Treatment Of Castration-resistant Prostate Cancer Research Articles

MP20-12 PiR-hsa-24683 IS ESSENTIAL FOR PROSTATE TUMOR-PROPAGATING CELLS AND PROMOTE THE DEVELOPMENT OF CASTRATION RESISTANCE

You have accessJournal of UrologyCME1 Apr 2023MP20-12 PiR-hsa-24683 IS ESSENTIAL FOR PROSTATE TUMOR-PROPAGATING CELLS AND PROMOTE THE DEVELOPMENT OF CASTRATION RESISTANCE Qiang Peng, Peter Ka-Fung Chiu, Tingting Xie, Jeremy Yuen-Chun Teoh, and Chi-Fai Ng Qiang PengQiang Peng More articles by this author , Peter Ka-Fung ChiuPeter Ka-Fung Chiu More articles by this author , Tingting XieTingting Xie More articles by this author , Jeremy Yuen-Chun TeohJeremy Yuen-Chun Teoh More articles by this author , and Chi-Fai NgChi-Fai Ng More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003245.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: PIWI-interacting RNAs (piRNAs) are a class of small non-coding RNAs (sncRNAs) mechanistically similar to but much less studied than microRNAs. piRNAs represent the most diversified sncRNAs that are widely involved in the pathogenesis of different types of cancers including prostate cancer (PCa). Our study aimed to investigate the role of piRNAs in the development of castration-resistant prostate cancer (CRPC). METHODS: Small RNA sequencing was used to explore the CRPC associated piRNAs on a basis of 10 benign prostate tissues, 10 paired hormone-sensitive PCa tissues and CRPC tissues from the same patients. The top 8 upregulated piRNAs were validated through qRT-PCR in a bigger cohort. piR-hsa-24683 was selected and investigated its biological function by gain of function in vitro. To study its loss of function role, an androgen-independent PCa cell (LNCaP-AI) was established. For mechanistic investigation, the mRNA sequencing analysis of differentially expressed genes (DEGs) was conducted in PCa cells transfected with control/piR-hsa-24683 mimics. Then, potential downstream targets were further predicted by miRanda program and validated by qRT-PCR. RESULTS: piR-hsa-24683 demonstrated a relatively higher expression level in both CRPC tissues and CRPC cell lines when compared with PCa tissues and cells. Functionally, overexpression of piR-hsa-24683 could confer resistance to androgen deprivation and anti-androgen in PCa cells in vitro, whereas anti-sense RNA against the piR-hsa-24683 could potentiate the sensitivity to androgen deprivation in LNCaP-AI cell. In addition, piR-hsa-24683 showed the ability in promoting sphere formation, migration and invasion of PCa cells. Mechanistically, mRNA sequencing results identified a panel of downstream target-genes. Among them, serine/threonine kinase 3 (STK3) was predicted to have a direct binding relationship with piR-hsa-24683, and was successfully verified to be negatively regulated by piR-hsa-24683. CONCLUSIONS: Our study showed, for the first time, that piR-hsa-24683 can contribute to androgen insensitivity in CRPC. This sheds a new insight into the regulation of CRPC by a sncRNA piRNA, which may form the basis of a novel target in the treatment of CRPC. Source of Funding: UGC Research Matching Fund 8601404 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e279 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Qiang Peng More articles by this author Peter Ka-Fung Chiu More articles by this author Tingting Xie More articles by this author Jeremy Yuen-Chun Teoh More articles by this author Chi-Fai Ng More articles by this author Expand All Advertisement PDF downloadLoading ...

Apalutamide as a therapeutic option in case of local failure in the nmCRPC

Apalutamide is a non-steroidal selective androgen receptor inhibitor approved for the treatment of high-risk non-metastatic castration-resistant prostate cancer and metastatic hormone-sensitive prostate cancer. The paper describes a case of a patient diagnosed with prostate cancer with a long-term course of the disease. The patient was diagnosed with a non-metastatic castration-resistant stage 18 years after primary treatment. Systemic treatment with apalutamide was recommended. Initially, the treatment was carried out as part of the extended access to apalutamide program and from March 2022 as part of the B.56 drug program. The study presents the effectiveness and safety of the therapy in a 12-month follow-up period and discusses controversial aspects of the patient's previous treatments.

Apalutamide as a new option for postponing metastatic disease in hormone-resistant patients with biochemical recurrence in prostate cancer

Treatment of non-metastatic castration-resistant prostate cancer is a radically new option for cancer patients. Novel anti-hormonal therapy not only improves metastasis free survival but overall survival times and positively impacts quality of life. This case shows how apalutamide lowered tPSA level and postponed metastatic disease.

Sequencing impact and prognostic factors in metastatic castration-resistant prostate cancer patients treated with cabazitaxel: A systematic review and meta-analysis.

