Survival Rate and Factors Influencing It in Triptorelin-Castrated Metastatic Prostate Cancer Patients

Background: Most newly diagnosed prostate cancers in Benin are metastatic diseases and patients are reluctant to undergo orchiectomy. Still, chemical androgen deprivation therapy is not always available and not every patient can afford it. Thus, it will be interesting to evaluate the results of that therapy in the country. Objective: To analyze the survival rate and factors influencing it in metastatic prostate cancer patients who underwent triptorelin-based androgen deprivation therapy at the former Military Teaching Hospital of Cotonou from January 1, 2012, to December 31, 2022. Patients and Method: Metastatic prostate cancer patients received intragluteal injections of triptorelin 11.25 mg every 3 months. We retrospectively collected follow-up data from the patients’ medical records. By means of the software StataTM version 15, we performed a descriptive analysis of qualitative data. We used Kaplan-Meir method to estimate the overall survival rate in the whole cohort and in specific subgroups of patients. We compared survival rates by using the log-rank test. Results: 68 metastatic prostate cancer patients aged 47-86 years (mean = 69.9) with initial PSA ranging from 24.25 to 6334 ng/mL (mean = 666.1) started triptorelin-based castration. The tumor grade in 21 (33.3%), 14 (22.2%), 15 (23.8), 8 (12.7%), and 5 (7.9%) patients was respectively ISUP grade groups 5, 4, 3, 2, and 1. 15 (22.1%), 4 (5.9%), 2 (2.9%), 1 (1.5%), 11 (16.2%), and 7 (10.3%) patients respectively had hypertension, diabetes mellitus, peptic ulcer, asthma, unilateral or bilateral hydronephrosis, and paralysis. The mean nadir PSA level was 22.5 ng/mL (range: 0.01-220.25). The mean time to nadir PSA level was 8.9 months (range: 3-57). The overall survival rate was 42.6%. There was no significant survival difference between age groups (p = 0.475), relating to the presence of diabetes or hypertension (p = 0.757) or to the presence of paralysis or hydronephrosis (p = 0.090). The initial PSA level exerted no significant impact on patients’ survival (p = 0.461). Neither did the time to PSA nadir (p = 0.263). The PSA nadir less than 4 ng/mL (p = 0.005) and the PSA nadir less than 4 ng/mL achieved in 12 months or less (p = 0.002) were predictive of longer survival rate. The difference in survival rate through the ISUP grade groups was not significant (p = 0.061). Conclusion: The overall survival rate was 42.6% at 5 years. Achieving PSA nadir of less than 4 ng/mL in less than 12 months of castration was predictive of longer survival rate in triptorelin-castrated metastatic prostate cancer patients.

Systemic treatment for metastatic prostate cancer

The management of metastatic prostate cancer(mPCa)has changed over the past ten years.Several new drugs have been approved with significant overall survival benefits in metastatic castration resistant prostate cancer(PCa)including chemotherapy(docetaxel,cabazitaxel),new hormonal therapies(abiraterone,enzalutamide),Radium-223 and immunotherapy.The addition of docetaxel to androgen deprivation therapy(ADT)versus ADT alone in the castration sensitive metastatic setting has gained significant overall survival benefit particularly for high volume disease.More recently two phase III trials have assessed the efficacy of abiraterone plus prednisone plus ADT over ADT alone in newly high risk castrate sensitive mPCa.Determination of the appropriate treatment sequence using these therapies is important for maximizing the clinical benefit in castration sensitive and castration resistant PCa patients.Emerging fields are the identification of new subtypes with molecular characterization and new therapeutic targets.

Specific bone region localization of osteolytic versus osteoblastic lesions in a patient-derived xenograft model of bone metastatic prostate cancer

