Treatment Of Metastatic Prostate Cancer Research Articles

Recomendaciones de tratamiento en el cáncer de próstata hormonosensible metastásico: selección de pacientes

The standard treatment for metastatic hormone-sensitive prostate cancer (mHSPC) is now a combination of androgen deprivation therapy plus an androgen receptor-targeted therapy (abiraterone, apalutamide, enzalutamide or darolutamide), with or without chemotherapy (docetaxel). The selection of suitable patients for each therapeutic approach has become a determining factor to ensure efficacy and minimize side effects. This article combines recent clinical evidence with the accumulated experience of experts in medical oncology, radiation oncology and urology, to provide a comprehensive view and therapeutic recommendations for mHSPC.

Tolerability of Olaparib Combined with Abiraterone in Patients with Metastatic Castration-resistant Prostate Cancer: Further Results from the Phase 3 PROpel Trial

BackgroundThe PROpel study (NCT03732820) demonstrated a statistically significant progression-free survival benefit with olaparib plus abiraterone versus placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer (mCRPC) setting, irrespective of homologous recombination repair mutation status. ObjectiveWe report additional safety analyses from PROpel to increase clinical understanding of the adverse-event (AE) profiles of olaparib plus abiraterone versus placebo plus abiraterone. Design, setting, and participantsA randomised (1:1), double-blind, placebo-controlled trial was conducted at 126 centres in 17 countries (October 2018–January 2020). Patients had mCRPC and no prior systemic mCRPC treatment. InterventionOlaparib (300 mg bid) or placebo with abiraterone (1000 mg od) plus prednisone/prednisolone (5 mg bid). Outcome measurements and statistical analysisThe data cut-off date was July 30, 2021. Safety was assessed by AE reporting (Common Terminology Criteria for Adverse Events v4.03) and analysed descriptively. Results and limitationsThe most common AEs (all grades) for olaparib plus abiraterone versus placebo plus abiraterone were anaemia (46.0% vs 16.4%), nausea (28.1% vs 12.6%), and fatigue (27.9% vs 18.9%). Grade ≥3 anaemia occurred in 15.1% versus 3.3% of patients in the olaparib plus abiraterone versus placebo plus abiraterone arm. The incidences of the most common AEs for olaparib plus abiraterone peaked early, within 2 mo, and were managed typically by dose modifications or standard medical practice. Overall, 13.8% versus 7.8% of patients discontinued treatment with olaparib plus abiraterone versus placebo plus abiraterone because of an AE; 3.8% versus 0.8% of patients discontinued because of anaemia. More venous thromboembolism events were observed in the olaparib plus abiraterone arm (any grade, 7.3%; grade ≥3, 6.8%) than in the placebo plus abiraterone arm (any grade, 3.3%; grade ≥3, 2.0%), most commonly pulmonary embolism (6.5% vs 1.8% for olaparib plus abiraterone vs placebo plus abiraterone). ConclusionsOlaparib plus abiraterone has a manageable and predictable safety profile. Patient summaryThe PROpel trial showed that in patients who had not received any previous treatment for metastatic castration-resistant prostate cancer, olaparib combined with abiraterone was more effective in delaying progression of the disease than abiraterone alone. Most side effects caused by combining olaparib with abiraterone could be managed with supportive care methods, by pausing olaparib administration for a short period of time and/or by reducing the dose of olaparib.

Symptoms and quality of life among men starting treatment for metastatic castration-resistant prostate cancer – a prospective multicenter study