Cabazitaxel is an effective treatment of post-docetaxel metastatic castration-resistant prostate cancer (mCRPC). We aimed to assess the sequencing impact and identify prognostic factors of oncologic outcomes in mCRPC patients treated with cabazitaxel. PUBMED, Web of Science, and Scopus databases were searched for articles published before January 2022 according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement. Studies were deemed eligible if they investigated pretreatment clinical or hematological prognostic factors of overall survival (OS) in mCRPC patients with progression after docetaxel treated with available treatments including cabazitaxel. Overall, 22 studies were eligible for the meta-analysis. In mCRPC patients treated with docetaxel, subsequent treatment with cabazitaxel was associated with better OS compared to that without cabazitaxel (pooled hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.56-0.89). Among the patients treated with cabazitaxel, several pretreatment clinical features and hematologic biomarkers were associated with worse OS as follows: poor performance status (PS) (pooled HR: 1.92, 95% CI: 1.33-2.77), presence of visceral metastasis (pooled HR: 2.13, 95% CI: 1.62-2.81), symptomatic disease (pooled HR: 1.47, 95% CI: 1.25-1.73), high PSA (pooled HR: 1.76, 95% CI: 1.27-2.44), high alkaline phosphatase (ALP) (pooled HR: 1.45, 95% CI: 1.28-1.65), high lactate dehydrogenase (LDH) (pooled HR: 1.54, 95% CI: 1.00-2.38), high c-reactive protein (CRP) (pooled HR: 4.40, 95% CI: 1.52-12.72), low albumin (pooled HR:1.09, 95% CI: 1.05-1.12) and low hemoglobin (pooled HR:1.55, 95% CI: 1.20-1.99). Sequential therapy with cabazitaxel significantly improves OS in post-docetaxel mCRPC patients. In mCRPC patients treated with cabazitaxel, patients with poor PS, visceral metastasis, and symptomatic disease were associated with worse OS. Further, pretreatment high PSA, ALP, LDH or CRP as well as low hemoglobin or albumin, were blood-based prognostic factors for OS. These findings might help guide the clinical decision-making for the use of cabazitaxel and prognostication of its OS benefit.

PD16-01 SYNERGISTIC EFFECTS OF CURCUMIN AND LACTOFERRIN TO INHIBIT THE PROSTATIC CANCER CELLS GROWTH AND MIGRATION ABILITY

You have accessJournal of UrologyCME1 Apr 2023PD16-01 SYNERGISTIC EFFECTS OF CURCUMIN AND LACTOFERRIN TO INHIBIT THE PROSTATIC CANCER CELLS GROWTH AND MIGRATION ABILITY Erica Costantini, Michele Marchioni, Lisa Aielli, Simone Ferretti, Antonio De Palma, Davide Ciavarella, Giulio Litterio, Marcella Reale, Marta Di Nicola, and Luigi Schips Erica CostantiniErica Costantini More articles by this author , Michele MarchioniMichele Marchioni More articles by this author , Lisa AielliLisa Aielli More articles by this author , Simone FerrettiSimone Ferretti More articles by this author , Antonio De PalmaAntonio De Palma More articles by this author , Davide CiavarellaDavide Ciavarella More articles by this author , Giulio LitterioGiulio Litterio More articles by this author , Marcella RealeMarcella Reale More articles by this author , Marta Di NicolaMarta Di Nicola More articles by this author , and Luigi SchipsLuigi Schips More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003271.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Castration resistant prostate cancer (CRPC) represents a challenge in urologic oncology. Several treatments are available for this tumor, but their efficacy tends to reduce in time. In recent years, several natural compounds have been tested as possible adjuvant treatment in CRPC patients. Among the other curcumin (CU) showed interesting bioactive properties, but low penetration within cells. We hypothesized that the combination with lactoferrin (LF) might exert a synergistic effect on prostatic cancer cells as anti-cancer. Their effects have been evaluated in PC3 and DU145 prostate cancer cells, that are in vitro models of CRPC. METHODS: Human CRPC cell lines (DU-145, PC3) were cultured in medium added with or without LF (175 µM) ± CU (2.5 µg/ml and 5 µg/ml). Cell viability was determined using a standard colorimetric 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) reduction assay. To test ability of cell migration observation at 6 and 24 h after scratch wounds were made. Quantitative Real-time PCR was performed to evaluate gene expression of death receptors (DR) and integrins (α3/β1). The human annexin V ELISA assay was used for the quantitative detection of annexin V, involved in apoptosis regulation. RESULTS: In PC3 cells, the proliferation rate is reduced by treatments alone or in association, with a significant reduction in presence of CU, both at 2.5 (p=0.007) and 5 ug/ml (p=0.001), in a dose-dependent manner. In DU145 cells, the inhibitory effect of CU is more significant in presence of LF. In PC3 migration, LF significantly weakened invasion capacity with an increase of the cell-free area of 24.9%, 31.8%, and 24% respectively in presence of LF alone, CU2.5+LF and CU5+LF, after 6 h, with similar results in DU145 cells. In accord the integrins α3/β1, showed a significant reduction in both prostate cell lines, in presence of CU2.5, CU5, and LF175 and their combination (p<0.005). Moreover, in PC3 and DU145 an upregulation of pro-apoptotic DR4 and DR5 gene expression have been observed. Finally, in both PC3 and DU145 cells line an increased concentration of human annexin V, a marker of apoptosis, have been recorded (p<0.005). CONCLUSIONS: Our results showed that the association of CU and LF might led to beneficial effect on CRPC prostate cancer reducing the proliferative activity of cancerous cells and their ability to migrate and produce metastases. In addition, we can suggest a potential pro-apoptotic effect of CU and LF leading to a potential application as an adjuvant treatment for the treatment of CRPC. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e489 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Erica Costantini More articles by this author Michele Marchioni More articles by this author Lisa Aielli More articles by this author Simone Ferretti More articles by this author Antonio De Palma More articles by this author Davide Ciavarella More articles by this author Giulio Litterio More articles by this author Marcella Reale More articles by this author Marta Di Nicola More articles by this author Luigi Schips More articles by this author Expand All Advertisement PDF downloadLoading ...

