Metastatic Hormone-naive Prostate Cancer Research Articles

Association of BTN2A1+ microvesicles with overall survival and the role of γδ T cells as a potential therapeutic target in patients with hormone-sensitive metastatic prostate cancer.

194 Background: Despite the recent progress in cancer management, metastatic prostate cancer remains incurable. In the context of immunotherapy failure, we need to identify new immune biomarkers, to improve patient therapy, and explore their potential as therapeutic target. To this end, we screened the prognostic value of soluble immune checkpoints in the plasma of metastatic prostate cancer patients at diagnosis, and depicted their role in anti-tumor activities. Methods: Patients with hormone naive metastatic prostate cancer were prospectively included in the NK-Prostate study (NCT02963155). Blood collection was performed before treatment and patients were followed for 5 years. We determined by ELISA assay plasma levels the soluble form of PD-L1, Pan-BTN3A, BTN3A1, BTN2A1 and BTLA. Large extracellular vesicles (MVs) were pelleted at 10 000g by sequential ultracentrifugation. Results: 66 patients were included in the NK-Prostate with a median follow-up of 42.6 months. Only plasma levels of BTN2A1 were associated with overall survival > 50 months. Patients with enriched sBTN2A1 (soluble form of BTN2A1) presented poorer overall survival (HR for death 2.91 95%CI 1.33 – 6.33, p=0.0072) and progression-free survival than low-level patients (HR for progression 2.73 95%CI 1.48 – 5.05, p=0.0012). Prostate cancer cell line produced sBTN2A1, with 40% associated with extracellular vesicles. High level of BTN2A1+ microvesicles (MVs) were identified by spectral cytometry in patient’ plasma but not in healthy volunteer plasma, and deep phenotyping revealed that B cell-derived BTN2A1+ MVs were associated with shorter overall survival (HR 4.22 95%CI 1.68 – 10.57, p=0.0021). To evaluate the impact of BTN2A1+ MVs on γδ T cells, we generated BTN2A1 KO MVs, BTN2A1 overexpressed MVs, and BTN2A1 mutant overexpressed MVs (that do not interact with γδ TCR). We demonstrated that BTN2A1 overexpressed MVs could specifically interact with γδ T cell; and impaired their proliferation and cytotoxicity against prostate cancer cell lines (LNCaP, DU145 and PC3). Conclusions: Our study shows the negative impact of B cell derived BTN2A1+ MVs in hormone naïve metastatic prostate cancer. Plasma MVs phenotyping is an easy-to-perform test, accessible for all patients. Our results highlight the role of γδ T cell in the anti-tumor immunity in prostate cancer, making them an interesting target for immunotherapy in this pathology. Clinical trial information: NCT02963155 .

Prognostic impact of serum testosterone in metastatic hormone-naive prostate cancer: a systematic review and meta-analysis.

In daily practice, there is an unmet medical need for biomarkers that facilitate therapeutic decision-making in the metastatic hormone sensitive prostate cancer (mHSPC) scenario. Although recent studies have highlighted the potential of testosterone as a prognostic and predictive marker in prostate cancer, the evidence is controversial. The objective of this review was to summarize and analyze the scientific evidence regarding the prognostic role of basal testosterone levels in patients with mHSPC. A systematic review was performed. Three authors selected the articles from Web of Science, PubMed, Scopus, and Cochrane Library electronic databases. Risk of bias was assessed by the Newcastle Ottawa Scale. Most of the selected articles suggest that low testosterone levels before starting hormonal blockade imply a worse prognosis for patients with mHSPC. However, the quality of the evidence is poor, the studies are heterogeneous, and it is not possible to meta-analyze most of the published results. Testosterone is an accessible and affordable biomarker. If it were correctly demonstrated that it harbors a prognostic and/or predictive role in the mHSPC setting, it could represent an advance in decision-making in these patients. Well designed prospective studies are needed to correctly answer this question.

A comparison of the sarcopenic effect of androgen receptor-axis-targeted agents vs. androgen deprivation alone in patients with metastatic prostate cancer.