Objective:Bone metastasis occurs in up to 90%of men with advanced prostate cancer and leads to fractures,severe pain and therapy-resistance.Bone metastases induce a spectrum of types of bone lesions which can respond differently to therapy even within individual prostate cancer patients.Thus,the special environment of the bone makes the disease more complicated and incurable.A model in which bone lesions are reproducibly induced that mirrors the complexity seen in patients would be invaluable for pre-clinical testing of novel treatments.The microstructural changes in the femurs of mice implanted with PCSD1,a new patient-derived xenograft from a surgical prostate cancer bone metastasis specimen,were determined.Methods:Quantitative micro-computed tomography(micro-CT)and histological analyses were performed to evaluate the effects of direct injection of PCSD1 cells or media alone(Control)into the right femurs of Rag2
/
gc
/
male mice.Results:Bone lesions formed only in femurs of mice injected with PCSD1 cells.Bone volume(BV)was significantly decreased at the proximal and distal ends of the femurs(p<0.01)whereas BV(p<0.05)and bone shaft diameter(p<0.01)were significantly increased along the femur shaft.Conclusion:PCSD1 cells reproducibly induced bone loss leading to osteolytic lesions at the ends of the femur,and,in contrast,induced aberrant bone formation leading to osteoblastic lesions along the femur shaft.Therefore,the interaction of PCSD1 cells with different bone region-specific microenvironments specified the type of bone lesion.Our approach can be used to determine if different bone regions support more therapy resistant tumor growth,thus,requiring novel treatments.

Cytoreductive radical prostatectomy after chemohormonal therapy in patients with primary metastatic prostate cancer

Objective:Cytoreductive radical prostatectomy(cRP)has been proposed as local treatment option in metastatic hormone-sensitive prostate cancer(mHSPC)to prevent local complications and potentially improve oncological outcomes.In this study,we examined the feasibility of a multimodal concept with primary chemohormonal therapy followed by cRP and analyzed prostate size reduction under systemic treatment,postoperative complication rates,as well as early postoperative continence.Methods:In this retrospective study,38 patients with mHSPC underwent cRP after primary chemohormonal therapy(3-monthly luteinising hormone-releasing hormone-analogue+six cycles 3-weekly docetaxel 75 mg/m2)at two centers between September 2015 and December 2018.Results:Overall,10(26%)patients had high volume and 28(74%)patients had low volume disease at diagnosis,according to CHAARTED definition.Median prostate-specific antigen(PSA)decreased from 65 ng/mL(interquartile range[IQR]35.0-124.5 ng/mL)pre-chemotherapy to 1 ng/mL(IQR 0.3-1.7 ng/mL)post-chemotherapy.Prostate gland volume was significantly reduced by a median of 50%(IQR 29%-56%)under chemohormonal therapy(p=0.003).Postoperative histopathology showed seminal vesicle invasion in 33(87%)patients and negative surgical margins in 17(45%)patients.Severe complications(Grade 3 according to Clavien-Dindo)were observed in 4(11%)patients within 30 days.Continence was reached in 87%of patients after 1 month and in 92%of patients after 6 months.Median time to castration-resistance from begin of chemohormonal therapy was 41.1 months and from cRP was 35.9 months.Postoperative PSA-nadir≤1 ng/mL versus>1 ng/mL was a significant predictor of time to castration-resistance after cRP(median not reached versus 5.3 months;p<0.0001).Conclusion:We observed a reduction of prostate volume under chemohormonal therapy going along with a low postoperative complication and high early continence rate.However,the oncologic benefit from cRP is still under evaluation.

Regional location of lymph node metastases predicts survival in patients with de novo metastatic prostate cancer

To report the regional locations of metastases and to estimate the prognostic value of the pattern of regional metastases inmen with metastatic hormone-sensitive prostate cancer (mHSPC), we retrospectively analyzed 870 mHSPC patients betweenNovember 28, 2009, and February 4, 2021, from West China Hospital in Chengdu, China. The patients were initially classifiedinto 5 subgroups according to metastatic patterns as follows: simple bone metastases (G1), concomitant bone and regional lymphnode (LN) metastases (G2), concomitant bone and nonregional LN (NRLN) metastases (G3), lung metastases (G4), and livermetastases (G5). In addition, patients in the G3 group were subclassified as G3a and G3b based on the LN metastatic plane(below or above the diaphragm, respectively). The associations of different metastatic patterns with castration-resistant prostatecancer-free survival (CFS) and overall survival (OS) were analyzed by univariate and multivariate analyses. The results showedthat patients in G1 and G2 had relatively favorable clinical outcomes, patients in G3a and G4 had intermediate prognoses, andpatients in G3b and G5 had the worst survival outcomes. We observed that patients in G3b had outcomes comparable to those inG5 but had a significantly worse prognosis than patients in G3a (median CFS: 8.2 months vs 14.3 months, P = 0.015;medianOS: 38.1 months vs 45.8 months, P = 0.038). In conclusion, metastatic site can predict the prognosis of patients with mHSPC,and the presence of concomitant bone and NRLN metastases is a valuable prognostic factor. Furthermore, our findings indicatethat the farther the NRLNs are located, the more aggressive the disease is.

