Treatment Options For Prostate Cancer Research Articles

Targeting the glutamine metabolism to suppress cell proliferation in mesenchymal docetaxel-resistant prostate cancer.

Docetaxel (DX) serves as a palliative treatment option for metastatic prostate cancer (PCa). Despite initial remission, acquired DX resistance is inevitable. The mechanisms behind DX resistance have not yet been deciphered, but a mesenchymal phenotype is associated with DX resistance. Mesenchymal phenotypes have been linked to metabolic rewiring, obtaining most ATP production by oxidative phosphorylation (OXPHOS) powered substantially by glutamine (Gln). Likewise, Gln is known to play an essential role in modulating bioenergetic, redox homeostasis and autophagy. Herein, investigations of Gln deprivation on DX-sensitive and -resistant (DR) PCa cells revealed that the DR cell sub-lines were susceptible to Gln deprivation. Mechanistically, Gln deprivation reduced OXPHOS and ATP levels, causing a disturbance in cell cycle progression. Genetic and chemical inhibition of the Gln-metabolism key protein GLS1 could validate the Gln deprivation results, thereby representing a valid therapeutic target. Moreover, immunohistological investigation of GLS1 revealed a high-expressing GLS1 subgroup post-docetaxel failure, exhibiting low overall survival. This subgroup presents an intriguing opportunity for targeted therapy focusing on glutamine metabolism. Thus, these findings highlight a possible clinical rationale for the chemical inhibition of GLS1 as a therapeutic strategy to target mesenchymal DR PCa cells, thereby delaying accelerated tumour progression.

A scoping review of the management of prostate cancer in Africa

Prostate cancer is one of the most frequently diagnosed cancers in menand a major cause of cancer-related deaths in men, globally. The managementof prostate cancer in Africa is unique; most patients present withadvanced disease as result of a largely under-developed healthcare delivery.However, due to the underdeveloped healthcare system in Africa,there are unique limitations to delivering these treatments. Thus, the needfor this scoping review on the management of prostate cancer in Africa.Aim: To give an account of the pattern of presentation, histological types,investigative and treatment modalities of prostate cancer in Africa. A literaturesearch through PubMed, Google Scholar, and African Journal Onlineon the management of prostate cancer in Africa was conducted. Results arethen reported according to the Preferred Reporting Items for SystematicReview and Meta-analyses extension for Scoping Review. Forty-three articlesfully satisfied the inclusion criteria and were used for this review.The commonest presentation of prostate cancer was lower urinarytract symptoms, followed by bone pain and urinary retention in that order.Adenocarcinoma was the commonest histological type for 98.5% of thestudy. A total 23.3% of patients had hormonal treatment which was the commonesttreatment option. Chemotherapy and open radical prostatectomywere used in 17.7 and 12.9% cases respectively. The use of robot-assistedradical prostatectomy was not an option of care noted in the review. Thefindings of this study highlight the need for integration of modern investigativemodalities and treatment options for prostate cancer in Africa.

Outcomes and patterns of use of Radium-223 in metastatic castration-resistant prostate cancer.

Radium-223 dichloride (Ra-223) is recommended as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients with symptomatic bone metastases and no visceral disease, after docetaxel failure, or in patients who are not candidates to receive it. In this study, we aimed to ambispectively analyze overall survival (OS) and prognostic features in mCRPC in patients receiving Ra-223 as per clinical routine practice and identify the most suitable treatment sequence. This study is observational, multicentric, and ambispective. Eligibility criteria included mCRPC patients treated with Ra-223, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, without visceral metastases, and no more than three cm involved lymph nodes. A total of 145 patients were included; the median age was 73.97 years, and a Gleason score of more than or equal to 7 in 61 (48%) patients; 73 (81%) had previously received docetaxel. The most important benefit was reached by those patients who received Ra-223 in the second-line setting, with a median OS of 17 months (95% CI, 12-21), and by patients who received six cycles of treatment, with a median OS of 19 months (95% CI, 14-21). An alkaline phosphatase (ALP) decrease was also identified as a prognosis marker. When performing the multivariate analysis, the time to develop castration-resistant disease longer than 24 months was the most important prognostic factor to predict the evolution of the patients receiving Ra-223. Ra-223 was well tolerated, with thrombocytopenia, anemia, and diarrhea being the main adverse events. There is a benefit for those patients who received Ra-223 in the second-line setting, regardless of prior use of docetaxel. In addition, a survival benefit for patients presenting with a decline in ALP was observed.