Androgen deprivation therapy (ADT) with androgen receptor axis-targeted (ARAT) therapy is the standard of care provided to patients with metastatic prostate cancer. While effective, it results in sequelae, such as loss of skeletal muscle mass. In this study, we compared the sarcopenic effects of abiraterone and enzalutamide, two ARATs used to treat metastatic prostate cancer. Our cohort was comprised of 55 patients diagnosed with metastatic hormonenaive prostate cancer from 2014-2019. Patients were divided into three treatment groups: gonadotropin-releasing hormone (GnRH ) agonist alone; GnRH agonist combined with abiraterone acetate; and GnRH agonist combined with enzalutamide. We then compared axial computed tomographic (CT) scans at the L3 level before and after the initiation of hormone therapy for each patient. A skeletal muscle index (SMI) was calculated for each patient, and alongside clinical data, was compared between the three groups. One-way analysis of variance (ANOVA) and Fisher's exact test were used to compare means and proportions, respectively. Baseline clinical characteristics were not significantly different between the three groups. The percent SMI change and number of newly sarcopenic patients were not found to be significantly different between the groups. The only variable that was significantly different across the three groups was time between CT scans. Although we found no significant difference in the sarcopenic effects of GnRH alone, GnRH with abiraterone, or GnRH with enzalutamide in our cohort of 55 hormone-naive metastatic prostate cancer patients, overall decreases in muscle mass were observed for all three groups. This highlights the importance of muscle-retaining strategies for patients undergoing ADT for metastatic prostate cancer, regardless of therapeutic regimen.

Retrospective validation of bone risk stratification criteria for men with de novo metastatic hormone-naive prostate cancer in China.

Bone metastasis has been suggested to be a significant impactor on the prognosis of newly diagnosed de novo metastatic hormone-sensitive prostate cancer (mHSPC), and some risk stratification models have been proposed on the basis of this hypothesis. However, the effectiveness of these risk stratification criteria has not been fully evaluated in China. This study aimed to evaluate the effectiveness of the risk stratification models in China. A total of 140 patients who were newly diagnosed with metastatic prostate cancer followed by primary androgen deprivation-based therapy from January 2008 to June 2021 at our institution were enrolled in this study. The patients were divided into different groups on the basis of high- and low-volume disease (H/LVD) criteria, high-and low-risk disease (H/LRD) criteria, extremity bone metastasis criteria (EBM), and extent of disease (EOD) criteria. The area under the receiver operating characteristic (ROC) curve (AUC) and decision curve analysis (DCA) were used to compare the validity and net benefit of these models. Using the Cox proportional hazards model, we performed univariable and multivariable analyses of the factors influencing overall survival (OS) and the time of progression to metastatic castration-resistant prostate cancer (CRPC). The median patient age was 72 years. Most patients had a Gleason score ≥8 (102 cases, 72.9%) and clinical T stage >2 (75 cases, 53.6%). The median follow-up time was 25 months (range, 2-95 months). Ninety-two patients progressed to CRPC and fifty-seven patients died during the follow-up. The AUC of OS and CRPC showed that the EOD model had higher validity than the other risk stratification models. DCA shows that the net benefit of the EOD model on OS was better than that of the other risk stratification models. As for CRPC, the net benefit of the EOD model was second only to that of the H/LRD model when the threshold was <0.5; however, when the threshold was >0.5, the EOD model outperformed the other models. The effectiveness of EOD as an independent prognostic variable was verified through univariable and multivariable analyses. The EOD model yields reasonable risk stratification for use in Chinese mHSPC patients, providing further evidence supporting its role in clinical decision-making.

Prospects of Treating Prostate Cancer through Apalutamide: A Mini-Review.

Prostate cancer is considered the second most diagnosed cancer, and one of the most common causes of death from cancer in men. Apalutamide is an effective, safe, and well-tolerated agent used for the treatment of men with non-metastatic Castration-Resistant Prostate Cancer (nmCRPC) and metastatic Hormone-Naive Prostate Cancer (mHNPC). Androgen receptor signaling is a leading factor that drives these prostate tumors. USFDA has approved apalutamide on 14 February 2018 as an agent that targets androgen receptor signaling through inhibition causing significant improvement in metastasis-free survival in patients with prostate cancer. In this review, various aspects related to apalutamide have been summarized which involve the mechanism of action, chemistry, synthesis, pharmacokinetics, pharmacodynamics, adverse reactions, and safety parameters. The literature was thoroughly searched in the relevant databases to identify studies published in this field during recent years. Special attention has been given to apalutamide clinical trials phases and its promising future as one of the first-line agents for the treatment of patients with advanced prostate cancer. Ongoing trials are progressing for apalutamide monotherapy and also for its combinations in other disease settings. The expected results of such trials will shape the future scenario of prostate cancer therapy. This review article has highlighted different aspects of Apalutamide like its mechanism of action, adverse effects, pharmacokinetics, pharmacodynamics, clinical trials among others. The contents of this article should make an excellent read for prospective researchers in this field.