Comprehensive treatment for metastatic castration-resistant prostate cancer with neuroendocrine differentiation:a case report

Retrospective analysis of the progression of a case of metastatic castration-resistant prostate cancer with neuroendocrine differentiation:the patient was a 65 year old man with prostate adenocarcinoma on prostate biopsy,Gleason 4+4 score=8,70%,ISUP4 group,localized invasion of nerves.Progressed to metastatic castration-resistant prostate cancer after 8 months of novel endocrine therapy,persistent elevated PSA after endocrine therapy,chemotherapy,and radiation,abdominal metastasis,brain metastasis,gastric metastasis,and staging as neuroendocrine differentiation after second prostate biopsy,which is a highly malignant subtype and has been concerned as a mechanism of resistance to targeted therapies.We discuss how to choose a more optimal treatment plan and outline the patient's diagnostic and therapeutic course.We provide a reflection for the clinical study of metastatic castration-resistant prostate cancer with neuroendocrine type.

Cost-effectiveness analysis of treatments for metastatic castration resistant prostate cancer

Objective:Treatment options for metastatic castration resistant prostate cancer(mCRPC)have expanded rapidly in recent years.Given the significant economic burden,we sought perform a cost-effectiveness analysis(CEA)of the contemporary treatment paradigm for mCRPC.Methods:We devised a treatment protocol consisting of sipuleucel-T,enzalutamide,abiraterone,docetaxel,radium-223,and cabazitaxel.We estimated number and length of treatments for each therapy using dosing schedules or progression free survival data from published clinical trials.We estimated treatment cost using billing data and Medicare reimbursement values and performed a CEA.Our analysis assumed US$100,000 per life year saved(LYS)as the threshold societal willingness to pay.Results:Incremental cost-effectiveness ratios(ICER)for strategies incorporating sipuleucel-T that were not eliminated by extended dominance exceeded the societal threshold willingnessto-pay of US$100,000 per LYS,the lowest of which was sipuleucel-T+enzalutamide+abiraterone+docetaxel at US$207,714 per LYS.Enzalutamide+abiraterone+docetaxel exhibited the most favorable ICER among strategies without sipuleucel-T at US$165,460 per LYS.Conclusion:Based on the available survival data and current costs of treatment,all treatment strategies greatly exceed a commonly assumed societal willingness-to-pay threshold of US$100,000 per LYS.Improvements in this regard can only comewith a reduction in pricing,better tailoring of treatment or significant enhancements in survival with clinical use of treatment combinations or sequences.

Serum testosterone level predicts the effective time of androgen deprivation therapy in metastatic prostate cancer patients

Androgen deprivation therapy （ADT） is the standard of care for patients with metastatic prostate cancer. However, whether serum testosterone levels, using a cut-off point of 50 ng d1-1, are related to the effective time of ADT in newly diagnosed prostate cancer patients remains controversial. Moreover, recent studies have shown that some patients may benefit from the addition of upfront docetaxel chemotherapy. To date, no studies have been able to distinguish patients who will benefit from the combination of ADT and docetaxel chemotherapy. This study included 206 patients who were diagnosed with metastatic prostate cancer and showed progression to castrate-resistance prostate cancer （CRPC）. Serum testosterone levels were measured prospectively after ADT for 1, 3, and 6 months. The endpoint was the time to CRPC. In univariate and multivariate analyses, testosterone levels 〈50 ng d1-1 were not associated with the effective time of ADT. Receiver operating characteristic and univariate analysis showed that testosterone levels of 〈25 ng d1-1 after the first month of ADT offered the best overall sensitivity and specificity for prediction of a longer time to CRPC （adjusted hazard ratio [HR], 1.46; 95% confidence interval [95% CI], 1.08-1.96; P = 0.013）. Our results show that serum testosterone level of 25 ng d1-1 plays a prognostic role in prostate cancer patients receiving ADT. A testosterone value of 25 ng dl-~ after the first month of ADT can distinguish patients who benefit from ADT effectiveness for only a short time. These patients may need to receive ADT and concurrent docetaxel chemotherapy.