Prostate size ≥ 100g and its association with long-term outcomes of Retzius-sparing robot-assisted radical prostatectomy.

It is unknown whether perioperative and functional outcomes of Retzius-sparing robot-assisted radical prostatectomy (RS-RARP) may be affected by large prostate sizes (PS). All patients treated with RS-RARP were identified and compared according to PS. The definition of PS relied on the prostatic weight at final pathology (PS < 100g vs ≥ 100g). Multivariable logistic regression models tested immediate and 12-month urinary continence recovery (UCR, namely, 0-1 safety pad per-day), and positive surgical margins (PSM). Multivariable Poisson log-linear regression analyses tested operative time (OT), estimated blood loss (EBL), and length of stay (LOS). The analyses relied on the database of a high-volume European institution (2010-2022). Of 1,555 overall patients, 1503 (96.7%) had a PS < 100g and 52 (3.3%) had a PS ≥ 100g. No differences were recorded in LOS (3days), and intraoperative (1.9 vs 2.3%) as well as postoperative complications (13 vs 12%; all p values > 0.05). No significant difference was recorded in PSM (25 vs 23%, p = 0.6). In patients with PS ≥ 100g vs < 100g, immediate UCR rate was 42 vs 64% (p = 0.002), and 12-month UCR rate was 87 vs 88% (p = 0.3). PV ≥ 100g independently predicted worse immediate UCR (odds ratio 0.55, 95% CI 0.30-0.98, p = 0.044), but not worse 12-month UCR (p = 0.3) or higher PSM (p = 0.7). PV ≥ 100g independently predicted longer OT (incidence rate ratio [IRR] 1.12, 95% CI 1.10-1.15, p < 0.001) and higher EBL (IRR 1.26, 95% CI 1.24-1.28, p < 0.001), but not longer LOS (p = 0.3). RS-RARP is a valid option for prostate cancer treatment, even in case of very large prostates. Specifically, no significant association was recognized between PS ≥ 100g and PSM or 12-month UCR.

Ten-year functional and oncological outcomes of a prospective randomized controlled trial comparing laparoscopic versus robot-assisted radical prostatectomy.

Among prostate cancer (PCa) treatment options, mini-invasive surgical approaches have gained a wide diffusion in the last decades. The aim of this study was to present oncological, functional, and quality of life data after 10 years of follow-up of a prospective randomized controlled trial (RCT) (ISRCTN11552140) comparing robot-assisted radical prostatectomy (RARP) versus laparoscopic radical prostatectomy (LRP) for the treatment of PCa. Patients with localized PCa were randomized to undergo LRP or RARP between January 2010 and January 2011. Functional (continence and potency) and oncological (prostate-specific antigen, biochemical recurrence [BCR] and BCR-free survival [BCRFS]) variables were evaluated. BCRFS curves were estimated by the Kaplan-Meier method and compared using the log-rank test. Machine learning partial least square-discriminant analysis (PLS-DA) was used to identify the variables characterizing more the patients who underwent RARP or LRP. Seventy-five of the originally enrolled 120 patients remained on follow-up for 10 years; 40 (53%) underwent RARP and 35 (47%) LRP. Continence and potency recovery rates did not show significant differences (p = 0.068 and p = 0.56, respectively), despite a Δ12% for continence and Δ8% for potency in favor of the robotic approach. However, the quality of continence (in terms of International Consultation on Incontinence Questionnaire-Short Form [ICIQ-SF] score) and erection (in terms of International Index of Erectile Function-5 [IIEF-5] score) was significantly better after 10 years in the robotic group (p = 0.02 and p < 0.001). PLS-DA revealed that LRP was characterized by the worst functional-related outcomes analyzing the entire follow-up period. Four (10%) and six (17%) patients experienced BCR in RARP and LRP groups, respectively (p = 0.36), with an overall 10-year BCR-free survival of 88% and 78% (p = 0.16). Comparable continence and potency rates were observed between RARP and LRP after a 10-year follow-up. However, the RARP group exhibited superior totally dry rate and erection quality. No difference in terms of oncological outcomes was found.