BackgroundMen with metastatic castration-resistant prostate cancer (mCRPC) have an incurable disease. Along with prolonging life, symptom management is one of the main goals with treatment. This is also important from a palliative care perspective where the life prolonging outcomes should be balanced with quality of life (QoL) in this late phase. It is also essential in symptom management to view different dimensions of symptoms, for example how severe or distressing symptoms are, to support best QoL. Therefore, more knowledge is needed about the symptom experience when these treatments are initiated and thus the aim of this study was to describe different dimensions of symptoms in men with mCRPC starting their first-line of life-prolonging treatment, and to describe the association between symptom burden and QoL.MethodsBaseline data from a prospective longitudinal study of 143 men with mCRPC starting their first-line life-prolonging treatment were used. Symptoms were measured using the Memorial Symptom Assessment Scale (MSAS) and global QoL was measured by the EORTC QLQ C-30. Data was analyzed using descriptive- and multivariable linear regression analyses.ResultsOn average, the men had more than 10 symptoms (range 0–31 of 33). 50% or more reported sweats, lack of energy, pain, problems with sexual activity and sexual desire. The symptoms they reported as most severe, or most distressing were not always the ones that were reported as most frequent. There was an association between QoL and physical symptoms, and also between QoL, and analgesic use and prostate-specific antigen (PSA) values.ConclusionEven if some men with mCRPC report many symptoms, the dimensions of severity and distress levels vary, and the most frequent symptoms was not always the most burdensome or distressing. There was an association between high physical symptom burden and QoL, suggesting that it is not the number of symptoms that affects QoL but rather the subjective perceived impact of the physical symptoms experienced. The knowledge of how men with mCRPC experience and perceive their symptoms may help health care professionals in symptom management aiming to improve QoL, which is a cornerstone in integrating early palliative care.

Abstract 6033: Preclinical evaluation of an actinium-225 labeled PSMA-targeting small molecule (225Ac-PSMA-Trillium (BAY 3563254)) for the treatment of metastatic castration resistant prostate cancer (mCRPC)

Abstract PSMA is a clinically validated target for the treatment of mCRPC. Since the linear energy transfer and degree of induced DNA damage of alpha particles far exceeds that of beta particles, several investigational PSMA-targeted small molecules labeled with the alpha-emitter actinium-225 (225Ac) have shown encouraging clinical signs of efficacy. However, xerostomia is often found as a dose-limiting side effect, presumably due to low levels of PSMA expression and efficient uptake of small molecules in salivary glands. To reduce these unwanted side effects a PSMA-targeted radioligand comprising a triad of important features was investigated. It consists of a high-affinity PSMA binder for specific tumor-targeting; a customized albumin-binding moiety designed to prolong plasma residence time and increase the therapeutic index by improving tumor uptake while reducing salivary gland uptake; and a chelator for efficient complexation of 225Ac. From a series of compounds containing the same high-affinity PSMA-targeting moiety, but different chain lengths and albumin-binding domains, compound RPS-072 containing a PEG-3 and PEG-8 chain and an iodobenzyl moiety as albumin-binder was selected for further evaluation (J Nucl Med 2019; 60:656-663). This compound was the basis for the PSMA-Trillium with a DOTA chelator for imaging applications in humans (NCT05773703) or a macropa chelator for 225Ac labeling resulting in 225Ac-PSMA-Trillium. In vitro preclinical characterization of 225Ac-PSMA-Trillium was performed to test affinities for PSMA and albumin. In a SPR assay, Kd was measured as 4.88x1011 M, Kon as 1.4x107 1/Ms and Koff as 6.6x10-4 1/Ms. 225Ac-PSMA-Trillium demonstrated good stability up to 48 h and induced potent in vitro cytotoxicity in the LNCaP subclone C4-2 (0.114 kBq/ml). In vivo biodistribution of 225Ac-PSMA-Trillium showed consistent with the albumin binding property a relatively slow pharmacokinetics profile with 5 % ID/g still in the blood after 24 h and tumor accumulation peaking at ~ 20 % ID/g after 5-7 days. Tumor penetration was investigated using autoradiography which demonstrated fast, homogeneous, and even distribution across the tumor within 15 mins after injection. This property was also reflected by strong therapeutic efficacy in several PrCa models. In the LNCaP model a tumor growth inhibition was observed at a single dose dependent efficacy at 150 kBq/kg and 300 kBq/kg and increased the time to reach 400 mm3 by 35 days for the 300 kBq/kg group. In the androgen independent PDX KuCaP-1 model, a single dose of 250 kBq/kg 225Ac-PSMA-Trillium induced strong tumor growth inhibition over the course of 35 days. A first-in-human trial with 225Ac-PSMA-Trillium is anticipated to start in the first half of 2024. Citation Format: Sabine Zitzmann-Kolbe, Alex Papple, Thorsten Poethko, Ingrid Moen, Christoph Schatz, Shawn Hillier, John W. Babich, Alan Cuthbertson, Urs B. Hagemann. Preclinical evaluation of an actinium-225 labeled PSMA-targeting small molecule (225Ac-PSMA-Trillium (BAY 3563254)) for the treatment of metastatic castration resistant prostate cancer (mCRPC) [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 6033.