Treatment strategy for metastatic prostate cancer with extremely high PSA level： reconsidering the value of vintage therapy

The prognostic significance of initial prostate-specific antigen （PSA） level for metastatic prostate cancer remains uncertain. We investigated the differences in prognosis and response to hormonal therapies of metastatic prostate cancer patients according to initial PSA levels. We analyzed 184 patients diagnosed with metastatic prostate cancer and divided them into three PSA level groups as follows： low （〈100 ng ml-1）, intermediate （100–999 ng ml-1）, and high （≥1000 ng ml-1）. All patients received androgen deprivation therapy （ADT） immediately. We investigated PSA progression-free survival （PFS） for first-line ADT and overall survival （OS） within each of the three groups. Furthermore, we analyzed response to antiandrogen withdrawal （AW） and alternative antiandrogen （AA） therapies after development of castration-resistant prostate cancer （CRPC）. No significant differences in OS were observed among the three groups （P = 0.654）. Patients with high PSA levels had significantly short PFS for first-line ADT （P = 0.037）. Conversely, patients in the high PSA level group had significantly longer PFS when treated with AW than those in the low PSA level group （P = 0.047）. Furthermore, patients with high PSA levels had significantly longer PFS when provided with AA therapy （P = 0.049）. PSA responders to AW and AA therapies had significantly longer survival after CRPC development than nonresponders （P = 0.011 and P 〈 0.001, respectively）. Thus, extremely high PSA level predicted favorable response to vintage sequential ADT and AW. The current data suggest a novel aspect of extremely high PSA value as a favorable prognostic marker after development of CRPC.

Prognostic value of PTEN in de novo diagnosed metastatic prostate cancer

The purpose of our study is to investigate the prognostic value of phosphatase and tensin homolog on chromosome 10(PTEN)expression in patients with de novo metastatic castration naive prostate cancer(mCNPC).A total of 205 patients with mCNPC at Fudan University Shanghai Cancer Center(Shanghai,China)were retrospectively examined.Immunohistochemical staining of PTEN was performed on prostate biopsy samples of these patients.Associations among clinicopathological features,patient survival and PTEN protein expression were analyzed.PTEN loss occurred in 58 of 205(28.3%)patients.Loss of PTEN was significantly correlated with high metastatic volume(P=0.017).No association between PTEN expression and Gleason score was observed.Patients with PTEN loss had significantly shorter progression-free survival(PFS,P<0.001)and overall survival(OS,P<0.001)compared with patients with intact PTEN expression.Multivariate analysis showed that elevated alkaline phosphatase,high metastatic volume and PTEN loss were independent poor prognostic factors for PFS.The Eastern Cooperative Oncology Group performance status(ECOG PS)≥2 and PTEN loss were independent poor prognostic factors for OS.The adjusted hazard ratio of PTEN loss for PFS and OS was 1.67(95%confidence interval[CI]:1.14–2.43,P=0.008)and 1.95(95%CI:1.23–3.10,P=0.005),respectively.PTEN loss was also significantly associated with shorter PFS(P=0.025)and OS(P<0.001)in patients with low-volume metastatic disease.Our data showed that PTEN loss is an independent predictor for shorter PFS and OS in patients with de novo mCNPC.

Clinical and oncologic findings of extraprostatic extension on needle biopsy in de novo metastatic prostate cancer