Apalutamide in the treatment of non-metastatic castration-resistant prostate cancer in an elderly patient with multiple comorbidities

Prostate cancer has been the most common malignant tumor in men in Poland since 2016 and is the second cause of death in this group of patients. The basic method of treatment in patients with advanced prostate cancer is androgen deprivation therapy, however, over time, the tumor evolves into a castration-resistant form, which poses a significant threat to the patient's life. This article presents a case of an elderly patient with internal diseases, who in the castration-resistant stage, was treated with a new generation androgen receptor blocker – apalutamide – in the first line of systemic treatment.

Development of a dual targeting scaffold of SET7/MLL inhibitor for castration-resistant prostate cancer treatment

Development of a dual targeting scaffold of SET7/MLL inhibitor for castration-resistant prostate cancer treatment

NIR-triggerable self-assembly multifunctional nanocarriers to enhance the tumor penetration and photothermal therapy efficiency for castration-resistant prostate cancer

Great challenges still remain in the management of patients with castration-resistant prostate cancer (CRPC) based on traditional treatments, and the rapid development of nanotechnology may find a breakthrough. Herein, a novel type of multifunctional self-assembly magnetic nanocarriers (IR780-MNCs) containing iron oxide nanoparticles (Fe3O4 NPs) and IR780 iodide was synthesized by an optimized process. With a hydrodynamic diameter of 122 nm, a surface charge of –28.5 mV and the drug loading efficiency of 89.6%, IR780-MNCs have increased cellular uptake efficiency, long-term stability, ideal photothermal conversion ability and excellent superparamagnetic behavior. The in vitro study indicated that IR780-MNCs have excellent biocompatibility and could induce significant cell apoptosis under the 808 nm laser irradiation. The in vivo study showed that IR780-MNCs highly accumulated at the tumor area could reduce the tumor volume of tumor-bearing mice by 88.5% under the 808 nm laser irradiation, but minimal damage to surrounding normal tissues. Since IR780-MNCs encapsulated a large number of 10 nm homogeneous spherical Fe3O4 NPs, which can be used as T2 contrast agent, the best window for photothermal therapy can be determined through MRI. In conclusion, IR780-MNCs have initially showed excellent antitumor effect and biosafety in the treatment of CRPC. This work provides novel insights into the precise treatment of CRPC by using a safe nanoplatform based on the multifunctional nanocarriers.

A Clinically-Achievable Injectable and Sprayable in Situ Lyotropic Liquid Crystalline Platform in Treating Hormone-Sensitive and Castration-Resistant Prostate Cancer.

When it comes to long-acting injections, lyotropic liquid crystals (LLCs) are considered as an effective and powerful drug delivery technology due to their low manufacturing and injection difficulty, consistent releasing behaviors with low burst, as well as broadly applicable drug loading capacity. However, monoolein and phytantriol, as two widely used LLC-forming materials, may give rise to tissue cytotoxicity and undesired immunological responses, which may hinder the wide application of this technology. In this study, we opted for two ingredients, phosphatidylcholine and α-tocopherol, as carriers on account of their nature-obtainable and biocompatible qualities. By changing the ratios between them, we conducted research on crystalline types, nanosized structures, viscoelastic differences, characteristics of releasing behaviors, and in vivo safety. To fully exploit this in situ LLC platform with both injectability and sprayability, we focused on the treatment of both hormone-sensitive (HSPC) and castration-resistant prostate cancer (CRPC). For HSPC, we found that spraying leuprolide and a cabazitaxel-loaded LLC platform on the tumor bed after resection greatly reduced tumor metastatic rate and prolonged the survival time. Besides, for CRPC, our results demonstrated that although leuprolide (a kind of drug for castration) alone could hardly limit the progression of CRPC with low MHC-I expression, its combination with cabazitaxel in our LLC platform achieved a significantly better tumor-inhibiting and anti-recurrent efficacy than single cabazitaxel-loaded LLC platform, owing to enhanced CD4+ T cell infiltration in tumors and immune-potentiating cytokines. In conclusion, our dual-functional and clinically achievable strategy might provide a treating solution toward both HSPC and CRPC.

LOX-1 Activation by oxLDL Induces AR and AR-V7 Expression via NF-κB and STAT3 Signaling Pathways Reducing Enzalutamide Cytotoxic Effects.