Abstract 6285: Defining androgen receptor function and the effects of PARP inhibition in BRCA1/2-deficient vs. proficient prostate cancer

Abstract Mutation or loss of the tumor suppressor genes BRCA1 and BRCA2 promotes the development of aggressive prostate cancer with poor outcomes and a high risk of metastatic relapse. Approximately 15% of metastatic prostate tumors are BRCA1/2-deficient. These tumors are frequently resistant to standard-of-care treatments that block androgen receptor (AR) function, although the mechanisms underlying this effect remain unclear. PARP inhibitors are synthetically lethal with BRCA1/2-deficiency and are commonly used as a late-line treatment in metastatic prostate cancer; however, both preclinical and clinical data have provided conflicting results on whether PARP inhibitors can be effective in BRCA1/2-proficient prostate tumors. BRCA1, BRCA2, PARP-1, and PARP-2 all have proposed roles in regulating transcription and the chromatin landscape. We therefore hypothesized that loss of BRCA1, BRCA2, and/or inhibition of PARP modulates AR function through changes in global chromatin structure and transcriptional pathways. We used patient-derived xenograft models and next-generation sequencing techniques to profile AR function in BRCA1/2-deficient vs. proficient prostate tumors. We found that loss of BRCA1 and BRCA2 is associated with chromatin accessibility changes, and differentially accessible regions correlate with DNA binding motifs for AR and AR cofactors. ChIP-seq for AR in these tumors demonstrated that BRCA1/2-deficiency is associated with an altered AR cistrome and a global decrease in AR genomic binding. Corresponding RNA-seq data confirmed a downregulated androgen response in BRCA1/2-deficient tumors. In cell line models, inhibition of PARP1 and PARP1/2 inhibited AR-driven transcription. Combining PARP inhibition with either androgen deprivation or the AR antagonist enzalutamide dampened the growth-inhibitory effects of PARP inhibitor treatment. Together, these results indicate that BRCA1/2-deficiency and PARP inhibition modulate AR function in prostate cancer. Citation Format: Nicole A. Traphagen, Esme Wheeler, Rong Li, Xintao Qiu, Myles Brown. Defining androgen receptor function and the effects of PARP inhibition in BRCA1/2-deficient vs. proficient 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 6285.

Abstract 6962: Shed Trop2 drives prostate cancer progression and Trop2 is a novel tissue prognostic biomarker and a candidate urinary marker for prostate cancer

Abstract Distinguishing indolent from clinically significant localized prostate cancer and treatment of metastatic prostate cancer are two major clinical challenges in prostate cancer. The development of novel predictive biomarkers will help with risk stratification, and influence clinical decision-making between treatment and active surveillance, leading to a decrease in over or under-treatment of patients with prostate cancer. Here, we report that Trop2, an oncogenic transmembrane surface protein, is a prognostic tissue biomarker for clinically significant prostate cancer by utilizing the Canary Prostate Cancer Tissue Microarray (CPCTA) cohort composed of over 1100 patients from a multi-institutional study. We demonstrate that higher Trop2 expression is correlated with worse clinical features and elevated Trop2 expression at radical prostatectomy predicts worse overall survival in men undergoing radical prostatectomy. Additionally, we detected shed Trop2 in urine from men with clinically significant prostate cancer. We further define the functional role of shed Trop2 on metastasis in prostate cancer and identify that shed Trop2 increases cell migration, invasion, metastatic colonization, and spontaneous metastasis in vitro and in vivo. Proteomic profiling reveals that shed Trop2 modulates a set of proteins associated with invasion, migration, mTOR signaling, and epithelial-to-mesenchymal transition. shed Trop2 binds to EGFR and results in the activation of the EGFR-PI3K-AKT-mTOR pathway in prostate cancer. Our study reveals the new function of shed Trop2 in driving prostate cancer progression and identifies Trop2 as a novel tissue prognostic biomarker and a candidate non-invasive marker for prostate cancer that could be used to optimize treatment decision-making. Citation Format: Shiqin Liu, Sarah Hawley, Christian Kunder, En-Chi Hsu, Michelle Shen, Merve Aslan, Fernando J. Marques, Chung S. Lee, Abel Bermudez, Lennart Westphalen, Heidi Auman, Lisa F. Newcomb, Daniel W. Lin, Peter S. Nelson, Ziding Feng, Maria S. Tretiakova, Lawrence D. True, Funda Vakar-Lopez, Peter R. Carroll, Jeffry Simko, Martin E. Gleave, Dean A. Troyer, Jesse K. McKenney, Donna Peehl, Sharon J. Pitteri, James D. Brooks, Michael A. Liss, Tanya Stoyanova. Shed Trop2 drives prostate cancer progression and Trop2 is a novel tissue prognostic biomarker and a candidate urinary marker for 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 6962.

