[Palliative surgery for metastatic prostate cancer]. / Palliative Chirurgie des metastasierten Prostatakarzinoms.

Androgen deprivation in combination with novel hormonal agents, docetaxel, or in combination with abiraterone/prednisone plus docetaxel or darolutamid plus docetaxel represent the standard therapeutic approach in metastatic hormone-sensitive prostate cancer (mHSPC). Patients with low-risk prostate cancer also benefit from additional radiation therapy or radical prostatectomy in terms of progression-free and overall survival. Despite favorable response rates, basically all patients will develop castration resistant prostate cancer (CRPC) within 2.5 to 4 years. In addition to systemic chemotherapy, second-line hormonal treatment of systemic application of radionuclides such as radium223 or 177Lu-PSMA represent salvage management options. However, nowadays about 50-65% of patients will develop symptoms due to local progression of prostate cancer which is the result of improved oncological outcomes with significantly prolonged survival times due to the new medical treatment options. Management of such symptomatic local progression will become more important in upcoming years so that all uro-oncologists need to be aware of the various surgical management options. Complications of the lower urogenital tract such as recurrent gross hematuria ± bladder clotting and with the necessity for red blood cell transfusions, subvesical obstruction and acute urinary retention, rectourethral or rectovesical fistulas might be managed by palliative surgery such as palliative transurethral resection of the prostate (TURP), radical cystectomy, radical cystoprostatectomy with urinary diversion, and pelvic exenteration. Symptomatic or asymptomatic obstruction of the upper urinary tract might be managed by endoluminal or percutaneous urinary diversion, ureteral reimplantation, ileal ureter replacement, or implantation of the Detour® system (Coloplast GmbH, Hamburg, Germany).

Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

Zhoushi Qi Ling decoction inhibits the progression of castration-resistant prostate cancer in vivo by regulating macrophage infiltration via IL6-STAT3 signaling.

Background and aim: Prostate cancer is a leading malignant tumor in men, associated with a high rate of mortality. Androgen deprivation therapy is commonly used to treat prostate cancer, which contributes to the progression of castration-resistant prostate cancer (CRPC). The current therapy has a low survival rate in patients with CRPC. Our study aims to develop a novel effective approach for CRPC treatment and improve survival benefits. Experimental procedure: CRPC cell line PC-3-Luc expressing luciferase and the CRPC cell line PC-3-IL6-Luc stably overexpressing IL-6 were used to establish the xenograft tumor mouse model. The tumor was monitored weekly using Bioluminescence imaging. Infiltrated macrophages were quantified by fluorescence-activated cell sorting using flow cytometry. IL6 mRNA level was determined using quantitative real-time PCR. The protein levels of total STAT3 and phosphorylated STAT3 were determined using Western blot. Results and conclusion: Zhoushi Qi Ling decoction (ZQD) treatment significantly reduced PC3 the xenograft tumor progression and the number of infiltrated macrophages when compared with saline treatment. IL6 mRNA level was remarkedly suppressed by ZQD treatment. Notably, the protein level of phosphorylated STAT3 was significantly decreased in PC3 the xenograft tumor treated with ZQD compared to saline treatment. Our findings demonstrated that ZQD treatment significantly reduced the progression of prostate cancer, evidenced by the reduced population of infiltrated macrophages and the inhibition of the IL6/STAT3 pathway.

PSMA-targeted radioligand therapy in prostate cancer: current status and future prospects.