The oxidized low-density lipoprotein receptor 1 (LOX-1) is one of the most important receptors for modified LDLs, such as oxidated (oxLDL) and acetylated (acLDL) low-density lipoprotein. LOX-1 and oxLDL are fundamental in atherosclerosis, where oxLDL/LOX1 promotes ROS generation and NF-κB activation inducing the expression of IL-6, a STAT3 activator. Furthermore, LOX-1/oxLDL function has been associated with other diseases, such as obesity, hypertension, and cancer. In prostate cancer (CaP), LOX-1 overexpression is associated with advanced stages, and its activation by oxLDL induces an epithelial-mesenchymal transition, increasing angiogenesis and proliferation. Interestingly, enzalutamide-resistant CaP cells increase the uptake of acLDL. Enzalutamide is an androgen receptor (AR) antagonist for castration-resistant prostate cancer (CRPC) treatment, and a high percentage of patients develop a resistance to this drug. The decreased cytotoxicity is promoted in part by STAT3 and NF-κB activation that induces the secretion of the pro-inflammatory program and the expression of AR and its splicing variant AR-V7. Here, we demonstrate for the first time that oxLDL/LOX-1 increases ROS levels and activates NF-κB, inducing IL-6 secretion and the activation of STAT3 in CRPC cells. Furthermore, oxLDL/LOX1 increases AR and AR-V7 expression and decreases enzalutamide cytotoxicity in CRPC. Thus, our investigation suggests that new factors associated with cardiovascular pathologies, such as LOX-1/oxLDL, may also promote important signaling axes for the progression of CRPC and its resistance to drugs used for its treatment.

A phase II randomized trial of metastasis-directed therapy with alpha emitter radium-223 in men with oligometastatic castration-resistant prostate cancer (MEDAL)

BackgroundThe significance of metastasis-directed therapy for oligometastatic prostate cancer has been widely discussed, and targeted therapy for progressive sites is a feasible option as a multidisciplinary treatment for castration-resistant prostate cancer (CRPC). When oligometastatic CRPC with only bone metastases progresses after targeted therapy, it tends to progress as multiple bone metastases. The progression of oligometastatic CRPC after targeted therapy may be due in part to the presence of micrometastatic lesions that, though undetected on imaging, were present prior to targeted therapy. Thus the systemic treatment of micrometastases in combination with targeted therapy for progressive sites is expected to enhance the therapeutic effect. Radium-223 dichloride (radium-223) is a radiopharmaceutical that selectively binds to sites of increased bone turnover and inhibits the growth of adjacent tumor cells by emitting alpha rays. Therefore, for oligometastatic CRPC with only bone metastases, radium-223 may enhance the therapeutic effect of radiotherapy for active metastases.MethodsThis phase II, randomized trial of Metastasis-Directed therapy with ALpha emitter radium-223 in men with oligometastatic CRPC (MEDAL) is designed to assess the utility of radium-223 in combination with metastasis-directed radiotherapy in patients with oligometastatic CRPC confined to bone. In this trial, patients with oligometastatic CRPC with three or fewer bone metastases on whole-body MRI with diffusion-weighted MRI (WB-DWI) will be randomized in a 1:1 ratio to receive radiotherapy for active metastases plus radium-223 or radiotherapy for active metastases alone. The prior use of androgen receptor axis-targeted therapy and prostate-specific antigen doubling time will be used as allocation factors. The primary endpoint will be radiological progression-free survival against progression of bone metastases on WB-DWI.DiscussionThis will be the first randomized trial to evaluate the effect of radium-223 in combination with targeted therapy in oligometastatic CRPC patients. The combination of targeted therapy for macroscopic metastases with radiopharmaceuticals targeting micrometastasis is expected to be a promising new therapeutic strategy for patients with oligometastatic CRPC confined to bone.Trial registration Japan Registry of Clinical Trials (jRCT) (jRCTs031200358); Registered on March 1, 2021, https://jrct.niph.go.jp/latest-detail/jRCTs031200358

Prostate-specific antigen response after Abiraterone treatment in mCRPC: PSA as a predictor of overall survival

Abiraterone Acetate (AA) is an important agent in the treatment of advanced prostate cancer. It was primarily approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) after failure of androgen deprivation therapy. There is still no available strong data regarding the impact of early decline of prostate-specific antigen (PSA) in the overall survival. The aim of this study was to evaluate the clinical efficacy of an early prostate-specific antigen response as a predictor of overall survival (OS) in metastatic castration-resistant prostate cancer when treated with Abiraterone Acetate. A dual center, retrospective, cohort study on patients diagnosed with mCRPC treated with abiraterone between 2013 and 2020 was performed. Primary end-point was to demonstrate the efficacy of AA, with the analysis of PSA decline, and the correlation with overall survival. The cohort analysis consisted of 84 patients with a median age of 71 ± 9 years. A PSA response of > 30% and > 50% at 60 and 90 days was associated with improved OS. Multivariate analysis revealed that a 60 day PSA decline of > 30% was predictive of overall survival. Median OS of diag-nosed mCRPC patients was 28 months. Docetaxel pre-treatment was not associated with longer OS. The median duration of drug exposure for patients submitted to AA was found to be 14 months. Early PSA response rate can offer clinically meaningful information and can be considered a surrogate of longer OS. A > 30% or > 50% prostate-specific antigen decline at 60 and 90 days provided an important low-cost clinical tool to predict subsequent events in mCRPC patients treated with abiraterone.