Abstract 1904: Preclinical development of MGC026, a glycan-linked, exatecan-based antibody-drug conjugate (ADC) targeting B7-H3 for solid cancer

Abstract Introduction: Antibody-drug conjugates (ADCs) have emerged as an important class of therapeutic agents for the treatment of cancer. A duocarmycin-based B7-H3-targeted DNA-alkylating ADC, vobramitamab duocarmazine (vobra duo), has shown encouraging clinical activity in the treatment of metastatic castration-resistant prostate cancer. Given the broad spectrum of tumor indications addressable by targeting B7-H3, we developed MGC026, an ADC incorporating a B7-H3-targeting antibody and a novel glycan-linked topoisomerase 1 inhibitor (TOP1i). With distinct mechanisms of action, vobra duo and MGC026 can address different cancers, tumor stages, or be used in combination with alternate agents to enhance their clinical utility. Methods: MGC026 is comprised of the cleavable linker-payload, bicyclononyne carbamoyl sulfamide Val-Ala-PABC exatecan (SYNtecan E™) site-specifically conjugated at asparagine 297 of the heavy chain through enzymatic glycan remodeling and metal-free click chemistry, using Synaffix’s GlycoConnect™ technology. In vivo efficacy studies were conducted in immunodeficient mice with human tumor cell-line or patient-derived xenografts to identify the spectrum of MGC026-sensitive tumors and the relationship between exposure and antitumor activity. A toxicology study was conducted in cynomolgus monkeys in which MGC026 was administered by 15-minute IV infusion once every three weeks. Pharmacokinetic (PK) analysis and detailed toxicology evaluation was performed. Results: MGC026 demonstrated specific, dose-dependent in vivo antitumor activity toward B7-H3-positive tumor xenografts representing lung, pancreatic, and prostate cancers, head and neck squamous cell carcinoma, and melanoma. Additionally, MGC026 demonstrated antitumor activity toward B7-H3-positive patient-derived xenograft models of lung and prostate cancer, with additional indications under investigation. MGC026, administered to cynomolgus monkeys at dose levels of 10, 30, and 50 mg/kg every 3 weeks for a total of 3 doses, exhibited approximate dose-proportional PK and high stability in circulation. MGC026 was well tolerated, with no lung toxicity observed, and the highest dose level tested (50 mg/kg) was declared as the highest non-severely toxic dose. Conclusions: MGC026 exhibited a favorable preclinical profile, with potent in vivo activity toward B7-H3-expressing tumor xenografts representing a range of cancer indications. MGC026 was tolerated in cynomolgus monkeys, a relevant toxicology model, at exposure levels exceeding those required for antitumor activity. These data support clinical development of MGC026 for the treatment of B7-H3-expressing solid cancers. Citation Format: Juniper A. Scribner, Jennifer G. Brown, Thomas Son, Linda Jin, Carroll McKenzie, Viktoriya Nam, Curtis Bush, Dienis Quinonez, James Tamura, Sergey Gorlatov, Hua Li, Shelley Butler, Ezio Bonvini, Deryk Loo. Preclinical development of MGC026, a glycan-linked, exatecan-based antibody-drug conjugate (ADC) targeting B7-H3 for solid 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 1904.

Evaluation of two-dimensional total bone uptake (2D-TBU) and bone scan index (BSI) extracted from active bone metastatic burden on the bone scintigraphy in patients with radium-223 treatment.

