Advanced Hormone-sensitive Prostate Cancer Research Articles

Surgical Castration as an Alternative to Improve Systemic Treatment for Advanced Prostate Cancer: A Window of Opportunity for Developing Countries.

The Brazilian Public Health System (BPHS) serves approximately 71,730 patients with prostate cancer (PC) every year for which androgen deprivation therapy (ADT) is the primary treatment for patients with advanced hormone-sensitive prostate cancer (aHSPC). Androgen receptor pathway inhibitors (ARPIs) are not accessible through the BPHS. Using the BPHS as a model, this study assesses the long-term economic effect of surgical versus medical castration in aHSPC treatment to strategize cost reduction and the incorporation of ARPI in developing countries. Data of patients with aHSPC (ie, TxN1M0 ineligible for local treatment or TxNxM1) from the BPHS database were analyzed from January 1, 2011, to December 31, 2021, using the TECHTRIALS artificial intelligence platform. The main outcomes were quantitative and descriptive analyses as well as a cost analysis of surgical versus chemical castration. Of the 274,519 patients with aHSPC who received active treatment during the 11-year study period, 90% (n = 246,683) underwent chemical castration and 10% (n = 27,836) underwent bilateral subcapsular orchiectomy (BSO). The median duration of chemical castration was 28 months. The BPHS spent an estimated total of $665,552,091.40 US dollars (USD) on chemical castration and $5,939,348.47 USD on BSO, respectively. The cost per patient was $2,698 USD and $213.37 USD for chemical castration and BSO, respectively. Hypothetically, if all patients with aHSPC had undergone BSO, the total direct cost for the BPHS would have been $42,774,832.20 USD, saving $622,777,259.20 USD over 11 years, making it possible to offer low-dose abiraterone to 65% of aHSPC patients. On the basis of this extensive financial analysis from the world's largest public health system database, BSO appears to be a valuable alternative to chemical castration for treating aHSPC. In resource-limited environments, the cost savings from using BSO may allow access to drugs that will improve survival such as ARPIs.

A Model-Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk.

Teverelix drug product (DP) is a parenteral gonadotropin-releasing hormone (GnRH) antagonist that has been successfully tested in phase 2 trials for hormone-sensitive advanced prostate cancer (APC) and benign prostatic hyperplasia (BPH). In previous APC trials, teverelix DP was administered as intramuscular (IM) and subcutaneous (SC) injections, using a loading dose and (in a single trial) a maintenance dose. Our objective was to derive an optimal dosing regimen for phase 3 clinical development, using a pharmacometrics modeling approach. Data from 9 phase 2 studies (229 patients) was utilized to develop a population pharmacokinetic (PK) model that described the concentration profile accommodating both IM and SC routes of administration. A 2-compartment model with sequential first-order absorption (slow and fast) and lag times best described the PK profiles of teverelix following SC and IM administration. An indirect response model with inhibition of production rate was fit to describe testosterone (T) concentrations based on physiological relevance. The final population PK-pharmacodynamic model was used to conduct simulations of various candidate dosing regimens to select the optimal dosing regimen to achieve clinical castration (T<0.5ng/mL by day 28) and to sustain clinical castration for 26 weeks. Model simulation showed that a loading dose of 360mg SC and 180mg IM with a maintenance dose of 360mg SC 6-weekly (Q6W) starting at day 28 can achieve a ≥95% castration rate up to 52 weeks. This dose regimen was selected for phase 3 clinical development, which includes cardiovascular safety assessment in comparison to a GnRH agonist.

GnRH antagonist monotherapy versus a GnRH agonist plus bicalutamide for advanced hormone-sensitive prostate cancer; KYUCOG-1401.