Costs of radium-223 and the pharmacy preparation 177Lu-PSMA-I&T for metastatic castration-resistant prostate cancer in Dutch hospitals

ObjectiveThe radiopharmaceuticals radium-223 and the pharmacy preparation 177Lu-PSMA-I&T are reimbursed in the Netherlands for metastatic castration-resistant prostate cancer (mCRPC) treatment. Although shown to be life-prolonging in patients with mCRPC, the treatment procedures associated with these radiopharmaceuticals can be challenging for both patients and hospitals. This study investigates the costs of mCRPC treatment in Dutch hospitals for currently reimbursed radiopharmaceuticals with a demonstrated overall survival benefit.MethodsA cost model that calculated the direct medical per-patient costs of radium-223 and 177Lu-PSMA-I&T was developed, following clinical trial regimens. The model considered six 4-weekly administrations (i.e. ALSYMPCA regimen) of radium-223. Regarding 177Lu-PSMA-I&T, the model used both the VISION regimen (i.e. five 6-weekly administrations) and the SPLASH regimen (i.e. four 8-weekly administrations). Based on health insurance claims, we also estimated the coverage a hospital would receive for providing treatment. No fitting health insurance claim for 177Lu-PSMA-I&T is currently available; therefore, we calculated a break-even value for a potential health insurance claim that would exactly counterbalance the per-patient costs and coverage.ResultsRadium-223 administration is associated with per-patient costs of €30,905, and these costs are fully covered by the coverage a hospital receives. The per-patient costs of 177Lu-PSMA-I&T range between €35,866 and €47,546 per administration period, depending on the regimen. Current healthcare insurance claims do not fully cover the costs of providing 177Lu-PSMA-I&T: hospitals must pay €4,414–€4,922 for each patient out of their own budget. The break-even value for the potential insurance claim covering 177Lu-PSMA-I&T administration with a VISION (SPLASH) regimen is €1,073 (€1,215).ConclusionThis study shows that, without consideration of the treatment effect, radium-223 treatment for mCRPC leads to lower per-patient costs than treatment with 177Lu-PSMA-I&T. The detailed overview of the costs associated with radiopharmaceutical treatment provided by this study is relevant for both hospitals and healthcare insurers.

Survival outcomes of metastatic castration-resistant prostate cancer in Brazil (LACOG 1818).

TPS272 Background: Treatment of metastatic castration-resistant prostate cancer (mCRPC) has been steadily evolving during the last decade, but access remains a significant issue in low- and middle-income countries (LMICs). As novel therapies emerge and translate into clinical practice, the gap in treatment patterns between patients who do or do not have access to these therapies is expected to increase. The resulting disparities in outcomes are likely to be more noticeable in countries with pronounced inequality, such as Brazil. In Brazil, while a minority of patients have private insurance and have access to nearly all available treatment options, approximately 75% of patients depend on the public health system, which is unable to afford most of the recent treatment innovations for mCRPC, such as novel hormonal agents (NHA) or PARP inhibitors. LACOG 1818 was developed to investigate and compare outcomes of patients with mCRPC treated at private and public hospitals in Brazil. Methods: LACOG 1818 (NCT04962919) is a retrospective multicentric study investigating disparities in cancer treatment and survival among public and private institutions in Brazil. Patients with mCRPC diagnosed within January 2014 and December 2017 will be included and their data will be abstracted from medical records. Primary endpoint is cause-specific survival, comparing patients from private and public institutions. We estimate that 299 events are needed to detect a hazard ratio of 0.75 indicating a lower risk of prostate cancer-related death for patients treated at private institutions with a power of 80% and a bicaudate significance level of 10%. Considering a follow up of 24 months and a median cause-specific survival of 20 months in patients from public institutions, 590 patients are planned to be included. Secondary endpoints include describing comorbidities, sociodemographic and clinicopathological characteristics of patients with mCRPC; comparing overall survival of patients with mCRPC treated at public and private institutions; comparing treatments patterns of patients with mCRPC treated at public and private institutions; and describing skeleton-related complications, bone-directed treatments, and admission rates. From January 2020 to August 2022, 244 of planned 590 patients have been enrolled in 7 Brazilian centers. Additional 12 centers are still planned to open before 2023. Results are expected in the first semester of 2023. Clinical trial information: NCT04962919 .

Nivolumab plus ipilimumab for the treatment of post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC): Additional results from the randomized phase 2 CheckMate 650 trial.