Radium-223 is a first alpha-emitting radionuclide treatment for metastatic castration-resistant prostate cancer (mCRPC) patients with bone metastases. Although the spread-based bone scan index (BSI) and novel index of the intensity-based two-dimensional total bone uptake (2D-TBU) from bone scintigraphy may provide useful input in radium-223 treatment, they have not been evaluated in detail yet. This study aimed to fill this gap by evaluating BSI and 2D-TBU in patients treated with radium-223. Twenty-seven Japanese patients with mCRPC treated with radium-223 were retrospectively analyzed. The patients were evaluated via blood tests and bone scans at baseline and 3 cycles intervals of treatment. BSI and 2D-TBU were analyzed via VSBONE BSI in terms of correlations, response to radium-223 treatment, association with treatment completion, and the Kaplan-Meier survival analysis was performed. Nineteen patients (70.4%) completed six cycles of radium-223 treatment, whereas eight patients (29.6%) did not complete the treatment regimen. A significant difference in baseline BSI and 2D-TBU was observed between these groups of patients. Both BSI and 2D-TBU were highly correlated (r = 0.96, p < 0.001). Univariate analysis showed an association between radium-223 completion in median BSI and 2D-TBU values (p = 0.015) and completion percentage differences (91.7% vs. 45.5%; p = 0.027). The Kaplan-Meier product limit estimator showed that the median overall survival was 25.2 months (95% CI 14.0-33.6 months) in the completion group and 7.5 months (95% CI 3.3-14.2 months) in the without completion group (p < 0.001). The overall survival based on median cutoff levels showed a significant difference in 2D-TBU (p = 0.007), but not in BSI (p = 0.15). The 2D-TBU may offer advantages over BSI in classifying patients towards radium-223 treatment based on the degree of progression of bone metastases. This study supports the importance of preliminary assessment of bone metastasis status using BSI and 2D-TBU extracted from VSBONE BSI for radium-223 treatment decisions.

Bilateral Choroidal Detachments following Novel CAR T-Cell Immunotherapy Regimen.

To describe a vision-threatening adverse event of a novel CAR T-cell immunotherapy for metastatic prostate cancer. Observational Case Report. 77-year-old male with history of metastatic prostate cancer and pulmonary embolism enrolled in a clinical trial investigating the use of CAR T-cell immunotherapy for treatment of metastatic prostate cancer presented with a subjective left temporal visual disturbance. The patient was found to have bilateral extensive choroidal detachments on examination. OCT macula demonstrated no intraretinal fluid or supraretinal fluid in both eyes. B-scan of both eyes redemonstrated choroidal detachments in both eyes and no retinal detachment in either eye. The patient was initiated on a topical and systemic steroid regimen and experienced symptomatic and clinical improvement. We exhibit a case of bilateral choroidal detachments secondary to systemic reaction to a novel immunotherapy for metastatic cancer successfully treated with systemic and topical steroids. Close follow up may be required for patients receiving similar novel immunotherapeutic regimens.

Three- and Seven-month Prostate-specific Antigen Levels as Prognostic Markers for Overall Survival in Metastatic Hormone-sensitive Prostate Cancer: Results from SWOG S1216, a Phase 3 Randomized Trial of Androgen Deprivation Plus Orteronel or Bicalutamide