The treatment landscape of metastatic prostate cancer.

The treatment landscape of metastatic prostate cancer has evolved significantly over the past two decades. Several landmark phase 3 trials led to new drug approvals and rapid changes in therapy options for patients, including drugs with distinct mechanisms of action (e.g., hormonal, chemotherapy, radionuclide, immunotherapy, and targeted therapies). Therapies initially developed in later stages of the disease (metastatic castration resistant prostate cancer) have started to move earlier in the prostate cancer continuum, with new standards of care for metastatic hormone naive prostate cancer and non-metastatic castration resistant prostate cancer. Overall, patients are living longer with a better quality of life. However, despite these significant advances, prostate cancer remains a leading cause of cancer death globally. Disease heterogeneity and the emergence of therapy resistance remain significant barriers, and the identification and application of molecular biomarkers to guide the choice and sequencing of systemic agents are still in early stages. Here we discuss the current treatment landscape of metastatic prostate cancer, clinical challenges, and the emerging role of molecular biomarkers for targeting biologic subsets of advanced disease and co-targeting heterogenous resistance patterns.

634P Prognostic value of the modeled PSA kinetic parameter (KELIM) in prostate cancer patients with rising PSA after primary local therapy treated in a prospective phase III trial with ADT +/- docetaxel

The addition of docetaxel to androgen-deprivation therapy (ADT) is associated with survival benefit in patients with hormone-naive metastatic prostate cancer (PCa), but was not found to be beneficial in high-risk patients presenting with rising PSA after primary local therapy (Oudard S et al, JAMA Oncol 2019). The objective was to assess the decline kinetics of PSA using mathematical modeling, and investigate the prognostic/predictive value of kinetic parameters.

Use of bisphosphonates and other bone supportive agents in the management of prostate cancer-A UK perspective.

To explore the practice and views of uro-oncologists in the UK regarding their use of bone supportive agents in patients with prostate cancer. An expert-devised online questionnaire was completed by members of the British Uro-oncology Group (BUG). Of 160 uro-oncologists invited, 81 completed the questionnaire. Approximately 70% of respondents never use a bone supportive agent in patients with metastatic hormone-naïve prostate cancer on androgen deprivation therapy (ADT). However, use was more frequent in men with metastatic castration-resistant prostate cancer, from first-line treatment onwards. The majority of uro-oncologists do not use a bone supportive agent to prevent skeletal-related events in men with non-metastatic disease unless the individual patient is at an increased risk of osteoporosis. In men with more advanced disease, respondents would use an oral or intravenous (IV) bisphosphonate in 41% and 61% of patients, respectively. Zoledronic acid is the first-choice bone supportive treatment in 77% of cases, with the lack of clinical data cited as a barrier to use for other IV bisphosphonates. Local guidelines also have a significant influence on the use of bone supportive agents, especially with respect to denosumab. Bone mineral density measurement is conducted in approximately 40% of men with ADT exposure of 2 years or longer, or those with metastatic prostate cancer. Uro-oncologists in the UK generally do not use bone supportive agents for men with metastatic hormone-naïve prostate cancer or those with non-metastatic disease. However, increasing the duration of ADT and the presence of castration-resistant metastatic prostate cancer increases use.

1117 - Oncological and functional outcomes of cytoreductive radical prostatectomy (cRP) in men with metastatic hormone-naive prostate cancer (mhnPCA)

1117 - Oncological and functional outcomes of cytoreductive radical prostatectomy (cRP) in men with metastatic hormone-naive prostate cancer (mhnPCA)

Treatment of the primary in metastatic prostate cancer.