INTRODUCTION: The prostate-specific membrane antigen (PSMA) targeted radioligand therapy (PRLT) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients has generated significant interest among the oncologic community, with several publications documenting good response rates and survival benefits with low toxicity profiles. AREAS COVERED: Indications, patient preparation, dose administration, post-treatment imaging, dosimetry, and side effect profiles of 177Lu-PSMA-617 are discussed in this article. We also discuss results from prospective studies, major retrospective studies, meta-analyses, clinical trials, and mentioned major ongoing clinical trials on PRLT. We have also portrayed our own experiences and future perspectives on PRLT. EXPERT OPINION: For PRLT, PSMA-617 and PSMA-I&T molecules have revolutionized the theranostic approach in the management of advanced prostate cancer, with solid backing from several published articles showing favorable outcomes and an excellent safety profile of 177Lu-PSMA-617. Improvement in quality of life and survival was seen in the majority of mCRPC patients after 177Lu-PSMA-617 PRLT. Patients with good performance status, asymptomatic, only lymph node metastases, high PSMA expressing lesions, and no discordant FDG avid lesions have a longer survival after 177Lu-PSMA-617 PRLT than patients with poor performance status, symptomatic, hepatic, brain, and skeletal metastases, discordant PSMA, and FDG-avid lesions. Docetaxel and cabazitaxel are approved treatments for mCRPC patients. 177Lu-PSMA-617 is approved as a third-line systemic treatment for mCRPC patients with failure to respond to androgen receptor pathway inhibitors and docetaxel therapy. PRLT is a safe and effective alternative to cabazitaxel (third-line systemic treatment), but it has a higher cost. 177Lu-PSMA-617 could be a more efficient therapeutic option for mCRPC patients as first-line or combined therapy, and it may be a useful therapeutic option for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) patients. Several clinical studies and clinical trials on PRLT are currently underway. In the future, the results of these trials will be helpful in evolving treatment strategies for prostate cancer patients.

Personalized [177Lu]Lutetium-PSMA Therapy for Patients with Pre-Treated Castration-Resistant Prostate Cancer: A Single Institution Experience from a Comprehensive Cancer Centre.

Castration resistant prostate cancer (CRPC) is characterized by an aggressive biological behavior with a relatively short survival time, especially in progressive tumors pretreated with new hormonal agents and taxane chemotherapy. [177Lu]-Lutetium-PSMA (Lu-PSMA) treatment has proven efficacy in these patients. However, around 30% of the CRPC patients do not benefit from Lu-PSMA treatment, and little is known about predictive factors for treatment success if Lu-PSMA is offered in an individualized approach based on clinical and laboratory features. In this monocentric retrospective study, 86 CRPC patients receiving Lu-PSMA treatment were evaluated. The focus of the study was to describe clinical factors at baseline and during early treatment that are related to overall survival (OS). In addition, PSMA PET/CT-, PSA-response, and safety and tolerability (CTCAE adverse event reporting) were assessed. Efficacy endpoints were calculated using stratified Kaplan-Meier methods and Cox regression models. Mean applied dose was 17.7 GBq (mean 5.3 ± 1.1 GBq per cycle) with an average of 3.6 (range 1-8) therapy cycles. Patients were followed up for a mean of 12.4 months (range 1-39). The median OS was 15 months (95% CI 12.8-17.2). The best overall response rate in patients assessed with PSMA PET/CT and PSA response was 27.9%, and 50.0% had at least stable disease. Nine patients had a ≥grade 3 adverse event with anemia being the most frequent adverse event. Positive predictors for prolonged OS from baseline parameters were pre-treatment hemoglobin level of ≥10 g/dL and a lower PSA values at treatment start, while the presence of visceral or liver metastases were not significantly associated with worse prognoses in this cohort. With careful patient selection, an individualized Lu-PSMA treatment approach is feasible and patients with dose-limiting factors or visceral metastases should be included in prospective trials.

Computer-aided analysis of quercetin mechanism of overcoming docetaxel resistance in docetaxel-resistant prostate cancer.