BackgroundA robust decrease in prostate-specific antigen (PSA) in response to androgen deprivation therapy (ADT) has been evaluated as a prognostic factor in patients with metastatic hormone-sensitive prostate cancer (mHSPC) since 2006, but the treatment of mHSPC has since evolved to include intensified therapy. ObjectiveWe assessed the association of PSA levels at 3 (PSA-3mo) and 7 (PSA-7mo) mo with overall survival (OS) in patients with mHSPC treated with ADT combined with either bicalutamide or orteronel in the S1216 phase 3 clinical trial. Design, setting, and participantsPSA responses to treatment of patients in the S1216 trial were categorized as: complete response (CR) if PSA was ≤0.2 ng/ml, partial response if PSA was >0.2 and ≤4 ng/ml, and no response (NR) if PSA was >4 ng/ml. Outcome measurements and statistical analysisA Cox analysis (adjusted for treatment arm and three stratification factors: performance status, severity of disease, and early vs late induction) was used for OS association. While PSA-7mo association was a prespecified objective, PSA-3mo association was also evaluated. Results and limitationsA total of 1251 and 1231 patients from the S1216 study were evaluable for PSA-3mo and PSA-7mo, respectively. A PSA-7mo CR was associated with improved OS compared with NR (HR: 0.20; p < 0.0001). A PSA-3mo CR showed a similar association to NR (HR: 0.34; p < 0.0001). The association of a PSA response with survival did not differ by treatment arm at either time point. ConclusionsThe PSA-3mo and PSA-7mo responses were strongly associated with OS; taken with other emerging prognostic biomarkers, these markers may allow for early identification of patients at the highest risk of death, aid with counseling in clinical practice, and permit design of future clinical trials targeting these patients. Patient summaryA low prostate-specific antigen level at 3 or 7 mo after starting treatment for metastatic hormone-sensitive prostate cancer predicts longer survival regardless of the first treatment given with androgen deprivation therapy.

Cost-effectiveness and budget impact analysis of enzalutamide in comparison to abiraterone in treatment of metastatic prostate cancer resistant to castration in Iran

IntroductionIn recent years, enzalutamide and abiraterone have been widely used as treatments for metastatic castration-resistant prostate cancer (mCRPC). However, the cost-effectiveness of these drugs in Iran is unknown. This study evaluated the cost-effectiveness of enzalutamide for the treatment of metastatic prostate cancer resistant to castration in Iran.MethodsA 3-state Markov model was developed to evaluate the cost-effectiveness of enzalutamide and abiraterone from a social perspective over 10 years. The clinical inputs were obtained from the meta-analysis studies. The direct medical costs were obtained from the tariffs of the healthcare system, while the direct non-medical and indirect costs were collected from the patients. The data of utilities were derived from the literature. In addition, sensitivity analyses were conducted to assess the uncertainties.ResultsCompared with Abiraterone, enzalutamide was associated with a high incremental cost-effectiveness ratio (ICER) of $6,260 per QALY gained. According to the one-way sensitivity analysis, ICER was most heavily influenced by the prices of enzalutamide and Abiraterone, non-medical costs, and indirect costs. Regardless of the variation, enzalutamide remained cost-effective. The budget impact analysis of enzalutamide in the health system during 5 years was estimated at $6,362,127.ConclusionsAt current prices, adding enzalutamide to pharmaceutical lists represents the cost-effective use of the healthcare resources in Iran for the treatment of metastatic castration-resistant prostate cancer.

Niraparib and Abiraterone Acetate (Akeega)

&#x0D; CADTH recommends that Akeega be reimbursed by public drug plans for the first-line treatment of metastatic castration-resistant prostate cancer (mCRPC) if certain conditions are met.&#x0D; Akeega should only be covered to treat patients with mCRPC who have BRCA mutations, have not been treated with an androgen receptor pathway inhibitor (ARPi) for earlier stages of prostate cancer, and have not received treatments that affect the entire body for mCRPC (except for treatments of less than 4 months with abiraterone acetate and prednisone) or a poly-(ADP-ribose) polymerase inhibitor (PARPi) for mCRPC. Moreover, patients should be in relatively good health.&#x0D; Akeega should only be reimbursed if it is prescribed by a clinician with expertise in treating prostate cancer with systemic anticancer therapy and if the cost of Akeega is reduced. Akeega should not be reimbursed when used in combination with other anticancer drugs.&#x0D;

High-fat diet promotes prostate cancer metastasis via RPS27

BackgroundMetastasis is the leading cause of death among prostate cancer (PCa) patients. Obesity is associated with both PCa-specific and all-cause mortality. High-fat diet (HFD) is a risk factor contributing to obesity. However, the association of HFD with PCa metastasis and its underlying mechanisms are unclear.MethodsTumor xenografts were conducted by intrasplenic injections. The ability of migration or invasion was detected by transwell assay. The expression levels of RPS27 were detected by QRT-PCR and western blot.ResultsThe present study verified the increase in PCa metastasis caused by HFD in mice. Bioinformatics analysis demonstrated increased RPS27 in the experimentally induced PCa in HFD mice, indicating that it is an unfavorable prognostic factor. Intrasplenic injections were used to demonstrate that RPS27 overexpression promotes, while RPS27 knockdown significantly reduces, PCa liver metastasis. Moreover, RPS27 inhibition suppresses the effects of HFD on PCa metastasis. Further mRNA sequencing analysis revealed that RPS27 promotes PCa metastasis by selectively enhancing the expression of various genes.ConclusionOur findings indicate that HFD increases the risk of PCa metastasis by elevating RPS27 expression and, subsequently, the expression of genes involved in PRAD progression. Therefore, RPS27 may serve as a novel target for the diagnosis and treatment of metastatic PCa.