This study aimed to explore the clinical and oncologic findings in patients with de novo metastatic prostate cancer(mPCa)and extraprostatic extension(EPE)on biopsy.We retrospectively evaluated data on 630 patients with de novo mPCa between January 2009 and December 2017 in the West China Hospital(Chengdu,China),including evaluating the relationships between EPE and other variables and the association of EPE with survival outcomes by the Chi-square test,Kaplan–Meier curves,and the Cox proportional-hazards model.EPE was found in 70/630 patients,making a prevalence of 11.1%.The presence of EPE on biopsy was associated with higher Gleason scores and higher incidence of neuroendocrine differentiation(NED),intraductal carcinoma of the prostate(IDC-P),and perineural invasion(PNI).Compared with those without EPE,patients with EPE had shorter castration-resistant prostate cancer-free survival(CFS;median:14.1 vs 17.1 months,P=0.015)and overall survival(OS;median:43.7 vs 68.3 months,P=0.032).According to multivariate analysis,EPE was not an independent predictor for survival.Subgroup analyses demonstrated that patients with favorable characteristics,including negative NED or IDC-P status,Eastern Cooperative Oncology Group(ECOG)score<2,and prostate-specific antigen(PSA)<50 ng ml−1,had worse prognoses if EPE was detected.In patients with PSA<50 ng ml−1,EPE was a negative independent predictor for OS(hazard ratio[HR]:4.239,95%confidence interval[CI]:1.218–14.756,P=0.023).EPE was strongly associated with other aggressive clinicopathological features and poorer CFS and OS.These data suggest that EPE may be an indicator of poor prognosis,particularly in patients,otherwise considered likely to have favorable survival outcomes.

Surface-enhanced Raman spectroscopy of serum predicts sensitivity to docetaxel-based chemotherapy in patients with metastatic castration-resistant prostate cancer

Docetaxel-based chemotherapy,as the first-line treatment for metastatic castration-resistant prostate cancer(mCRPC),has succeeded in helping quite a number of patients to improve quality of life and prolong survival time.However,almost half of mCRPC patients are not sensitive to docetaxel chemotherapy initially.This study aimed to establish models to predict sensitivity to docetaxel chemotherapy in patients with mCRPC by using serum surface-enhanced Raman spectroscopy(SERS).A total of 32 mCPRC patients who underwent docetaxel chemo-therapy at our center from July 2016 to March 2018 were included in this study.Patients were dichotomized in prostate-specific antigen(PSA)response group(n=17)versus PSA failure group(n=15)according to the response to docetaxel.In total 64 matched spectra from 32 mCRPC patients were obtained by using SERS of serum at baseline(q0)and after 1 cycle of docetaxel chemotherapy(ql).Comparing Raman peaks of serum samples at baseline(q0)be-tween two groups,significant differences revealed at the peaks of 638,810,890(p<0.05)and 1136cm^(-1)(p<0.01).The prediction models of peak 1363 cm^(-1)and principal component anal-ysis and linear discriminant analysis(PCA-LDA)based on Raman data were established,re-spectively.The sensitivity and specificity of the prediction models were 71%,80%and 69%,78%through the way of leave-one-out cross-validation.According to the results of five-cross-valida-tion,the PCA-LDA model revealed an accuracy of 0.73 and AUC of 0.83.

Radium-223 in metastatic castration resistant prostate cancer

In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer （mCRPC）. For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival benefit in phase III studies. These agents include sipuleuceI-T, cabazitaxel, abiraterone, enzalutamide and （most recently） radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer （e.g. samarium-153 and strontium-89）, radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors influencing clinical implementation.

Bone flare after initiation of novel hormonal therapy in patients with metastatic hormone-sensitive prostate cancer:A case report

BACKGROUND The 2020 European Association of Urology prostate cancer guidelines recommend androgen deprivation therapy(ADT)in combination with apalutamide and enzalutamide,a new generation of androgen receptor antagonists,as first-line therapy.A decrease in prostate-specific antigen(PSA)levels may occur in the early stages of novel hormonal therapy;however,radionuclide bone imaging may suggest disease progression.During follow-up,PSA,radionuclide bone imaging,and prostate-specific membrane antigen(PSMA)positron emission tomography–computed tomography(PET-CT)are needed for systematic evaluation.CASE SUMMARY We admitted a 56-year-old male patient with metastatic hormone-sensitive prostate cancer.Initial radionuclide bone imaging,magnetic resonance imaging(MRI),and PSMA PET-CT showed prostate cancer with multiple bone metastases.Ultrasound-guided needle biopsy of the prostate revealed a poorly differentiated adenocarcinoma of the prostate with a Gleason score:5+4=9.The final diagnosis was a prostate adenocarcinoma(T4N1M1).ADT with novel hormonal therapy(goseraline sustained-release implant 3.6 mg monthly and apalutamide 240 mg daily)was commenced.Three months later,radionuclide bone imaging and MRI revealed advanced bone metastasis.However,PSMA PET-CT examination showed a significant reduction in PSMA aggregation on the bone,indicating improved bone metastases.Considering that progressive decrease in the presenting lumbar pain,treatment strategies were considered to be effective.CONCLUSION ADT using novel hormonal therapy is effective for treating patients with prostate adenocarcinoma.Careful evaluation must precede treatment plan changes.