Long-Term Trends in Decisional Regret Among Men with Localized Prostate Cancer

Purpose: There are several evidence-based treatment options for localized prostate cancer (PCa). Decisional regret (DR), or regret based on the treatment a patient chooses, is poorly understood in patients with PCa. We describe long-term trends in DR for patients with localized PCa and factors associated with regret. Materials and Methods: We surveyed an established prospective cohort of patients with PCa in North Carolina who were diagnosed between 2011 and 2013. DR was assessed by a validated instrument at 12, 24, 36, 48, 60, 72, 84, and 120 months after treatment or active surveillance (AS). We estimated the overall trend of DR and examined how DR was associated with treatment and demographic data using generalized linear mixed-model regressions. Results: The sample included 1456 men. At 12 months, 88% (n = 1100) of patients did not regret their treatment. With all time points included, DR increased slightly in early months and the speed of increase slowed over time (P = .003 for time, .02 for time-squared). Divorced men were more likely to have DR compared with married men (odds ratio [OR] = 1.5; 95% confidence interval [CI] 0.9-2.7). African Americans (OR = 1.5; 95% CI 1.0-2.1) and those who underwent surgery had significantly more regret (14.6%; 95% CI 11.3-18.0, P = .01) than patients of other racial groups or who underwent AS, respectively. Conclusions: Although DR is low overall in this cohort, being married and AS were associated with lower regret than those who were not married or who underwent surgery, respectively. Understanding factors that affect DR can guide urologists to more effectively direct resources and counseling.

Lonidamine Induced Selective Acidification and De-Energization of Prostate Cancer Xenografts: Enhanced Tumor Response to Radiation Therapy.

Prostate cancer is a multi-focal disease that can be treated using surgery, radiation, androgen deprivation, and chemotherapy, depending on its presentation. Standard dose-escalated radiation therapy (RT) in the range of 70-80 Gray (GY) is a standard treatment option for prostate cancer. It could be used at different phases of the disease (e.g., as the only primary treatment when the cancer is confined to the prostate gland, combined with other therapies, or as an adjuvant treatment after surgery). Unfortunately, RT for prostate cancer is associated with gastro-intestinal and genitourinary toxicity. We have previously reported that the metabolic modulator lonidamine (LND) produces cancer sensitization through tumor acidification and de-energization in diverse neoplasms. We hypothesized that LND could allow lower RT doses by producing the same effect in prostate cancer, thus reducing the detrimental side effects associated with RT. Using the Seahorse XFe96 and YSI 2300 Stat Plus analyzers, we corroborated the expected LND-induced intracellular acidification and de-energization of isolated human prostate cancer cells using the PC3 cell line. These results were substantiated by non-invasive 31P magnetic resonance spectroscopy (MRS), studying PC3 prostate cancer xenografts treated with LND (100 mg/kg, i.p.). In addition, we found that LND significantly increased tumor lactate levels in the xenografts using 1H MRS non-invasively. Subsequently, LND was combined with radiation therapy in a growth delay experiment, where we found that 150 µM LND followed by 4 GY RT produced a significant growth delay in PC3 prostate cancer xenografts, compared to either control, LND, or RT alone. We conclude that the metabolic modulator LND radio-sensitizes experimental prostate cancer models, allowing the use of lower radiation doses and diminishing the potential side effects of RT. These results suggest the possible clinical translation of LND as a radio-sensitizer in patients with prostate cancer.

Abstract 7525: Investigating B7-H3 as a checkpoint and antibody drug conjugate target across prostate cancer variants- both androgen receptor dependent and independent