The standard treatment in metastatic prostate cancer (mPCa) is systemic, based on androgen deprivation therapy recommended in different forms, alone or combined with abiraterone acetate or docetaxel. The aim of this review is to synthesize the available data from literature regarding the optimal treatment of the primary in patients diagnosed with metastatic prostate cancer. Multimodal treatments offer the best chance for survival for these patients, but the optimal strategy lacks consensus. Using retrospective studies as an argument, recent articles sustain the clinical and oncological benefits of local therapies in hormone-naïve metastatic prostate cancer, represented by radical prostatectomy or radiotherapy. Through these procedures, local control of disease can be achieved, thus avoiding potential complications and further surgical interventions. Even if the current results are not evenly relevant, the treatment of the primary along with metastasis-directed therapy could improve survival and even cure-selected patients. This article emphasizes important aspects regarding a feasible management of mPCa, with possible impact on subsequent guidelines. The expected results from ongoing trials may provide another perspective in treatment of these cases.

An evaluation of apalutamide for the treatment of prostate cancer

ABSTRACT Introduction Novel androgen signaling inhibitors are currently standard of care in the treatment of patients with prostate cancer. Second-generation androgen receptor antagonists have demonstrated efficacy in earlier disease settings, fulfilling an unmet need in the treatment of patients with advanced prostate cancer. Areas covered The present article focuses on the development and establishment of apalutamide among the available treatment options for prostate cancer. A literature search was performed in Pubmed/Medline for past studies and reviews of the drug. Ongoing clinical trials were also examined in the Clinicaltrials.gov online database. Expert opinion Apalutamide has demonstrated benefit for patients with non-metastatic castration resistant and metastatic hormone naive prostate cancer. It is an efficacious, tolerable, and convenient oral agent, thus a valuable addition in the armamentarium of prostate cancer therapeutics for both non-metastatic castrate resistant and metastatic hormone naïve prostate cancer. Ongoing trials are investigating the drug as monotherapy and in combinations in other disease settings. Results are expected to further expand the drug’s indications and shape the future landscape of prostate cancer therapy.

MP09-16 IDENTIFICATION OF IL13RA2 AS A BIOMARKER FOR PREDICTING CASTRATION-RESISTANCE OF PROSTATE CANCER USING PATIENT DERIVED XENOGRAFT MODELS

INTRODUCTION AND OBJECTIVE:There are some treatment strategies using up-front chemotherapy or androgen receptor axis targeting therapies for metastatic hormone-naive prostate cancer (mHNPC). Howeve...

Prostate radiotherapy in newly diagnosed metastatic prostate cancer.

The aim of this article is to review the role of prostate radiotherapy in the multimodal management of newly diagnosed metastatic hormone naïve prostate cancer. Two randomized controlled trials have evaluated the role of prostate radiotherapy with systemic therapy (androgen deprivation therapy ± docetaxel) in newly diagnosed metastatic hormone-naive prostate cancer. In a combined cohort of over 2000 patients, prostate radiotherapy with systemic therapy improved survival over systemic therapy alone in patients with low metastatic burden but not in high-burden patients. Prostate radiotherapy with systemic therapy is now a recommended first-line option for newly diagnosed men with low metastatic burden prostate cancer. The current recommended definition for low metastatic burden is based on conventional imaging (Tc bone scans and CT/MRI). Cross-correlative studies are required to pick an appropriate threshold for sensitive-imaging modalities such as PSMA PET or whole-body MRI. Ongoing trials are evaluating prostate radiotherapy in this setting combined with abiraterone/docetaxel and metastasis-directed therapy. Prostate radiotherapy with systemic therapy improves survival in patients with newly diagnosed, low metastatic burden prostate cancer and is a recommended first-line treatment option. Ongoing trials are evaluating combination with metastasis-directed therapy and other systemic treatments.

The prognostic value of nadir PSA level and time to nadir in high risk mHNPC patients