To compare the effectiveness and safety of gonadotropin-releasing hormone (GnRH) antagonist monotherapy to combined androgen blockade (CAB) with a GnRH agonist and bicalutamide in patients with advanced hormone-sensitive prostate cancer (HSPC). The study was conducted as KYUCOG-1401 trial (UMIN000014243) and enrolled 200 patients who were randomly assigned to either group A (GnRH antagonist monotherapy followed by the addition of bicalutamide) or group B (CAB by a GnRH agonist and bicalutamide). The primary endpoint was PSA progression-free survival. The secondary endpoints were the time to CAB treatment failure, radiographic progression-free survival, overall survival, changes in serum parameters, including PSA, hormones, and bone and lipid metabolic markers, and adverse events. PSA progression-free survival was significantly longer in group B (hazard ratio [HR], 95% confidence interval [CI]; 1.40, 1.01-1.95, p = 0.041). The time to CAB treatment failure was slightly longer in group A (HR, 95% CI; 0.80, 0.59-1.08, p = 0.146). No significant differences were observed in radiographic progression-free survival or overall survival. The percentage of patients with serum testosterone that did not reach the castration level was higher at 60 weeks (p = 0.046) in group A. No significant differences were noted in the serum levels of bone metabolic or lipid markers between the two groups. An injection site reaction was more frequent in group A. The present results support the potential of CAB using a GnRH agonist and bicalutamide as a more effective treatment for advanced HSPC than GnRH antagonist monotherapy.

Stent-ception: implementation of soft double-J stents in the ureteric Memokath-051&lt;sup&gt;TM&lt;/sup&gt; in bilateral ureteric stricture post radiotherapy for advanced prostate cancer

Narrowing of ureter can be due to malignant or benign causes. Temporary double-J (DJ) stents, various metallic stent designs, or definitive corrective surgery can be the options management for ureteric stricture. As an alternative from DJ stents, Memokath-051TM (MMK-051TM) can be inserted in strictured ureters post radiotherapy for advanced prostate cancer patients. We present a case of an advanced prostate cancer which bilateral DJ Stents placed within MMK-051TM. A 76-year-old man with underlying hormone sensitive advanced prostate cancer completed radiotherapy. Post radiotherapy he developed bilateral ureteric strictures and bilateral DJ stents inserted. He had to underwent multiple change of stents due to blockage. Patient had MMK-051TM inserted, however complicated with blockage due to encrustation. Improvisation method done by putting the bilateral DJ stents within the MMK-051TM. Patient had no more blockage of MMK-051TM after the placement of DJ stents within it. However, patient succumbed to death a year after the last procedure. Our case report highlighted encrustation of metallic ureteric stents and a novel approach to overcome this problem. Introduction of additional DJ stents not only reduced the incidence of MMK-051TM blockage but also improved the quality of life of the patient.

Docetaxel in hormone-sensitive advanced prostate cancer; GENESIS-SEFH evaluation reporta

Prostate cancer (PC) is the most common urogenital malignancy in older men and the second leading cause of death by cancer in men in Europe. Current therapeutic practice considers Androgen Deprivation Therapy (ADT) as first line treatment for clinically localized prostate cancer at high-risk, either locally advanced or metastatic. ADT can be achieved through orchiectomy (surgical castration), luteinizing hormone-releasing hormone (LHRH) agonists, or through complete androgen blockade (LHRH agonist combined with an anti-androgen). Docetaxel in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone-refractory metastatic prostate cancer. The CHAARTED and STAMPEDE clinical trials studied the effect of bringing forward the use of docetaxel added on to ADT in the context of hormone-sensitive patients. The CHAARTED clinical trial showed a significant increase in a variable with maximum relevance such as Overall Survival (OS), with a difference of 13.6 months between medians. There was also clinical benefit in the secondary variables: median time until castration-resistant disease or until clinical progression. In the STAMPEDE clinical trial, which included 39% of non-metastatic patients, a 10-month difference between medians was demonstrated in OS, and 17 months in the primary co-variable of Progression Free Survival. The most frequent adverse events were: neutropenia, febrile neutropenia, leucopenia, and general disorders such as asthenia, lethargy or fever. According to data from the CHAARTED and STAMPEDE studies, and the incremental cost of € 3 196.98 for adding on docetaxel to standard treatment, the estimated additional cost for each year of life gained is compatible with an incremental cost-effectiveness ratio between € 2 26736 and € 3 851.78. In view of the efficacy and safety results, the proposed positioning is: to advance the use of docetaxel added to androgen deprivation therapy to first-line metastatic hormone-sensitive prostate cancer, regardless of metastatic volume, in those patients who meet the CHAARTED study criteria.