BACKGROUND: Prostate cancer (PC) is a silent but potent killer among men. In 2018, PC accounted for more than 350, 000 death cases while more than 1.2 million cases were diagnosed. Docetaxel, a chemotherapeutic drug belonging to the taxane family of drugs, is one of the most potent drugs in combating advanced PC. However, PC cells often evolve resistance against the regimen. Hence, necessitating the search for complementary and alternative therapies. Quercetin, a ubiquitous phytocompound with numerous pharmacological properties, has been reported to reverse docetaxel resistance (DR) in docetaxel-resistant prostate cancer (DRPC). Therefore, this study aimed to explore the mechanism via which quercetin reverses DR in DRPC using an integrative functional network and exploratory cancer genomic data analyses. RESULTS: The putative targets of quercetin were retrieved from relevant databases, while the differentially expressed genes (DEGs) in docetaxel-resistant prostate cancer (DRPC) were identified by analysing microarray data retrieved from the Gene Expression Omnibus (GEO) database. Subsequently, the protein-protein interaction (PPI) network of the overlapping genes between the DEGs and quercetin targets was retrieved from STRING, while the hub genes, which represent the key interacting genes of the network, were identified using the CytoHubba plug-in of Cytoscape. The hub genes were further subjected to a comprehensive analysis aimed at identifying their contribution to the immune microenvironment and overall survival (OS) of PC patients, while their alterations in PC patients were also revealed. The biological roles played by the hub genes in chemotherapeutic resistance include the positive regulation of developmental process, positive regulation of gene expression, negative regulation of cell death, and epithelial cell differentiation among others. CONCLUSION: Further analysis revealed epidermal growth factor receptor (EGFR) as the most pertinent target of quercetin in reversing DR in DRPC, while molecular docking simulation revealed an effective interaction between quercetin and EGFR. Ultimately, this study provides a scientific rationale for the further exploration of quercetin as a combinational therapy with docetaxel.

LncFALEC recruits ART5/PARP1 and promotes castration-resistant prostate cancer through enhancing PARP1-meditated self PARylation.

Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are abnormal expression in various malignant tumors. Our previous research demonstrated that focally amplified long non-coding RNA (lncRNA) on chromosome 1 (FALEC) is an oncogenic lncRNA in prostate cancer (PCa). However, the role of FALEC in castration-resistant prostate cancer (CRPC) is poorly understood. In this study, we showed FALEC was upregulated in post-castration tissues and CRPC cells, and increased FALEC expression was associated with poor survival in post-castration PCa patients. RNA FISH demonstrated FALEC was translocated into nucleus in CRPC cells. RNA pulldown and followed Mass Spectrometry (MS) assay demonstrated FALEC directly interacted with PARP1 and loss of function assay showed FALEC depletion sensitized CRPC cells to castration treatment and restored NAD+. Specific PARP1 inhibitor AG14361 and NAD+ endogenous competitor NADP+ sensitized FALEC-deleted CRPC cells to castration treatment. FALEC increasing PARP1 meditated self PARylation through recruiting ART5 and down regulation of ART5 decreased CRPC cell viability and restored NAD+ through inhibiting PARP1meditated self PARylation in vitro. Furthermore, ART5 was indispensable for FALEC directly interaction and regulation of PARP1, loss of ART5 impaired FALEC and PARP1 associated self PARylation. In vivo, FALEC depleted combined with PARP1 inhibitor decreased CRPC cell derived tumor growth and metastasis in a model of castration treatment NOD/SCID mice. Together, these results established that FALEC may be a novel diagnostic marker for PCa progression and provides a potential new therapeutic strategy to target the FALEC/ART5/PARP1 complex in CRPC patients.

Mitochondrial respiration inhibitor enhances the anti-tumor effect of high-dose ascorbic acid in castration-resistant prostate cancer.

Previous evidences have demonstrated that anti-tumor effect of high-dose ascorbic acid is associated with the generation of reactive oxygen species (ROS) via autoxidation. Hypoxia induces therapy resistance in castration-resistant prostate cancer. As a mitochondrial respiration inhibitor, metformin has the potential to improve tumor oxygenation. In this study, we evaluate the anti-tumor effect of ascorbic acid combined with metformin in prostate cancer. We demonstrated that ascorbic acid inhibits prostate cancer cells proliferation by generating ROS, and metformin enhances the anti-tumor effects of ascorbic acid. Mechanistically, metformin reduces oxygen consumption rate and NADP+/NADPH value in prostate cancer cells, thereby increases the ROS content induced by ascorbic acid. In addition, our data demonstrated that ascorbic acid inhibits p-AKT signaling in a ROS-dependent pathway, leading to inhibition of p-mTOR expression. And metformin inhibits the p-mTOR expression by activating the AMPK signaling pathway, exerting a synergistic effect on tumor suppression with ascorbic acid. Furthermore, metformin improves tumor oxygenation, and the combined treatment effect of ascorbic acid and metformin were demonstrated in a xenograft model of prostate cancer. Taken together, our data demonstrate that metformin enhances the anti-tumor proliferation effect of ascorbic acid by increasing ROS content in castration-resistant prostate cancer. This provides a new strategy for the clinical application of high-dose ascorbic acid as an anti-tumor drug. KEY MESSAGES: Ascorbic acid inhibits tumor growth by inducing ROS generation. As a mitochondrial respiration inhibitor, metformin inhibits cellular oxygen consumption rate to improve oxygenation of prostate cancer. Metformin enhances anti-tumor effect of ascorbic acid by increasing ROS content. Ascorbic acid inhibits the mTOR expression via PI3K-AKT pathway, and metformin inhibits the mTOR expression by inhibiting AMPK signaling in prostate cancer cells.