Abstract Background: CD276 (B7-H3) has recently emerged as a promising presumptive immune checkpoint inhibitor (ICI) and antibody-drug conjugate (ADC) target for PCa. Unfortunately, current immunotherapy trials have yielded few objective responses in PCa and hormonal therapy seldom cures necessitating the need to develop new immunotherapy or targeted antibody-drug conjugate (ADC) treatment options for PCa, including B7-H3 targeted approaches. Method: In this work, we evaluated important ADC targets and immune checkpoints (PD-1, PD-L1, PD-L2, LAG3, TIGIT, OX40, 4-1BB, CTLA4, STEAP1, STEAP2, PSMA, NECTIN1, TROP-2, DLL3 and B7-H3) in various PCa cell lines and multiple patients spanning various subtypes of PCa using publicly available bulk RNA sequencing data and single-cell RNA sequencing (scRNA-seq) data respectively. The results were validated at RNA and protein levels in listed cell lines. Further, the impact of androgen receptor (AR) signaling on B7-H3 expression was quantified using charcoal stripped media, AR agonist (R1881) and antagonist (enzalutamide) using real-time PCR and flow cytometry at RNA and protein levels respectively. Results: We found that B7-H3 shows high expression and very low variability compared to other ADC targets and immune checkpoints in AR-positive (LnCAP), hormone-refractory (VCAP), Castrate resistant (22RVI), AR negative (PC3, DU145), and neuroendocrine (H660) cell lines, as well as in—PCa cells and tumor microenvironment (TME) myeloid cells—of multiple patients spanning various subtypes of PCa. Western blotting confirms the ubiquitous presence of B7-H3 in all these cell lines, even when PSMA is absent. Furthermore, B7-H3 expression was modifiable via androgen depletion, R1881 supplementation, or addition of the AR antagonist enzalutamide. These changes were significant in AR-positive LnCAP cells compared to AR-negative DU145 cells further endorsing the crosstalk between AR and B7-H3 signaling pathways, which will be presented in greater detail. Conclusion: This work explores the therapeutic relevance of important ADC targets and immune checkpoints for Prostate Cancer (PCa), highlighting B7-H3 as a unique therapeutic ADC and ICI candidate across the continuum of PCa—androgen sensitive, castration resistant, and neuroendocrine—due to its stable expression across various subtypes and on TME myeloid cells. The relationship between AR and B7-H3 opens the possibility of future combination therapies based on this interaction. Citation Format: Nikita Mundhara, Shivang Sharma, Emirhan Tekoglu, Ezra G. Baraban, Nathan A. Lack, Eugene Shenderov. Investigating B7-H3 as a checkpoint and antibody drug conjugate target across prostate cancer variants- both androgen receptor dependent and independent [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 7525.

Abstract 5838: Un-methylation of NUDT21 promotes the development of enzalutamide resistance in prostate cancer by regulation of 3’UTR usage switch

Abstract Enzalutamide, a second-generation anti-androgen drug, is a new treatment option for castration resistant prostate cancer (CRPC) patient. However, almost all CRPC patients develop drug resistance for enzalutamide after six to twelve months of treatment. According to our current findings, 3'UTR usage switches of RNA transcripts were observed in the prostate cancer specimen after acquiring enzalutamide resistance and nudix hydrolase 21 (NUDT21), an alternative polyadenylation (APA) regulator, was overexpressed in the enzalutamide resistant (EnzaR) cells, suggesting its potential role involved in regulation of 3'UTR usage switch. However, the underlying mechanism of how NUDT21 regulates 3'UTR usage switch during the development of enzalutamide resistance is still unclear. Interestingly, a potential mono-methylation (MME) is identified in NUDT21 protein by us, and it has never been examined before. Thus, we hypothesize that MME of NUDT21 may regulate the specificity of 3'UTR usage switch and involve in the development of EnzaR. To test the idea, a monoclonal antibody recognized NUDT21 MME was generated by us. Moreover, protein arginine methyltransferase 7 (PRMT7) was identified to be responsible for adding MME to NUDT21. In addition, androgen treatment increased both expression levels of NUDT21 MME and PRMT7 while decreased the expression level of NUDT21 total form in LNCaP cells via androgen receptor (AR) dependent manner. Next, co-treatment of enzalutamide and PRMT7 inhibitor leaded to increase of un-MME form of NUDT21 and it greatly enhanced the enzalutamide resistance in LNCaP cells. Importantly, binding profile of NUDT21 total form indeed had 3'UTR usage switch from distal to proximal APA site in COUP-TFII transcript after acquiring enzalutamide resistance, while its MME form attenuated this phenomenon. In addition, expression levels of NUDT21 MME and its total form were shown to conversely express in prostate cancer specimens. Finally, un-MME form of NUDT21 promoted the cancer growth in vitro and in vivo while its MME form did not. Taken together, our results suggest that down-regulation of PRMT7 by enzalutamide may lead to decrease of NUDT21 MME level and contribute to develop enzalutamide resistance by causing the 3'UTR usage switch of NUDT21 downstream transcript. Citation Format: Shin-Chih (Kenny) Lin, Shih-Chieh Lin. Un-methylation of NUDT21 promotes the development of enzalutamide resistance in prostate cancer by regulation of 3’UTR usage switch [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 5838.