Comparative analysis of the effectiveness of abiraterone before and after docetaxel in patients with metastatic castration-resistant prostate cancer

AIM: To study the efficacy and safety of abiraterone in patients with and without prior chemotherapy.METHODS: The databases including Pub Med and abstracts presented at the American Society of Clinical Oncology meetings up to April 2014 were systematically searched. Eligible studies included randomized controlled trials(RCTs) in which abiraterone plus prednisone was compared to placebo plus prednisone in metastatic castration-resistant prostate cancer(CRPC) patients. The summary incidence, relative risk, hazard ratio and 95%CI were calculated using random or fixed-effects models. Heterogeneity test was performed to test between-study differences in efficacy and toxicity.RESULTS: A total of two phase III RCTs were included in our analysis, with metastatic CPRC patients before(n = 1088) and after chemotherapy(n = 1195). Prior chemotherapy did not significantly alter the effect of abiraterone on overall survival(P = 0.92) and prostatespecific antigen(PSA) progression-free survival(P = 0.13), but reduced its effect on radiographic-prog-ression-free survival(P = 0.04), objective response rate(P < 0.001), and PSA response rate(P < 0.001). Prior chemotherapy significantly increased the specific risk of fluid retention and edema(P < 0.001) and hypokalemia(P < 0.001), but decreased the risk of all-grade hypertension(P < 0.001) attributable to abiraterone. There was no significant difference of cardiac disorders associated with abiraterone between the two settings(P = 0.58). CONCLUSION: Prior chemotherapy may reduce the effectiveness of abiraterone in patients with metastatic CRPC.

Metastatic hormone-sensitive prostate cancer:How should it be treated?

The number of treatment options for metastatic hormone-sensitive prostate cancer has increased substantially in recent years.The classic treatment approach for these patients—androgen-deprivation therapy alone—is now considered suboptimal.Several randomized phase III clinical trials have demonstrated significant clinical benefits—including significantly better overall survival and quality of life—for treatments that combine androgen-deprivation therapy with docetaxel,abiraterone acetate,enzalutamide,apalutamide,and/or radiotherapy to the primary tumour.As a result,these approaches are now included in treatment guidelines and considered standard of care.However,the different treatment strategies have not been directly compared,and thus treatment selection remains at the discretion of the individual physician or,ideally,a multidisciplinary team.Given the range of available treatment approaches with varying toxicity profiles,treatment selection should be individualized based on the patient’s clinical characteristics and preferences,which implies active patient participation in the decision-making process.In the present document,we discuss the changing landscape of the management of patients with metastatic hormonesensitive prostate cancer in the context of several recently-published landmark randomized trials.In addition,we discuss several unresolved issues,including the optimal sequencing of systemic treatments and the incorporation of local treatment of the primary tumour and metastases.

Circulating cell-free nucleic acids as prognostic and therapy predictive tools for metastatic castrate-resistant prostate cancer

Metastatic castrate-resistant prostate cancer remains a disease hard to cure,and for this reason predictive tools to monitor disease progression and therapy response are an urgent need.In this respect,liquid biopsy on circulating cell-free nucleic acids represents an interesting strategy based on robust data.The low invasiveness and the possibility to target circulating cell-free tumor deoxyribonucleic acid underline the high specificity,sensitivity and clinical usability of the technique.Moreover,it has been observed that the cell-free tumor deoxyribonucleic acid of metastatic castrate-resistant prostate cancer patients can be representative of the tumor heterogeneity.Cell-free tumor deoxyribonucleic acids express the same behaviors as mutations:Variation in gene copy number or the methylation rate of the tumor tissue.Recently,circulating cell-free ribonucleic acid molecules have emerged as interesting markers to stratify the disease.Due to high-throughput technologies,liquid biopsy on circulating cell-free nucleic acids will soon be utilized in the clinical management of metastatic castrate-resistant prostate cancer patients.