Management of metastatic castration-resistant prostate cancer in Middle East African countries: Challenges and strategic recommendations.

Despite the reliance on Western guidelines for managing prostate cancer (PC), there are wide variations and gaps in treatment among developing countries such as the Middle East African (MEA) region. A multidisciplinary team of experts from the MEA region engaged in a comprehensive discussion to identify the real-world challenges in diagnostics and treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC) and provided insights on the urgent unmet needs. We present a consensus document on the region-specific barriers, key priority areas and strategic recommendations by experts for optimizing management of mCRPC in the MEA. Limited access to genetic testing and economic constraints were highlighted as major concerns in the MEA. As the therapeutic landscape continues to expand, treatment selection for mCRPC needs to be increasingly personalized. Enhanced genetic testing and judicious utilization of newer therapies like olaparib, articulated by reimbursement support, should be made accessible for the underserved populations in the MEA. Increasing awareness on testing through educational activities catalyzed by digital technologies can play a central role in overcoming barriers to patient care in the MEA region. The involvement of multidisciplinary teams can bridge the treatment gaps, facilitating holistic and optimal management of mCRPC. Region-specific guidelines can help health-care workers navigate challenges and deliver personalized management through collaborative efforts - thus curb health-care variations and drive consistency. Development of region-specific scalable guidelines for genetic testing and treatment of mCRPC, factoring in the trade-off for access, availability, and affordability, is crucial.

Glucose-Functionalized Silver Nanoparticles as a Potential New Therapy Agent Targeting Hormone-Resistant Prostate Cancer cells.

Purpose: Silver nanoparticles (AgNPs) have shown great potential as anticancer agents, namely in therapies' resistant forms of cancer. The progression of prostate cancer (PCa) to resistant forms of the disease (castration-resistant PCa, CRPC) is associated with poor prognosis and life quality, with current limited therapeutic options. CRPC is characterized by a high glucose consumption, which poses as an opportunity to direct AgNPs to these cancer cells. Thus, this study explores the effect of glucose functionalization of AgNPs in PCa and CRPC cell lines (LNCaP, Du-145 and PC-3). Methods: AgNPs were synthesized, further functionalized, and their physical and chemical composition was characterized both in water and in culture medium, through UV-visible spectrum, dynamic light scattering (DLS), transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR). Their effect was assessed in the cell lines regarding AgNPs' entering pathway, cellular proliferation capacity, ROS production, mitochondrial membrane depolarization, cell cycle analysis and apoptosis evaluation. Results: AgNPs displayed an average size of 61nm and moderate monodispersity with a slight increase after functionalization, and a round shape. These characteristics remained stable when redispersed in culture medium. Both AgNPs and G-AgNPs were cytotoxic only to CRPC cells and not to hormone-sensitive ones and their effect was higher after functionalization showing the potential of glucose to favor AgNPs' uptake by cancer cells. Entering through endocytosis and being encapsulated in lysosomes, the NPs increased the ROS, inducing mitochondrial damage, and arresting cell cycle in S Phase, therefore blocking proliferation, and inducing apoptosis. Conclusion: The nanoparticles synthesized in the present study revealed good characteristics and stability for administration to cancer cells. Their uptake through endocytosis leads to promising cytotoxic effects towards CRPC cells, revealing the potential of G-AgNPs as a future therapeutic approach to improve the management of patients with PCa resistant to hormone therapy or metastatic disease.