Abstract 3238: Therapeutic targeting of the genome guardian sirtuins in metastatic prostate cancer

Abstract Introduction: The effective treatment paradigm for the lethal form of metastatic prostate cancer (mPCa) remains challenging. Almost all mPCas eventually develops therapy resistance against androgen receptor (AR) inhibitors (e.g., Enzalutamide, Abiraterone) or to poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors (Olaparib, Niraparib, Talazoparib) (HRRd) when used as monotherapy. Although the patients in the ARSi+PARPi combination produced significantly longer radiologic progression-free survival (rPFS), a substantial number had attained therapy resistance by the end of the study tenure. So, a newer therapy is urgently needed. In recent years, a new targetable therapeutics development domain has been unfolding with an expanding understanding of the role of SIRTuins in prostate cancer cell survival, invasion, and progression to an aggressive metastatic state. Here, we will investigate the therapeutic efficacy of SIRT1/7 inhibitor (SIRT1/7i) and determine synergy with DNA-damaging PARP inhibitor combinations through a battery of cell and molecular assays using various prostate cancer cellular models. Methods: We have treated the mPCa cell lines 22Rv1, LAPC4, PC3 and LnCAP as well as prostate epithelial cell line RWPE1 with SIRT1 inhibitor SIRT1-IN-2 (MedChemExpress, HY-146689), SIRT7 inhibitor 97491 (MedChemExpress, HY-135899) and AR inhibitor Enzalutamide individually as well as in combination of PARP inhibitor Olaparib. The treatment of the SIRT1 and SIRT7 monotherapy arm was 72 hours long, and combination therapy continued for 7 days. The cell viability was assessed with CellTiter-Glo® 2.0 Cell Viability Assay (Promega). The cell cycle progression and proliferation analysis were done using flow cytometry through Propidium iodide staining and AnnexinV-FITC apoptosis detection chemistry. Cell survival was orthogonally assessed using colony counting assays. We adopt RAD51 foci counting assays and COMET assays for evaluating treatment-induced genome instability. Results: The preliminary result suggested that the SIRT1i+Olaparib and SIRT7i+Olaparib combination significantly sensitized the mPCa cell lines 22Rv1, PC3, and LnCAP for cell death compared to the prostate epithelial cell RWPE1. Upon the combination treatment, the mPCa cell lines showed elevated apoptotic cell death, reconfirmed through colony counting assay. Conclusion: Therapeutic combination treatment of SIRT1 and SIRT7 inhibition with Olaparib could be an effective treatment option for aggressive metastatic prostate cancer. Citation Format: Subhajit Giri. Therapeutic targeting of the genome guardian sirtuins in metastatic 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 3238.

Abstract 1310: Social determinants of migrant health factors impacting prostate cancer care and survivorship among sub-Saharan African immigrant men diagnosed with prostate cancer

Abstract Background: Sub-Saharan African Immigrants (SSAI) represent one of the fastest-growing segments of the immigrant population in the United States (US). Between 2010 and 2018, the SSAI population in the US increased by 53%, significantly outpacing the 12% growth rate for the overall foreign-born population in the US during that time frame. Despite these growing numbers, little is published about the extent to which SSAIs adapt to health behaviors more common in the US or remain immersed in the values, beliefs and practices reflective of their country of origin. Importantly, no study has comprehensively examined the Social Determinants of Health (SDOH) among this population relative to their migration experiences and their influence on health-seeking behaviors and decision-making regarding prostate cancer care and treatment options. Methods: This qualitative study employed grounded theory and the social determinants of migrant heath framework to better understand the needs of SSAI prostate cancer survivors in the United States and how to effectively support these survivors. In-depth interviews were conducted with 8 survivors who live in the states of Florida and Minnesota. Findings: Some participants reported limited access to care and financial challenges paying for drugs. In terms of coping with diagnosis and treatment, most of the participants relied on their faith, a positive outlook about survivorship and support of family members. Some participants relied on the coaching and support of a loved one who experienced prostate cancer in the past. Erectile dysfunction severely impacted the sexual life of most participants as they experienced difficulty getting an erection. Conclusion: Participants expressed the benefit of belonging to support groups with other survivors for social and emotional support. As the number of immigrants from sub-Saharan continue to rise, so too will the demand for culturally tailored care to address and reduce disparities in survivorship among this sub-population. Citation Format: Ernest Kaninjing, Gladys Asiedu, Kaitlin Van Voorhis, Mary Ellen Young, Ebenezer Erefah, Emmanuel Agboola, Folakemi Odedina, Roxana Dronca, Kimlin Ashing, Solomon Rotimi, Che Ngufor, Arnola Merriweather, John McCall, Anthony Hill. Social determinants of migrant health factors impacting prostate cancer care and survivorship among sub-Saharan African immigrant men diagnosed with 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 1310.

