PCa) results in long-term benefits in selected patients. But insufficient sensitivity of conventional examinations which are pelvic MRI and bone scan, limits the diagnosis of bone and lymph node metastasis of PCa. This affects the surgical management strategy of a large number of patients. The purpose of this study was to investigate whether 18F-prostate-specific membrane antigen (PSMA) PET-MRI could improve the clinical detection of PCa metastases compared with the conventional pelvic MRI plus bone scan. From April 2020 to April 2023, we prospectively enroled 472 patients with histologically proven PCa in our centre, and 120 patients underwent 18F-PSMA PET-MRI, multiparametric MRI, and bone scan before laparoscopic radical prostatectomy plus lymph node dissection. The accuracy of imaging results in detecting lymph node and bone metastatic lesions was compared between PSMA PET-MRI and MRI plus bone scan. In diagnosing lymph node metastasis, PSMA PET-MRI had an area under the curve (AUC) of 0.844 (95% CI: 0.738-0.949, P < 0.001), sensitivity and specificity of 75% and 96%, which performed apparently better than MRI [AUC=0.615 (95% CI: 0.480-0.750, P =0.073)]. PSMA PET-MRI showed excellent expression in the diagnosis of bone metastases, with an AUC of 0.910 (95% CI: 0.840-0.981, P <0.001) compared to 0.700 (95% CI: 0.577-0.823, P =0.001) in bone scanning. PSMA PET-MRI also had higher sensitivity than bone scanning (90% vs. 43%), while lower specificity (92% vs. 97%). PSMA PET-MRI is superior to conventional imaging at diagnosing metastases in lymph nodes and bones in PCa and can provide a more accurate stagement.

Outcomes in patients with high- and very high-risk localized prostate cancer treated with definitive IMRT and long-term hormone therapy.

The aim of this study was to evaluate the effectiveness of intensity-modulated radiation therapy in combination with long-term androgen deprivation therapy for high-risk and very high-risk localized prostate cancer while also investigating factors associated with the therapeutic effect. Men who fulfilled criteria for the National Comprehensive Cancer Network high-risk or very high-risk localized prostate cancer and were treated with definitive intensity-modulated radiation therapy (74-78Gy) of the prostate and the seminal vesicle combined with androgen deprivation therapy in our institution from 2007 to 2016 were identified (n=197). In principle, patients received androgen deprivation therapy for 3-6months before radiation, concurrently, and for 2years after completion of intensity-modulated radiation therapy. The median follow-up period was 96months. The 5-year and 10-year overall survival rates in the overall population were 96.9% and 89.3%, respectively. The 5-year and 10-year cumulative incidence rates of biochemical failure were 2.5% and 16.3% in the high-risk group, and 8.6% and 32.0% in the very high-risk group, respectively, indicating a significant difference between the two groups (P=0.023). Grade Group 5 and younger age (cutoff: 70years old) were independent predictors of recurrence (P=0.016 and 0.017, respectively). Patients exhibiting biochemical failure within <18months after completion of androgen deprivation therapy displayed an increased risk of cancer-specific mortality (P=0.039) when contrasted with those who had a longer interval to biochemical failure. Patients with the National Comprehensive Cancer Network very high-risk prostate cancer, particularly those with Grade Group 5 and younger age, showed worse outcomes following intensity-modulated radiation therapy and long-term androgen deprivation therapy.

Timing of High-Dose-Rate Brachytherapy With External Beam Radiation Therapy in Patients With Intermediate- and High-Risk Localized Prostate Cancer and Its Effects on Toxicity and Quality of Life: A Randomized Controlled Trial (THEPCA)

BackgroundHDR brachytherapy(HDR-BT) and external beam radiotherapy(EBRT) are effective treatments for prostate cancer(PC) but cause genitourinary(GU) and gastrointestinal(GI) toxicities. There is no consensus on the timing of HDR-BT in relation to EBRT and the effect of sequencing on patients. ObjectiveThe primary objective was to assess differences, if any, in the incidence of Grade 3 or higher GU toxicities from treatment. We also aimed to explore the incidence of G1-4 GI toxicities, quality of life and patient satisfaction. Suppression of PSA and signals for survival differences were also analysed. MethodologyA single-centre randomised trial in intermediate and high-risk localised PC patients to receive HDR-BT before (Arm A) or after (Arm B) EBRT. Toxicities were graded using CTCAE. IIEF and FACT-P were used to assess erectile dysfunction and QOL at 0, 3, 9 and 12 months. Results50 patients were recruited to each arm, with 48 and 46 patients completing treatment and follow up in each arm. 81.5% had high-risk disease. There were no G3 or G4 GU or GI toxicities. G1 urinary frequency was the most common adverse event experienced in both arms, peaking in incidence 3 months after commencing treatment (45.7 and 42.2% in Arm A and B, respectively). Up to 11 % of patients reported G1 urinary frequency at 12 months. Other G1 GU toxicities experienced by >10% of patients were urinary tract obstruction, tract pain and urgency. These symptoms also peaked in incidence at 3 months. G2 GU toxicities were uncommon and experienced in a maximum of 2 patients within each arm at any time point.Over 30% of patients had G1 flatulence at baseline and this remained the most frequently occurring G1 GI toxicity throughout the study, peaking at 12months (21.4% and 25.6% in Arm A and Arm B, respectively). Other GI toxicities experienced by more than 10% of patients were GI pain, proctitis and rectal mucositis, most of which demonstrated a peak incidence at 3 or 9 months. G2 GI toxicities were uncommon, except G2 flatulence.No significant difference was found in CTCAE, IPSS, IIEF, FACT-P and QOL scores between the arms.Median PSA follow-up was 5 years. 7 patients had treatment failure in each arm. DFRS was 93.3% and 90.7% at 5 years in Arm A and B respectively, with median failure time of 60 and 48 months in Arm A and B respectively. There were no statistically significant difference between arms. ConclusionsThe sequencing of HDR-BT and EBRT did not impact the incidence of G3 or G4 toxicities and no significant differences were seen in other patient reported outcomes. Treatment was well tolerated with maintained QOL scores. Treatment failure was low in both arms in a high-risk cohort, however a larger study with longer follow up is underway to establish whether the difference in median time to failure between the two arms is a signal of superiority.