Therapeutic targets and signaling pathways of active components of QiLing decoction against castration-resistant prostate cancer based on network pharmacology.

QiLing decoction (QLD) is a traditional Chinese medicine compound. This study aims to explore the therapeutic effect of QLD in castration-resistant prostate cancer (CRPC) and its potential bio-targets. A total of 51 active components and QLD 149 targets were identified using bioinformatics analysis. Additionally, five optimal hub target genes were screened including tumor protein P53 (TP53), interleukin-6 (IL-6), vascular endothelial growth factor-A (VEGF-A), caspase-3 (CASP-3), and estrogen receptor-1 (ESR-1). The interrelated network between active components of QLD and their potential targets was constructed. The molecular function, biological processes, and signaling pathways of QLD-against CRPC were identified. Moreover, QLD was found to efficiently exert a repressive effect on CRPC tumor growth mainly by suppressing the activation of HIF-α/VEGFA and TNF-α/IL6 signaling pathways, and increasing the P53 expression level. These results successfully indicated the potential anti-CRPC mechanism of the active components of QLD.

DAB2IP regulates intratumoral testosterone synthesis and CRPC tumor growth by ETS1/AKR1C3 signaling.

The intratumoral androgen synthesis is one of the mechanisms by which androgen receptor (AR) is aberrantly re-activated in castration-resistant prostate cancer (CRPC) after androgen ablation. However, pathways controlling steroidogenic enzyme expression and de novo androgen synthesis in prostate cancer (PCa) cells are largely unknown. In this study, we explored the potential roles of DAB2IP in testosterone synthesis and CRPC tumor growth. Indeed, DAB2IP loss could maintain AR transcriptional activity, PSA re-expression and tumor growth under castrated condition in vitro and in vivo, and reprogram the expression profiles of steroidogenic enzymes, including AKR1C3. Mechanistically, DAB2IP could dramatically inhibit the AKR1C3 promoter activity and the conversion from androgen precursors (i.e., DHEA) to testosterone through PI3K/AKT/mTOR/ETS1 signaling. Consistently, there was a high co-expression of ETS1 and AKR1C3 in PCa tissues and xenografts, and their expression in prostate tissues could also restore AR nuclear staining in castrated DAB2IP-/- mice after DHEA supplement. Together, this study reveals a novel regulation of intratumoral de novo androgen synthesis in CRPC, and provides the DAB2IP/ETS1/AKR1C3 signaling as a potential therapeutic target.

Prognostic nutritional index is an independent prognostic factor for treatment response, survival and drug choice in metastatic castration-resistant prostate cancer treated with abiraterone acetate or enzalutamide.

PURPOSE: We designed this study to identify the prognostic value of baseline prognostic nutritional index (PNI) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate or enzalutamide. METHODS: 101 mCRPC patients were included. PNI was calculated using formula 10 x serum albumin value (gr/dL) + 0.005 × total lymphocyte count (per mm3). ROC analysis was used for determining prognostic PNI value. RESULTS: The statistically significant cut-off value for PNI was 46.62. Initial PSA response and PSA kinetics (early PSA response and 30 %-50%-90% PSA response at any time) were much better in PNI > 46.62 group than the PNI ≤ 46.62 group (p < 0.01). In multivariate analysis, baseline PNI level >46.62 was an independent predictor of PSA-PFS (HR: 0.42, p < 0.01), radiologic PFS (HR: 0.53, p < 0.01), and OS (HR: 0.42, p < 0.01). In the PNI ≤ 46.62 group, median OS was 7.4 months (95% CI: 4.1-10.7) for the abiraterone acetate subgroup vs. 17.6 months (95% CI: 10.1-25.1) for enzalutamide subgroups (p < 0.01). CONCLUSION: PNI is a useful, independent prognostic marker for mCRPC patients treated with either abiraterone acetate or enzalutamide. Using pre-treatment PNI may help clinicians in the prediction of survival and decision making based on abiraterone acetate or enzalutamide.

Redox-responsive nanoparticles enhance radiation therapy by altering multifaceted radio-resistance mechanisms in human castration-resistant prostate cancer cells and xenografts.