22 Background: In preliminary analyses from the randomized phase 2, open-label CheckMate 650 trial, nivolumab (NIVO) 1 mg/kg (N1) plus ipilimumab (IPI) 3 mg/kg (I3) Q3W × 4 doses showed clinical activity in patients (pts) with post-chemotherapy (post-CT) mCRPC, particularly those with high tumor mutational burden (TMB), but early toxicity contributed to treatment discontinuations. Here, we report results from pts with post-CT mCRPC receiving alternative NIVO+IPI dosing regimens vs IPI alone vs cabazitaxel (CABA) in CheckMate 650. Methods: Newly enrolled pts previously treated with docetaxel for mCRPC were randomized 2:2:1:2 to cohorts D1 (NIVO 3 mg/kg [N3] + IPI 1 mg/kg [I1] Q3W × 4 doses then NIVO 480 mg Q4W), D2 (N1 Q3W × 8 doses + I3 Q6W × 4 doses then NIVO 480 mg Q4W), D3 (I3 Q3W × 4 doses), or D4 (CABA 20 or 25 mg/m2 Q3W + prednisone 10 mg × 10 doses). Crossover from cohorts D3 and D4 to cohort D1 was allowed after radiographic progressive disease. Outcomes included safety, objective response rate (ORR), prostate-specific antigen response rate (PSA-RR; confirmed PSA decline ≥ 50% from baseline), radiographic progression-free survival (rPFS) per blinded independent central review (BICR), and overall survival (OS). Associations between efficacy and TMB were assessed. Results: Overall, 259 pts were randomized (D1, n = 73; D2, n = 74; D3, n = 38; D4, n = 74). Median (range) follow-up for OS was 23.3 (6.0–31.5) months. In the NIVO+IPI cohorts (D1 and D2), median duration of therapy was 2.8 and 2.4 months; the median number of IPI doses received was 4 and 2, and 15% and 26% of pts discontinued due to study drug toxicity, respectively. Two pts died due to study drug toxicity (1 each in cohorts D1 and D2). Key safety and efficacy data are shown. Several pts in cohorts D1 and D2 showed notable reductions (75-100%) in tumor size and PSA. Approximately one-third of pts in cohorts D3 and D4 crossed over to D1. Based on preliminary analyses in small numbers of evaluable pts, there was no clear and consistent association between efficacy and tissue or blood TMB in the NIVO+IPI cohorts (D1 and D2). Conclusions: These results further support the clinical activity of NIVO+IPI in select pts with post-CT mCRPC. Detailed evaluations of the characteristics of responders to NIVO+IPI, including more expansive biomarker analyses, are warranted. Clinical trial information: NCT02985957 . [Table: see text]

Comparative effectiveness of abiraterone and enzalutamide in the first-line treatment of metastatic castration-resistant prostate cancer (mCRPC): A retrospective cohort study in a large database of deeply curated EHR real-world data (RWD) from community oncology practices in the US.

175 Background: Abiraterone(A) and enzalutamide(E), both oral androgen receptor targeted agents, are available as first-line treatment options for mCRPC patients. Direct comparisons of efficacy have not been performed for mCRPC patients primarily receiving their cancer care outside of academic centers or integrated health care systems. The study aims to evaluate the real-world effectiveness between first-line A and E-containing regimens in mCRPC patients primarily receiving care in the US community oncology setting. Methods: Patients were selected from ConcertAI Patient 360 Prostate data product, a large de-identified database of deeply curated EHR RWD, sourced from data sharing agreements with community oncology practices. mCRPC patients treated with a first-line A or E-cont. regimen between 1/2011 and 6/2022 were included. OS, TTNT, TTD outcomes were described using KM estimates and evaluated with Cox proportional hazard (HR) model. Confounding was addressed with inverse probability treatment weighting (IPTW) propensity scores based on age, BMI, ECOG, prior anti-androgen exposure, smoking status, comorbidities, and nadir PSA. Sensitivity analysis evaluated KM and HR for each covariate strata. Hazard ratios were also evaluated with multiple imputation by chained equations for missing covariates. Results: From 3,578 mCRPC patients, 1,210 (33.8%) received E-cont. regimen and 1,357 (37.9%) received A-cont. regimen(ref) with a median of 8 months duration for both drugs. Adjusted HR (aHR) for all three outcomes showed a slight increase in effectiveness for E albeit not significant (OS (aHR 0.99, CI 0.87-1.12), TTNT (aHR 0.98, CI 0.89-1.08). Adjusted model including imputation (iHR) supported unimputed results (OS (iHR 0.97, CI 0.88-1.07), TTNT (aHR 0.94, CI 0.9-1.10). The HRs for OS, TTNT and TTD in sicker patients were consistent (2+ ECOG TTNT (aHR 0.95, 0.81-1.12)), (BMI &gt;30, TTNT (aHR 0.84, 0.61-1.18)), and reached significance for some models (2+ ECOG TTD (aHR 0.66, 0.48-0.91)). Conclusions: First-line E-cont. regimens consistently showed increased effectiveness in outcomes compared to A-cont. regimens in mCRPC patients treated in community oncology setting. The effects sizes are modest and did not reach significance, however analysis of the sickest patients showed a trend of consistently larger effect sizes which reached significance for some outcomes. More work needs to be done to evaluate if these results support findings from other RWD sources.

Machine-learning to predict utility of circulating tumor DNA (ctDNA) for somatic genotyping.