Long-Term Follow-Up After Laparoscopic Radical Prostatectomy for Localized and Locally Advanced Prostate Cancer

Objective To explore the impact of laparoscopic radical prostatectomy (LRP) on lower urinary tract symptoms and erectile function. Materials and Methods A retrospective study was conducted on patients who underwent LRP at the Civil Hospital Ahmedabad’s Urology Department from June 2008 to June 2023. Results Major complications following LRP are generally rare, including bladder neck stenosis, erectile dysfunction, and urinary incontinence. The incidence of erectile dysfunction varies widely, ranging from 11-87%, and urinary incontinence ranges from 0-87%, depending on the definitions used. Functional decline typically peaks shortly after surgery, with the most rapid recovery occurring within the first year post-LRP. Some patients continue to improve gradually over time. However, for some men, these adverse effects can be long-lasting. Other, less common side effects should also be considered. Despite significant technological advancements in the past 20 years, no single surgical technique has emerged as superior in terms of long-term outcomes, as surgical volume, surgeon experience, and patient characteristics remain key determinants. Conclusion When discussing treatment options for prostate cancer, it is crucial to consider potential complications like erectile dysfunction and urinary incontinence following LRP, as well as the expected recovery period. Counseling is provided to patients, taking into account their age and overall health profile. Surgical advice is given to eligible patients after evaluating the risk-benefit ratio. Patients who are older or do not meet the criteria are given appropriate guidance. All patients are informed about the possible complications after surgery and are presented with the option of palliative care or surgical treatment.

Updates in Precision Oncology in Prostate and Urothelial Cancer

Basic science, translational, and clinical genomic advances in prostate and urothelial cancer have therapeutic implications. Poly(ADP-ribose) polymerase (PARP) inhibitors target cancer cells with homologous recombination repair genomic deficiencies to induce synthetic lethality. PARP inhibitors are approved for BRCA-altered castration resistant prostate cancer treatment either as single agent or in combination with novel hormonal therapies. Another genomic target in prostate cancer is the androgen receptor, especially overcoming resistance via the AR-V7 splice variant and other mechanisms. Strategies for overcoming this resistance, including N-terminal domain inhibitors and PROTAC degraders, are under investigation. Immune checkpoint inhibition is a treatment option for metastatic castrate resistant prostate cancer for patients with mismatch repair deficiency, and neoantigen-based vaccines are under development to harness the immune system to fight prostate cancer. In urothelial cancer, FGFR3 is an important prognostic and predictive marker, often indicative of luminal tumors by gene expression profiling. Erdafitinib targets FGFR alterations and is approved for treatment of refractory metastatic urothelial cancer. Antibody-drug conjugates, including enfortumab vedotin and sacituzumab govitecan, are additional targeted approaches utilized to manage urothelial cancer.

Revolutionizing localized prostate cancer treatment: Stereotactic radiotherapy "Moroccan experience".

Prostate cancer is the most common urological cancer, and its incidence is increasing. Radical prostatectomy and radiotherapy are theprimary treatments for localized forms. Stereotactic Body RadioTherapy (SBRT), a new and innovative therapy, has been validated for some cancer localizations but not yet for localized prostate cancer. Our study aims to report the efficacy and tolerance results of SBRT for localized prostate cancer. This is a retrospective study of 27 patients with localized prostate cancer (CaP) who were treated with SBRT in our department from 2017 to 2021 using transponders for tumor tracking. The dose was 36.25 Gy delivered in five fractions of 7.25 Gy. The delineation and doses of organs at risk were determined based on the recommendations of the SFRO and the TG101 report of medical physics. All patients were treated using a latest-generation linear accelerator (True Beam STXÒ). Acute toxicities were observed in 33.3% of cases, with 22.2% grade 1 or 2 genitourinary (GU) and no grade 3 while 11.1% gastrointestinal (GI) toxicities were reported as grade 1-2 (7.4%) and one case grade 3 (3.7%). Late grade 1 or 2 GU toxicity was observed in 14.84% of cases, with no reports of late GI toxicity. After a 26-month follow-up period, the biochemical failure-free survival rate was 92.6%. The results of our study are consistent with the existing literature and support the safety and effectiveness of SBRT as a treatment option for localized prostate cancer (CaP). In the United States, both ASTRO and the NCCN recognize SBRT as a valid treatment option for localized CaP. Ongoing phase III trials are being conducted to further substantiate these long-term results and to establish SBRT as the future standard of care for localized CaP.