Abstract Background The prognosis of patients with high risk metastatic hormone-naive prostate cancer is poor.The present study investigated the prognostic significance in Japanese men with high-risk mHNPC when stratified by the criteria in the LATITUDE trial, and initial experience with upfront abiraterone in high-risk mHNPC Methods The present study retrospectively enrolled 60 men who were considered to be High risk mHNPC, at our institution from 2010 to 2018. Results The median OS was 40 months (95% CI 33.1-49.2 months).The median time to CRPC was 34 months (95% CI 28.7-57.5 months ) in the low-risk mHNPC group and 15 months (95% CI 14.0-25.4 months, P = 0.019) in the high-risk mHNPC group.In the high-risk mHNPC, the median time to CRPC was 36 months (95% CI 5.4-66.5 months ) in the low-PSA nadir group ( PSA nadir was less than 0.2 ng/ml) and 12 months (95% CI 6.8-17.1 months, P = 0.005) in the high-PSA nadir group ( PSA nadir was more than 0.2 ng/ml).The median time to CRPC was 15 months (95% CI 10.8-19.1 months ) in the low-iPSA group ( iPSA was less than 330 ng/ml) and 15 months (95% CI 4.7-25.2 months, P = 0.83) in the high-iPSA group ( PSA nadir was more than 330 ng/ml).Time to nadir is positively associated with time to nadir (P > 0.001 ).Multivariate analysis revealed that longer time to nadir was significant prognostic factor. Conclusion Prognosis of high-risk mHNPC was poor in Japanese population.It revealed that PSA response play an important role in progression of high-risk mHNPC.

The Effect of Treatment Sequence on Overall Survival for Men With Metastatic Castration-resistant Prostate Cancer: A Multicenter Retrospective Study.

We aimed to evaluate the treatment sequence for patients with metastatic castration-resistant prostate cancer (mCRPC) in real-world practice and compare overall survival in each sequential therapy. We retrospectively evaluated 146 patients with mCRPC who were initially treated with androgen deprivation therapy as metastatic hormone-naive prostate cancer in 14 hospitals between January 2010 and March 2019. The agents for the sequential therapy included new androgen receptor-targeted agents (ART: abiraterone acetate or enzalutamide), docetaxel, and/or cabazitaxel. We evaluated the treatment sequence for mCRPC and the effect of sequence patterns on overall survival. The median age was 71 years. A total of 35patients received ART-ART, 33 received ART-docetaxel, 68 received docetaxel-ART, and 10 received docetaxel-cabazitaxel sequences. The most prescribed treatment sequence was docetaxel-ART (47%), followed by ART-ART (24%). Overall survival calculated from the initial diagnosis reached 83, 57, 79, and 37 months in the ART-ART, ART-docetaxel, docetaxel-ART, and docetaxel-cabazitaxel, respectively. Multivariate Cox regression analyses showed no significant difference in overall survival between the first-line ART (n= 68) and first-line docetaxel (n= 78) therapies (hazard ratio [HR], 0.84; P= .530), between the ART-ART (n= 35) and docetaxel-mixed (n= 111) sequences (HR, 0.82; P= .650), and between the first-line abiraterone (n= 32) and first-line enzalutamide (n= 36) sequences (HR, 1.58; P=.384). The most prescribed treatment sequence was docetaxel followed by ART. No significant difference was observed in overall survival among the treatment sequences in real-world practice.

Changes in conditional net survival and dynamic prognostic factors in patients with newly diagnosed metastatic prostate cancer initially treated with androgen deprivation therapy.

BackgroundThe purpose of this study was to identify predictive factors associated with conditional net survival in patients with metastatic hormone‐naive prostate cancer (mHNPC) initially treated with androgen deprivation therapy (ADT).MethodsAt nine hospitals in Tohoku, Japan, the medical records of 605 consecutive patients with mHNPC who initially received ADT were retrospectively reviewed. The Pohar Perme estimator was used to calculate conditional net cancer‐specific survival (CSS) and overall survival (OS) for up to 5 years subsequent to the diagnosis. Using multiple imputation, proportional hazard ratios for conditional CSS and OS were calculated with adjusted Cox regression models.ResultsDuring a median follow up of 2.95 years, 208 patients died, of which 169 died due to progressive prostate cancer. At baseline, the 5‐year CSS and OS rates were 65.5% and 58.2%, respectively. Conditional 5‐year net CSS and OS survival gradually increased for all the patients. In patients given a 5‐year survivorship, the conditional 5‐year net CSS and OS rates improved to 0.906 and 0.811, respectively. Only the extent of disease score (EOD) ≥2 remained a prognostic factor for CSS and OS up to 5 years; as survival time increased, other variables were no longer independent prognostic factors.ConclusionsThe conditional 5‐year net CSS and OS in patients with mHNPC gradually increased; thus, the risk of mortality decreased with increasing survival. The patient's risk profile changed over time. EOD remained an independent prognostic factor for CSS and OS after 5‐year follow‐up. Conditional net survival can play a role in clinical decision‐making, providing intriguing information for cancer survivors.