232 Background: ctDNA genotyping is increasingly used to evaluate patient eligibility for genomics-driven treatments ( e.g., PARP inhibitors) in metastatic castration-resistant prostate cancer (mCRPC), but low ctDNA-fraction (ctDNA%) causes false negatives and is unpredictable. We investigated whether a machine-learning model exploiting routine clinical prognostic markers can predict if a mCRPC patient will have sufficient ctDNA% for informative ctDNA testing. Methods: We analysed plasma cell-free DNA (cfDNA) collected at baseline prior to first-line therapy from 463 consecutive mCRPC patients. ctDNA% was quantified using somatic allele frequencies and genome-wide copy number profiles via deep targeted sequencing. We built an XGBoost model (70:30 train-test split) using 18 clinical factors to predict synchronously measured ctDNA% (binary classification &gt;2% or ≤2%, i.e., the conventional ctDNA% limit of detection for mutations employed by commercial tests), with performance evaluated using area under the curve (AUC) of receiver operating characteristics. Results: Median age was 73 (range: 45-98) and 86% of patients had ECOG 0-1. Median ctDNA% was 5% (range: 0-89%) and correlated with serum and radiographic metrics of disease burden, including total cfDNA concentration (ng/mL of plasma, reflecting cfDNA released by both normal and tumor cells; Spearman ρ=0.55), alkaline phosphatase (ALP) per upper limit of normal (ULN) ( ρ=0.46), lactate dehydrogenase (LDH) per ULN ( ρ=0.41), PSA ( ρ=0.3), presence of liver metastases, and ≥10 bone lesions. We trained an XGBoost model incorporating these and 13 additional clinical factors achieving an AUC for ctDNA &gt;2% of 0.83 (F1 score: 0.79). SHAP interpretability scores indicated that cfDNA concentration most strongly informed prediction of ctDNA &gt;2%, followed by ALP/ULN and PSA—consistent with our prior bivariate rank correlations—whereas features associated with initial prostate cancer diagnosis (Gleason Grade Group, de novo versus metachronous M1 disease) were less informative. Recognizing that comprehensive and standardised clinical annotation is not always available in real-world settings, we built a secondary parsimonious ctDNA%-prediction tool restricted to 8 highly informative and clinically practical factors (cfDNA concentration, ALP/ULN, LDH/ULN, PSA, albumin, ECOG, liver metastases, lung metastases) and flexible to incomplete input data, achieving a comparable AUC for ctDNA&gt;2% of 0.76. Conclusions: Our results demonstrate the feasibility of a machine learning framework to estimate ctDNA% in patients with mCRPC. This point-of-care tool would enable prioritisation of mCRPC patients for ctDNA somatic genotyping with a predicted ctDNA &gt;2%, versus tissue or germline-only testing in patients with a predicted ctDNA ≤2%.

Characteristics of long-term responder (LTR) patients (pts) treated with androgen-receptor signaling inhibitors (ARSI) as a first-line treatment for metastatic castration-resistant prostate cancer (mCRPC): Real-world evidence from four high-volume institutions.

164 Background: ARSI [enzalutamide (ENZA) and abiraterone (ABI)] demonstrated to be efficacious as a first-line therapy for mCRPC, showing a median progression-free survival of 16 and 20 months (mos) in pivotal trials, respectively. Nevertheless, some pts of daily clinical practice show exceptionally prolonged disease control with very long duration of treatment. The present study aimed at identifying the characteristics of LTR pts who received one ARSI as a first-line for mCRPC. Methods: We retrospectively reviewed the clinical records of a consecutive series of 647 pts treated in the daily clinical practice with one ARSI as first-line mCRPC in four Italian high-volume Institutions. Pts who had previously received docetaxel in castration-sensitive setting were excluded. Pts received standard AA or ENZA doses (1,000 mg po daily plus prednisone 10 mg po daily or 160 mg po daily, respectively). ARSI were administered until progression and were followed according to each Institution policy. For each pt we recorded pre and post-ARSI clinical history, baseline characteristics, treatment details and clinical outcomes. Pts were considered as LTR in presence of an ARSI exposure ≥ 36 mos. LTR were compared to the progressed pts with an ARSI exposure &lt; 36 mos. On-treatment pts with an ARSI exposure &lt; 36 mos were not considered. Results: We identified 81 LTR pts (53 treated with ENZA and 28 treated with ABI). The median age was 76 yrs (range 56-89). The median treatment duration was 46.1 mos (range 36.4-88.6) and 52 pts were still on treatment. LTR were compared to no-LTR 415 pts (233 treated with ENZA and 182 treated with ABI). Compared to no-LTR, LTR pts showed longer PSA doubling time (PSADT) (PSADT) (p = 0.001) and time to mCRPC (p &lt; 0.0001), lower levels of basal PSA (p = 0.01), and alkaline phosphatase (ALP) (p = 0.01), better ECOG PS (p = 0.01), lower Gleason score (p = 0.01), and less pain level (p = 0.04). ECOG PS, ALP, time to mCRPC and PSADT were all identified as independent predictors of time to treatment interruption in multivariate analysis. LTR showed an 89% decreased risk of death compared to no-LTR (HR = 0.11 IC95% 0.06-0.18). Conclusions: In our experience, several variables, which are usually considered as having a prognostic value, demonstrated to be able to predict the probability of prolonged disease control in mCRPC pts treated with first-line ARSI.