(362) Stress Urinary Incontinence Rates in Men Undergoing Optilume Balloon Dilation for Radiation-Induced Posterior Urethral Stenosis: A Single Center Experience

Abstract Introduction While radiation can be a viable treatment option for prostate cancer, development of radiation-induced urethral stenosis occurs in approximately 2% of patients. Optilume, a paclitaxel-coated urethral dilation balloon was FDA approved in 2021 and has shown improved urethral patency and reduced rates of reintervention for anterior urethral strictures relative to standard endoscopic procedures. As the utility of Optilume expands into posterior urethral stenosis, it is important to identify the associated potential complications. Incidence of stress urinary incontinence (SUI) has been reported to be as high as 33% following urethroplasty for patients with radiation-induced urethral stenoses. Rates of SUI following Optilume balloon dilation have yet to be evaluated in this high-risk population. Objective To evaluate rates of SUI in patients undergoing Optilume balloon dilation for radiation-induced posterior urethral stenosis. Methods From March 2022 to February 2023, select men with radiation-induced posterior urethral stenoses underwent Optilume balloon dilation. Initial evaluation included retrograde urethrogram and/or diagnostic cystoscopy. Dilation was performed with a 30-French Optilume and left inflated for five minutes per standard protocol. A 16-French catheter was inserted and left in place for three to five days. Patients were scheduled for a three-month post-dilation cystoscopy. Pre- and post-dilation continence rates were compared. Results A total of 16 men with confirmed radiation-induced posterior urethral stenoses underwent Optilume balloon dilation. Of the 16 patients, 12 patients had documentation regarding their pre- and post-treatment continence status. No patients developed de novo SUI. Baseline pre-treatment SUI was noted in one patient (8.3%) requiring an average of 4 Depends per day. This patient noted no change in his degree of SUI following Optilume dilation and the dilation site was found to be widely patent on his follow up cystoscopy. He is scheduled for artificial urinary sphincter in the near future. Mean follow up was 77 days (range 30-180 days). Repeat intervention was required in three patients (18.8%) for repeat stenosis. Conclusions Optilume balloon dilation for radiation-induced posterior urethral stenosis does not appear to lead to de novo SUI in short to intermediate term follow up. Further prospective studies with a larger group of patients and longer follow up duration are warranted in this complex population. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Laborie.

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.

Impact of exposure to clinical trials and standard-of-care therapy in metastatic or recurrent prostate cancer: An update.

76 Background: Treatment (tx) options for metastatic prostate cancer (mPC) have advanced significantly. Literature shows that access to, and uptake of, clinical trials or standard intensified tx in mPC may be low. Methods: We conducted further survival analysis on all consecutive patients (pts) diagnosed with any stage of PC between 2016-2017 in British Columbia, and only included pts with de novo metastasis or later recurrence. We performed descriptive statistics, univariate and multivariate analysis to examine overall survival (OS). Results: This study included 796 pts with either de novo metastatic (n=554, 69.6%) or recurrent PC (N=242; 30.4%); 743 (93.3%) had metastasis by time of cutoff (Sep 1, 2022). Median age at diagnosis of mPC in all patients was 73 (range 45-98). 790 (99.2%) started androgen deprivation tx (ADT). 263 (35.4%) had additional line of tx started with ADT at hormone sensitive mPC (mHSPC); 309 (38.8%) had 1st line tx started at castrate resistant mPC (mCRPC). Radiotherapy (RT) to prostate for mPC were given to 93 (11.6%). 307 (38.6%) received 1 line of tx; 181 (22.7%), 2; 128 (16.1%), 3 or more. 432 (54.3%) received ≥1 androgen receptor pathway inhibitors (ARPI). At cutoff, 474 (59.5%) died; most (n=400; 84.4%) died of prostate cancer. 35 pts who went on trial had longer mOS than those who did not go on trial (63.6 vs 39.5m, p=0.025). Pts with 5 or 6 lines of therapy had numerically longer but statistically similar mOS than those who had 1 (51.7m vs. 63.7m vs. 38.1m, p=0.47). Pts who got 1 line of ARPI had statistically similar mOS than those not exposed to ARPI (43.3m vs. 39.5m, p=0.89). In pts with de novo mPC, more than 1 line (44.3m) or 1 line of ARPI (42.1m) were associated with numerically longer but statistically similar mOS compared to no ARPI (30.1m, p=0.47); pts with recurrent mPC showed an opposite trend (22.5 vs 48.5m vs. not reached, p=0.009). In multivariable analysis, RT to prostate for mPC was associated with better mOS in mHSPC (HR 0.409, 95% CI 0.180 – 0.92, p=0.032) but not mCRPC. None of age, PSA at metastasis, Gleason score, or ADT type was identified as an independent factor affecting mOS. No significant differences in mOS was seen with varying years of mPC diagnosis (2015-2022). Conclusions: Our multicentre data suggest that access to clinical trials and timely RT to prostate in appropriate pts with mPC are associated with longer mOS and should be considered standard of care. Access to clinical trials may be challenging for a significant proportion of pts. Exposure to as many lines of tx/ARPI as possible may potentially help in pts with de novo mPC, but more data are required to determine benefit in all subgroups.