INTRODUCTION: Radiation therapy (RT) is a major modality for the treatment of prostate cancer (PCa), especially castration-resistant PCa (CRPC). However, hypoxia, often seen in PCa tumors, leads to radiation-resistance. This work investigates the effect of a novel oxygen-generating polymer-lipid manganese dioxide nanoparticle (PLMDs) on improving RT outcomes in CRPC xenograft models by modulating the tumor microenvironment (TME) both before and after RT. MATERIALS AND METHODS: Human PC3 and DU145 PCa cells were used to investigate clonogenic inhibition and DNA repair pathways in vitro. Tumor hypoxia and post-RT angiogenesis were evaluated in a PC3-bearing SCID mouse model. PC3 and DU145 xenografts were used to study the efficacy of PLMD in combination with single or fractionated RT. RESULTS: PLMD plus RT significantly inhibited clonogenic potential, increased DNA double-strand breaks, and reduced DNA damage repair in hypoxic PC3 and DU145 cells as compared to RT alone. PLMD significantly reduced hypoxia-positive areas, hypoxia induced factor 1α (HIF-1α) expression, and protein carbonyl levels (a measure of oxidative stress). Application of PLMD with RT decreased RT-induced angiogenic biomarkers by up to 3-fold. Treatment of the human CRPC xenografts with PLMD plus RT (single or fractionated doses) significantly prolonged median survival of the host compared to RT alone resulting in up to a 40% curative rate. CONCLUSION: PLMD treatment modulated TME and sensitized hypoxic human CRPC cells to RT thus enhancing the efficacy of RT. These results confirmed the potential of PLMD as an adjuvant to RT for the treatment of hypoxic CRPC.

A Pitfall of the Androgen Deprivation Therapy for Salivary Duct Carcinoma: Hormonal Therapy-Induced Castrate-Resistant Prostate Cancer.

Introduction: Salivary duct carcinoma (SDC) is a rare, high-grade salivary gland malignancy. Recently, targeting the androgen receptor (AR) is one of the most promising new therapeutic strategies for AR-positive SDC. Case Review: In this report, a 70-year-old man who was diagnosed with an AR-positive SDC underwent androgen deprivation therapy (ADT) as a treatment for recurrence after primary therapy. The ADT well contributed to control of SDC; however, the patient was referred to urologists for urinary hesitancy and slow flow and he was diagnosed as having castration-resistant prostate cancer. Literature Review: Since SDC is a rare disease, it has been difficult to establish the most effective therapy. Nevertheless, several papers have reported the clinical benefit of ADT for AR-positive SDC, and the latest version of the National Comprehensive Cancer Network guidelines also states the importance of assessing for the presence of AR in SDC.On the other hand, in the field of urology, it is also known that although ADT is initially effective in prostate cancer patients, prostate cancer often develops into castrate-resistant prostate cancer due to the adaptation of prostate cancer cells to ADT for survival and growth. Conclusion: We reported a case of castrate-resistant prostate cancer diagnosed during the ADT for metastatic SDC. The present case emphasizes the importance of screening for prostate cancer at the initiation of ADT treatment and during treatment.

Genetic testing for homologous recombination repair (HRR) in metastatic castration-resistant prostate cancer (mCRPC): challenges and solutions.

Patients with metastatic castration-resistant prostate cancer (mCRPC) have an average survival of only 13 months. Identification of novel predictive and actionable biomarkers in the homologous recombination repair (HRR) pathway in up to a quarter of patients with mCRPC has led to the approval of targeted therapies like poly-ADP ribose polymerase inhibitors (PARPi), with the potential to improve survival outcomes. The approval of PARPi has led to guideline bodies such as the National Comprehensive Cancer Network (NCCN) to actively recommend germline and or somatic HRR gene panel testing to identify patients who will benefit from PARPi. However, there are several challenges as genetic testing is still at an early stage especially in low- and middle-income countries, with cost and availability being major impediments. In addition, there are issues such as choice of optimal tissue for genetic testing, archival, storage, retrieval of tissue blocks, interpretation and classification of variants in the HRR pathway, and the need for pretest and post-test genetic counseling. This review provides insights into the HRR gene mutations prevalent in mCRPC and the challenges for a more widespread gene testing to identify actionable germline pathogenic variants and somatic mutations in the HRR pathway, and proposes a clinical algorithm to enhance the efficiency of the gene testing process.