Real-world treatment of metastatic hormone-sensitive prostate cancer in the USA, Europe and Asia.

Aim: To characterize real-world patients with metastatic hormone-sensitive prostate cancer (mHSPC) and treating physicians and evaluate treatment trends and baseline concordance versus guidelines internationally. Materials & methods: Retrospective, cross-sectional data from the Ipsos Global Oncology Monitor database 2018-2020 were used for descriptive analysis of mHSPC patients, treating physicians and treatment utilization. Results: Among the 6198 mHSPC patients from five countries, the most common treatment was either androgen deprivation therapy (ADT) monotherapy or first-generation androgen receptor inhibitor+ADT. Second-generation androgen receptor inhibitor use was only initiating but increasing over the study period. Conclusion: Despite contemporaneous guidelines recommending treatment intensification of ADT in combination with novel antihormonals or docetaxel, 76.1% of reported mHSPC patients received non-guideline-concordant care.

Precision Medicine in Castration-Resistant Prostate Cancer: Advances, Challenges, and the Landscape of PARPi Therapy-A Narrative Review.

After recent approvals, poly-adenosine diphosphate [ADP]-ribose polymerase inhibitors (PARPis) have emerged as a frontline treatment for metastatic castration-resistant prostate cancer (mCRPC). Unlike their restricted use in breast or ovarian cancers, where approval is limited to those with BRCA1/2 alterations, PARPis in mCRPC are applied across a broader spectrum of genetic aberrations. Key findings from the phase III PROPEL trial suggest that PARPis' accessibility may broaden, even without mandatory testing. An increasing body of evidence underscores the importance of distinct alterations in homologous recombination repair (HRR) genes, revealing unique sensitivities to PARPis. Nonetheless, despite the initial effectiveness of PARPis in treating BRCA-mutated tumors, resistance to therapy is frequently encountered. This review aims to discuss patient stratification based on biomarkers and genetic signatures, offering insights into the nuances of first-line PARPis' efficacy in the intricate landscape of mCRPC.

Remission Depth in Metastatic Hormone-Sensitive Prostate Cancer Is Associated With Prognosis in Patients With Initial Prostate-Specific Antigen Values Above 100 Ng/ML.

Recently, new drugs have caused a paradigm shift in the treatment of metastatic hormone-sensitive prostate cancer (HSPC). Meanwhile, research has identified several prognostic factors of metastatic HSPC. The present study focused on remission depth in metastatic HSPC and evaluated its association with remission depth. We analyzed 427 patients diagnosed with metastatic HSPC with serum initial prostate-specific antigen (PSA) > 100 ng/ml. The nadir serum PSA value was used as a marker of remission depth for each duration to castration resistanceby using receiver operating characteristic (ROC) curves.Cox proportional hazards regression was used to assess for any correlation of progression-free survival (PFS) and overall survival (OS) with the nadir PSA level. The cut-off value for the nadir PSA level per time to castration resistance (TTCR) at three, five, seven, and nine years was calculated. The nadir PSA value alone was able to predict prognosis because of its high sensitivity, high specificity, and high AUC in ROC analysis. The nadir PSA level can be an independent prognostic marker not only for TTCR but also for OS on multivariate analysis. We identified the cut-off value for nadir PSA per TTCR period in patients with metastatic HSPC. The nadir PSA value alone can predict prognosis; this demonstrates utility in routine clinical practice due to its simplicity and accuracy.

A Phase 1/2 multicenter trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC)

A Phase 1/2 multicenter trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC)

Impact of presentation timing in metastatic hormone-sensitive prostate cancer: Characterization of patients and identification of prognostic factors.