A Novel Nomogram for Identifying the Patients at Risk for Rapid Progression of Advanced Hormone-Sensitive Prostate Cancer.

The goal of this study was to assess the prognostic impact of the lower urinary tract symptoms (LUTS) in advanced prostate cancer (PCa) patients before progression to castration-resistant prostate cancer (CRPC). A retrospective analysis of the follow-up data for 152 CRPC patients was performed. Severe LUTS symptom was defined as an International Prostate Symptoms Score (IPSS) ≥20 at baseline. Cox regression analysis was conducted to assess CRPC prognostic factors. Nomogram model was created and assessed using the concordance index (C-index), calibration curves, receiver operating characteristic (ROC) curves, and decision curve analyses (DCA). The median CRPC free survival of patients with severe LUTS was 20.5 months, significantly longer than that (7.5 months) of less symptomatic patients. Furthermore, severe LUTS, the hemoglobin, albumin, lymphocyte, and platelet (HALP) score, and Gleason sum were determined to be independent prognostic markers and combined to establish a nomogram, which performed well in the customized prediction of CRPC progression at 6th, 12th, 18th and 24th month. The C-index (0.794 and 0.816 for the training and validation cohorts, respectively), calibration curve, and ROC curve all validated the prediction accuracy. DCA curve showed that it could be effective in helping doctors make judgments. The Nomogram-related risk score separated the patients into two groups with notable progression differences. Severe LUTS was significantly associated with decreased risk for rapid progression to CRPC. The developed nomogram could help identify patients who are at a high risk of rapid CRPC progression and provide tailored follow-up and therapeutic advice.

Profile of Relugolix in the Management of Advanced Hormone-Sensitive Prostate Cancer: Design, Development, and Place in Therapy.

Androgen deprivation therapy, primarily via a gonadotropin-releasing hormone receptor agonist or antagonist together with or without an androgen receptor antagonist, remains the mainstay of medical treatment for advanced prostate cancer. Meanwhile, relugolix has been developed as the first orally active, non-peptide, selective antagonist for the gonadotropin-releasing hormone receptor. Previous randomized studies involving patients with prostate cancer have demonstrated comparable efficacy in androgen suppression between relugolix vs other gonadotropin-releasing hormone antagonists or agonists. This review summarizes available data on the design and development of relugolix and its therapeutic application, and discusses if relugolix represents a promising oral alternative to injectable androgen deprivation therapy. Based on current published evidence, further investigation is likely required to determine the actual clinical benefits of relugolix therapy against prostate cancer.

Prostate Cancer: Side-Effect Management for Androgen Deprivation Therapy

Drug-based hormonal ablation is an essential component of therapy in hormone-sensitive advanced prostate cancer and as a backbone in castration resistance. LHRH agonists are among the most widely used medicinal products. Since these are usually given for life, therapy management is very important. Common side-effects typical of the substance class, such as weight gain, cardiovascular problems, hot flushes, erectile dysfunction or osteoporosis, can significantly reduce patients' quality of life and increase morbidity and mortality. This endangers adherence and, hence, treatment success. This paper provides an overview of how to deal with side-effects during LHRH therapy based on current data and practical experience.

Optimising bone health management in advanced prostate cancer: A comparative cohort study.