Prostate radiotherapy for metastatic hormone sensitive prostate cancer—myth or reality?

Previously, local radiotherapy (RT) was only limited to palliate local symptoms, including bleeding or obstructive symptoms in metastatic prostate cancer patients. However, a population-based database and retrospective studies suggested that the local treatment of the prostate could improve survival in metastatic hormone-naive prostate cancer with a small metastatic burden, ‘oligometastatic’ state (1-3). Recently two randomized trials demonstrated the efficacy of local RT to prostate in metastatic prostate cancer patients (4,5).

The prognostic value of tumor PD-L1 status in patients with metastatic prostate cancer

Background. New potential biomarker for patients with metastatic hormone-naive prostate cancer (PCa) might be detection of programmed death ligand 1 (PD-L1) expression in tumor which is associated with worsened results of treatment and decreased survival in patients with pancreatic cancer, lung cancer and other malignant tumors. Objective : to evaluate the prognostic value of positive tumor PD-L1 status on time to castration resistance (CRPCa) in patients with meta­static PCa receiving hormonal androgen deprivation therapy in first-line systemic treatment. Materials and methods. A total of 35patients with metastatic hormone-naive PCa receiving androgen deprivation therapy with luteinizing hormone-releasing hormone analogue and follow-up at N.N. Blokhin National Medical Research Center of Oncology were recruited in our prospective study. Tumor features of all patients were evaluated for PD-L1 expression on tumor cells by immunohistochemical studies of paraffin block sections obtained under the visual control of the pathologist using a set of monoclonal anti-PD-L1 antibody (28-8) (ab 205921) and Ventana BenchMark GXSlide staining system. Tumor tissue was obtained before starting androgen deprivation therapy. The expression level of PD-L1 &gt;1 % in tumor cells was taken for the positive tumor PD-L1(+) status. Results . Median follow-up was 32.8 months. Positive tumor PD-L1(+) status was identified in 10 (28.6 %) cases. Median time to CRPCa was significantly lower in patients with PD-L1(+) status, than in negative PD-L1(—) status (21.44 vs. 49.12, p = 0.006 log rank test). Multi­variate Cox regression analysis confirmed independence prognostic value of PD-L1(+) associated with decreased time to CRPCa (hazard ration 5.95, 95 % confidence interval 1.97—17.99; p = 0.002), including in subgroup of patients with low-volume metastatic disease (hazard ration 7.33, 95 % confidence interval 1.81—29.60; p = 0.005). Discussion . Interaction of PD-1 receptors and its ligands PD-L1/PD-L2 is the key mechanism causing tumor immune escape and progression of the cancer. There are discussed certain ways of inducing PD-L1 expression and its prognostic value on aggressive nonmetastatic PCa. High frequency of positive PD-L1 status was revealed in rare histological subtypes of PCa associated with unfavorable prognosis and visceral metastasis. Conclusion. The results of our study demonstrated the positive tumor PD-L1 status as an independent unfavorable prognostic factorfor patients with metastatic hormone-naive PCa associated with decreased time to castration resistance, including in patients with low volume metastatic disease.

PT209 - External validation of the CHAARTED and LATITUDE criteria in patients with hormone-naive metastatic prostate cancer: A multi-institutional study in Japan

PT209 - External validation of the CHAARTED and LATITUDE criteria in patients with hormone-naive metastatic prostate cancer: A multi-institutional study in Japan

Androgen Deprivation Therapy with Chemotherapy or Abiraterone for Patients with Metastatic Hormone-Naive Prostate Cancer: A Systematic Review and Meta-Analysis

Patients with metastasis prostate cancer underwent androgen deprivation therapy (ADT) in the considering of the leading role of androgen receptor pathway. However, the resistance occurred within 1 year or more. The combination of cytotoxic chemotherapy and abiraterone for ADT therapy was performed in recent randomized controlled trials. The meta-analysis was focused on the treatment comparisons between additional treatment with ADT and ADT alone. A significant difference was observed that the overall survival benefit of early and active additional treatment with ADT in patients with hormone-sensitive metastatic prostate cancer. However, a great proportion of patients with metastatic disease have metastases after receiving ADT. It will be important to further improve the treatment options.