The treatment and surveillance of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved since the introduction of several treatment intensification options associated with hormonal blockade and classifications based on the timing of metastatic disease presentation and disease volume. Using a hospital-based registry, we aimed to assess whether these new classifications are applicable to our population, as few studies have demonstrated their prognostic value for overall survival (OS) and time to development of castration-resistant prostate cancer (CRPC), and to establish prognostic factors in our population. A retrospective cohort of mHSPC patients who were attended at an oncology referral hospital in Bogota between 2017 and 2021 were included in this study. The primary and secondary endpoints were OS and time to CRPC. The distribution of outcome measures was estimated using the Kaplan-Meier method. Proportional hazard models were constructed using the Cox regression approach and stratified according to risk factors. The study cohort included 373 patients. The median castration resistance-free survival was 48 months (CI: 32-73 months), and OS was 43 months (CI: 37-48 months). In multivariate analysis, nodal staging, ECOG status, and surgical castration were independent prognostic factors. In our hospital-based registry, the independent impact of the time of presentation on castration-resistant-free survival or OS could not be demonstrated, nor could the grouping of prognostic categories based on metastatic presentation temporality and volume. Other independent prognostic factors have been proposed.

A study to evaluate patient benefit/risk preferences for treatment of metastatic prostate cancer (mPC) in Hong Kong: A discrete choice experiment.

104 Background: The patient’s preference for treatment is dynamic across different cultures and at various stages of cancer. Yet little is known regarding their priorities in making treatment decisions. The study's primary objective is to examine the preference weightings in terms of risk/ benefit attributes of therapy in metastatic prostate cancer (mPC) patients in both the hormone-sensitive (mHSPC) and castration-resistant (mCRPC) settings. Methods: This is a non-interventional cross-sectional survey study. A discrete choice experiment was used to assess their priorities on treatment options. 300 consecutive patients with mPC (200 mHSPC and 100 mCRPC) diagnosed within 5 years were recruited from the specialty clinics of our hospital from Feb 2023 to Jul 2023. A facilitated group interview session of 5 patients was conducted to evaluate the importance and relevance of potential attributes selected from the literature search. Five attributes were adopted, and each has 3 levels compromised between real-life rates and expectations of patients from the interview session. Patients were randomized into 2 blocks by recruitment sequence and chose 1 medication profile out of 2 throughout the 9 questions in each block of the questionnaire. A mixed logit model was used for data analysis. Results: Median age was 75 (IQR:71-81). One hundred and seventy (56.7%) had no income, and 245 (81.7%) claimed to take care of themselves. The mean maximum amount affordable for treatment was US$20,456 (SD:43,568), and 160 (53.3%) said they would not consider further treatment if the cost exceeded their affordability. Compared to intravenous formulation, oral medication once/day had a non-statistically significant favorable preference (0.06 p:0.272), and oral medication twice/day had a negative statistically significant preference (-0.20 p:0.040). The percentage of retained self-care ability (4.37 p&lt;0.001) and percentage of extension in life expectancy (2.83 p&lt;0.001) had a statistically significant favorable preference. In contrast, the chance of adverse effects leading to complicated medication treatment or hospitalization (-6.97, p&lt;0.001) and treatment cost (in HK$ million) (-3.14 p&lt;0.001) had a negative statistically significant preference. The mCPRC group was more sensitive to changes in treatment cost (-3.61 vs. -2.97), percentage of extension in life expectancy (3.47 vs. 2.55) and the chance of adverse effects (-7.55 vs -6.80) than the mHSPC group. Those who could afford treatment were more sensitive to the percentage of retained self-care ability (4.89 vs. 4.02) and the chance of adverse effects (-7.57 vs -6.70) than those who could not. Conclusions: The chance of adverse effects took the largest weighting in treatment decisions, followed by the percentage of retained self-care ability.

Comparison of standard-dose and reduced-dose treatment of metastatic prostate cancer with enzalutamide, apalutamide or darolutamide: a rapid review

ObjectiveTo review the efficacy and safety of low-dose versus standard-dose enzalutamide, apalutamide or darolutamide treatment for metastatic prostate cancer.Methods and analysisKeyword searches in MEDLINE and EMBASE up to 1 June...