Follow-up of vascular-targeted photodynamic therapy in a real-world setting

PurposeVascular-targeted photodynamic therapy (VTP) is an approved treatment option for unilateral low-risk prostate cancer (PCa).MethodsPatients with unilateral low- or intermediate-risk PCa undergoing hemiablation by VTP were evaluated in a real-world setting. Oncological outcome after VTP was measured by MRI-based re-biopsy at 12 and 24 months. Functional outcome after 1 year was investigated by IIEF-5 and IPSS questionnaires. Progression was defined as the evidence3 of ISUP ≥ 2 PCa.ResultsAt any control biopsy (n = 46) after VTP, only 37% of patients showed no evidence of PCa. Recurrence-free survival was 20 months (95% CI 4.9–45.5) and progression-free survival was 38.5 months (95% CI 33.5–43.6 months). In-field and out-field recurrent PCa occurs in 37% (55% ISUP ≥ 2 PCa) and 35% (56% ISUP ≥ 2 PCa). Seventy-nine percent of patients preserved erectile function, respectively. Ten percent of patients presented long-term bladder outlet obstruction. None of the patients presented incontinence.ConclusionDue to the high-recurrence in- and out-field recurrence rate in a mainly low-risk prostate cancer cohort, VTP has to be regarded critically as a therapy option in these patients. Pre-interventional diagnostic evaluation is the main issue before focal therapy to reduce the risk of tumor recurrence and progression.

Quantitative imaging for 177Lu-PSMA treatment response monitoring and dosimetry

PSMA-targeted radiopharmaceutical therapy is an established treatment option for metastatic castration-resistant prostate cancer (mCRPC). However, response rates and duration using 177Lu-PSMA-617 vary considerably between patients. Quantitative 177Lu SPECT imaging is one approach that may be leveraged to more closely monitor inter-cycle response, as well as patient-specific absorbed doses. In this work, we describe our experience implementing quantitative imaging throughout the course of 177Lu-PSMA treatment, including serial SPECT imaging to monitor response and for individualized dosimetry. We also describe our imaging protocols and dose calculation workflows for 3D voxelized patient-specific organ and tumor dosimetry, including a review of the current landscape and efforts towards harmonized dosimetry.

Versatile Design of Organic Polymeric Nanoparticles for Photodynamic Therapy of Prostate Cancer.

Radical prostatectomy is a primary treatment option for localized prostate cancer (PCa), although high rates of recurrence are commonly observed postsurgery. Photodynamic therapy (PDT) has demonstrated efficacy in treating nonmetastatic localized PCa with a low incidence of adverse events. However, its limited efficacy remains a concern. To address these issues, various organic polymeric nanoparticles (OPNPs) loaded with photosensitizers (PSs) that target prostate cancer have been developed. However, further optimization of the OPNP design is necessary to maximize the effectiveness of PDT and improve its clinical applicability. This Review provides an overview of the design, preparation, methodology, and oncological aspects of OPNP-based PDT for the treatment of PCa.