Physician preferences for nonmetastatic castration-resistant prostate cancer treatments: A discrete choice experiment among men in mainland China.

88 Background: A range of medication options are available for non-metastatic castration-resistant prostate cancer (nmCRPC), with varying efficacy and safety profiles. We used a discrete choice experiment (DCE) to explore how physicians make treatment decisions between adverse events (AEs) and survival gains in nmCRPC in mainland China. Methods: Physicians’ preferences for medication attributes were assessed through an online survey including 14 treatment choice questions, each comparing 2 hypothetical treatment profiles, which varied safety (fatigue, skin rash, cognitive problems, falls, and fractures) in terms of severity and frequency and efficacy (overall survival [OS] and time to pain progression [TPP]) in terms of duration of effect. Preference weights and importance scores for each attribute were estimated using random parameters logit models. The amount of survival gain physicians were willing to trade off for a reduction in specific AEs was also estimated. Results: In total, 80 physicians who had experience in treating nmCRPC patients were involved in this study. Physicians’ duration of clinical practice was about 18.4±7.39 years. In addition, 57.6% of participants were from regions with more developed economics, including North, East and South China. The results indicated that physician preferences were logically ordered, with higher efficacy and lower risks for AEs being favored over lower efficacy and higher risks for AEs. The most important attributes for treatment decision were OS (Relative importance, RI = 29.2%), serious fracture (RI = 24.4%), serious fall (RI =15.4%) and TPP (RI =10.6%). Comparing non-serious AEs including fatigue, skin rash and cognitive problems, physicians emphasized the risk reduction of fatigue the most. The trade-off analysis between OS and adverse events suggested that physicians were willing to trade 7.5 and 4.7 months of OS to reduce the risk of severe fracture from 8% to none, and the risk of serious fall from 8% to none. In an exploratory subgroup analysis, it was found that physicians with more than 15 years of clinical practice put more emphasis on overall survival, risk of serious fracture, and risk of serious fall compared to less experienced physicians (≤15 years). Physicians from regions with more developed economics tended to put more value on reduction of AEs as compared to physicians from the rest regions. Conclusions: OS is the most important attribute for physicians when treating nmCRPC patients. Physicians were willing to trade the duration of OS to reduce the risk of serious adverse events. These results emphasize the importance of carefully balancing therapies’ benefits and risks to ultimately optimize the overall quality of nmCRPC patients’ survival.

Enzalutamide-Induced Acute Maculopapular Rash in Treatment of Metastatic Prostate Cancer: First Case Report from a Tertiary Cancer Care Center of North India.

Enzalutamide is a new potent inhibitor of the signaling pathway for the androgen receptor with a half-life of 5.8 days. It has been on the market for the treatment of metastatic castration-resistant prostate cancer since November 2013.We report a case of acute generalized exanthematous maculopapular rash induced by enzalutamide. In summary, newer androgen receptor blockers have a propensity to cause skin related adverse effects. Most common among these are apalutamide. Enzalumatamide, per se, is a safe drug and has not been associated frequently in causing maculopapular rash. Few cases has been reported. In all these cases, the drug was discontinued and 2nd line therapy was instituted. In this report, Enzalutamide was withheld for 10 days and anti-histaminics was instituted. After a full recovery, Enzalutamide was reinstituted in treatment.A 62-year-old male patient with no significant medical history, was diagnosed in March 2020 with metastatic prostatic adenocarcinoma. Baseline PSA was 456 ng/ml. PSMA PET scan showed evidence of multiple bony metastasis. He was started on Degarelix subcutaneous injection with oral abiraterone initially. PSA level showed initial decreasing trend till September 2021 followed by sudden increase. Intramuscular Injection leuprolide was started and initial responses were good followed by later rise of PSA from January. Tab Xtandi (Enzalutamide) was added to the regimen from 31.1.22. Three days after starting enzalutamide treatment, the patient experienced an acute skin reaction. It is about of the plaques covered with widespread millimetric non-follicular papules. Enzalutamide was stopped after appearance of rashes to avoid further serious adverse effects. Anti-histaminics were started. Complete resolution of skin lesions occurred within 10 days. Tab Enzalutamide was reinstituted on 11th day after stoppage and on complete resolution of skin resolutions. According to the CTCAE 5.0 criteria, these skin rash was graded as grade 2. In view of evidence in literature and clinical improvement after stoppage, the acute drug reaction was attributed to enzalutamide.Uro oncologist can be confronted with adverse skin drug reactions attributable to new therapeutic molecules. The slow resolution of symptoms seems be due to the long half-life of enzalutamide. It should not be withdrawn from therapy owing to these effects. Rather, it should be with stopped for 10-14 days. Basic treatment with anti-histaminics or topical steroids may be enough to warranty the resolution of symptoms, and the drug (Enzalutamide) can be continued thereafter.