Multicenter randomized phase II study comparing docetaxel plus curcumin versus docetaxel plus placebo in first-line treatment of metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) patients have a poor prognosis, and curcumin is known to have antineoplastic properties. On the basis of previous phase I and phase II studies, we investigated whether the association of curcumin with docetaxel could improve prognosis among mCRPC patients. METHODS: A total of 50 mCRPC patients (included from June 2014 to July 2016) treated with docetaxel in association with oral curcumin (6 g/d for 7 days every 3 weeks) versus placebo were included in this double-blind, randomized, phase II study. The primary endpoint was to evaluate the time to progression. Among the secondary endpoints, compliance, overall survival, prostate-specific antigen (PSA) response, safety, curcumin absorption, and quality of life were investigated. An interim analysis was planned in the modified intention-to-treat population with data at 6 months (22 patients per arm). RESULTS: Despite good compliance and a verified absorption of curcumin, no difference was shown for our primary endpoint: progression-free survival (PFS) between the placebo and curcumin groups was, respectively, 5.3 months versus 3.7 months, p = 0.75. Similarly, no difference was observed for the secondary objectives: PSA response rate (p = 0.88), overall survival (p = 0.50), and quality of life (p = 0.49 and p = 0.47). CONCLUSION: Even though our previous studies and data in the literature seemed to support an association between curcumin and cancer therapies in order to improve patient outcome and prognosis, the results from this interim analysis clearly showed that adding curcumin to mCRPC patients' treatment strategies was not efficacious. The study was discontinued on the grounds of futility.

An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer.

Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.

Metastasis-Directed Radiotherapy for Oligoprogressive Castration-Resistant Prostate Cancer Recurrence Revealed by Choline PET/CT.

We report a 49-year-old male with castration-resistant prostate cancer (CRPC) with oligometastasis diagnosed by 11C-choline positron emission tomography-computed tomography (PET/CT) and treated with target radiotherapy. In the diagnosis of CRPC (serum prostate-specific antigen [PSA] level of 6.53 ng/mL after maximum androgen blockade (MAB) therapy, high-dose brachytherapy, and external beam radiotherapy), 11C-choline PET/CT detected one tiny obturator lymph node metastasis which fluorodeoxyglucose PET/CT could not detect. He underwent intensity-modulated radiation therapy and MAB was restarted. The PSA value decreased and reached nadir (0.091 ng/mL) after 6 months. The time to PSA progression was 10 months. The choline PET/CT finding and the corresponding local treatment could play an important role in the management sequence of oligoprogressive CRPC.

Effectiveness of Vintage Hormone Therapy as Alternative Androgen Deprivation Therapy for Non-metastatic Castration-resistant Prostate Cancer.

BACKGROUND/AIM: Vintage hormone therapy for non-metastatic castration-resistant prostate cancer (nmCRPC) is not recommended under the current guidelines, but is widely practiced in Japan. This study assessed effectiveness of vintage hormone therapy as alternative androgen deprivation therapy (AADT) for treatment of nmCRPC. PATIENTS AND METHODS: In this retrospective study we examined patients with nmCRPC that received vintage hormone therapy as AADT between 1999 and 2018. RESULTS: Of 53 patients with nmCRPC, 25 patients (47.2%) had stage 1 nodal disease (N1) at diagnosis of nmCRPC. Prostate specific antigen (PSA) reduction rate≥30% was observed in 32 patients (72.7%). The median PSA nadir was 0.7, and the duration of the response was 14.3 months. The median metastasis-free survival (MFS) for the entire patient population was 62.2 months, and the median overall survival (OS) was not reached. In the multivariate analysis, the duration of response in AADT>18 months was a predictor of prolonged OS. CONCLUSION: There is a certain number of nmCRPC patients who respond well to vintage hormone therapy as AADT. Further studies are expected to differentiate such cases.