Role of androgen receptor splice variants in prostate cancer metastasis

Prostate cancer(PCa)is one of the most lethal cancers in western countries.Androgen receptor(AR)signaling pathway plays a key role in PCa progression.Despite the initial effectiveness of androgen deprivation therapy(ADT)for treatment of patients with advanced PCa,most of them will develop resistance to ADT and progress to metastatic castration resistant prostate cancer(mCRPC).Constitutively transcriptional activated AR splice variants(AR-Vs)have emerged as critical players in the development and progression of mCRPC.Among AR-Vs identified to date,AR-V7(a.k.a.AR3)is one of the most abundant and frequently found in both PCa cell lines and in human prostate tissues.Most of functional studies have been focused on AR-V7/AR3 and revealed its role in regulation of survival,growth,differentiation and migration in prostate cells.In this review,we will summarize our current understanding of regulation of expression and activity of AR-Vs in mCRPC.

Development of a Ready-to-Use PSMA-11 Kit Formulation and Biological Evaluation of Binding Affinity

Introduction: 68Ga-PSMA-11 is considered the gold standard in detection of micro and oligometastases in advanced prostate cancer, being used for therapeutic planning, as well as, potentially, for evaluating response to treatment. The development of ready-to-use lyophilized kit of PSMA-11 adds quality and safety to the routine use of this radiopharmaceutical and represents a pharmacotechnical challenge as it must preserve the integrity and specificity of the ligand. Methods: PSMA-11 kit formulation was proposed, considering radiolabeling parameters and the preservation of the peptide during the lyophilization process, using mannitol as an excipient. Critical temperature characterization studies were carried out using DSC equipment and the freeze-drying process was developed. The direct radiolabeling conditions were evaluated and standardized using 68Ge/68Ga generator eluate from two different manufacturers (ITG and Eckert & Ziegler). The radiochemical purity was evaluated by TLC and HPLC. Biological evaluation was carried out with lyophilized PSMA-11 to demonstrate the integrity of the peptide and preservation of biological activity after the lyophilization process. Results: Based on critical temperature characterization studies, the freeze-drying cycle was designed to reach a freezing temperature of around −40˚C and primary drying at 2˚C. Using 20 mg of mannitol, an intact and elegant lyophilized cake was obtained. PSMA-11 lyophilized kit was directly labeled with 68Ga eluate from 68Ge/68Ga GMP generators (ITG and Eckert & Ziegler) resulting in % RP > 95% at pH 4.0 to 4.5. The results obtained from in vitro and in vivo biological competition studies confirmed the preservation of PSMA-11 affinity for the receptor after lyophilization. Conclusion: A lyophilized formulation (Kit) of PSMA-11 was successfully obtained, which preserved the integrity and biological activity of the peptide and guaranteed radiolabeling efficiency.

Apalutamide for metastatic castration-sensitive prostate cancer:final analysis of the Asian subpopulation in the TITAN trial

The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen(TITAN)trial showed improvement in overall survival(OS)and other efficacy endpoints with apalutamide plus androgen deprivation therapy(ADT)versus ADT alone in patients with metastatic castration-sensitive prostate cancer(mCSPC).As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer,a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation.Event-driven endpoints were OS,and time from randomization to initiation of castration resistance,prostate-specific antigen(PSA)progression,and second progression-free survival(PFS2)on first subsequent therapy or death.Efficacy endpoints were assessed using the Kaplan–Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity.Participating Asian patients received once-daily apalutamide 240 mg(n=111)or placebo(n=110)plus ADT.After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide,apalutamide reduced the risk of death by 32%(hazard ratio[HR]:0.68;95%confidence interval[CI]:0.42–1.13),risk of castration resistance by 69%(HR:0.31;95%CI:0.21–0.46),PSA progression by 79%(HR:0.21;95%CI:0.13–0.35)and PFS2 by 24%(HR:0.76;95%CI:0.44–1.29)relative to placebo.The outcomes were comparable between subgroups with low-and high-volume disease at baseline.No new safety issues were identified.Apalutamide provides valuable clinical benefits to Asian patients with mCSPC,with an efficacy and safety profile consistent with that in the overall patient population.