133 Background: Survival in prostate cancer is increasing due to advances in hormonal therapy. The recommended duration of Androgen Deprivation Therapy (ADT) is 18 months or more for patients with Non-Metastatic (NM) high risk disease, and lifelong in Metastatic disease. ADT is, however, an independent risk factor for osteoporosis, a disease characterised by low Bone Mineral Density (BMD) and subsequent increased risk of fractures, which can lead to significant disability and early death. In patients with advanced prostate cancer, it is therefore recommended that BMD is assessed yet there remains no established national guidance on how bone health should be managed. Methods: In total, 515 case notes for patients with newly diagnosed advanced hormone sensitive prostate cancer were retrospectively reviewed for assessment of bone health management. Our data analysis included a comparison of outcomes between patient cohorts managed at a dedicated Cancer Bone Health Unit (CBHU) and the Northern centre for Cancer Care (Oncology Centre, OC). Results: 1) Baseline characteristics: The cohorts were well balanced in terms of age and cancer stage. Data was available for 410 patients in the CBHU and 105 in the OC. Median age was 75 (range 59-94) in the CBHU and 71 (range 46-86) in the OC. The majority of patients had metastatic disease and were therefore receiving lifelong ADT. 2) Fracture incidence: was consistently higher in the OC (p&lt;0.001). The most common fractures were hip, spine and wrist. Median time to first fracture in the CBHU was 112 (range 2 to 240) vs 83 weeks (8 to 229) in the OC (p=0.252). 3) Survival: for all patients 2 years after ADT commenced was 96.7% in the CBHU vs 91.8% in the OC (HR 0.321, 95% CI 0.19-0.55, p&lt;0.001). Median survival has not yet been reached. Conclusions: This comparative analysis suggests that a strategy of standardised bone health management within a CBHU is associated with reduced fracture incidence and may delay time to first fracture compared with clinician discretion in an OC. Additionally the data suggests that this strategy also improves survival at 2 years in patients with NM high risk disease. Bone health strategies for prostate cancer should be implemented within hospital trusts to provide standardised care across the region. This could reduce costs associated with fractures and improve quality of life for patients who avoid fractures through timely introduction of treatment. The Northern Cancer Alliance (NCA) has recently approved guidance on the management of bone health in prostate cancer, and implementation has since commenced.

Relugolix: A Review in Advanced Prostate Cancer.

Relugolix (Orgovyx®), an orally active nonpeptide gonadotropin-releasing hormone (GnRH) receptor antagonist that provides rapid testosterone suppression, is indicated in the USA for the treatment of advanced prostate cancer and in the EU for advanced hormone-sensitive prostate cancer. In the pivotal phase III HERO trial in men with advanced prostate cancer, once-daily oral relugolix (with a loading dose on day 1) led to a sustained castration rate over 48weeks of treatment of > 90%, a rate that was non-inferior to that provided by intramuscular leuprolide depot every 3months (with an exploratory analysis further indicating the superiority of relugolix over leuprolide). Relugolix was generally well tolerated, having an adverse event profile that is consistent with testosterone suppression. Furthermore, there is evidence that relugolix may be associated with a lower risk of major adverse cardiac events compared with leuprolide. With the ability to provide the rapid testosterone suppression (with no initial surge in testosterone upon treatment initiation) combined with the benefits of oral administration and potentially improved cardiac safety, relugolix presents a valuable treatment option for men with advanced prostate cancer where androgen deprivation therapy is indicated.

Prostate-specific Antigen Kinetics During Androgen-deprivation Therapy Predict Response to Enzalutamide in Metastatic Castration-resistant Prostate Cancer.

No practical predictive biomarkers exist to date for the response to androgen receptor-axis targeted (ARAT) therapies in metastatic castration-resistant prostate cancer (mCRPC). This study investigated whether prostate-specific antigen (PSA) kinetics in primary androgen-deprivation therapy for advanced hormone-sensitive prostate cancer may be associated with the response to ARAT agents in mCRPC. This study assessed 102 patients with mCRPC treated with enzalutamide or abiraterone to evaluate the associations between clinical outcomes and PSA kinetics, including the ratio of initial to nadir PSA (I/N PSA) level in primary combined androgen blockade. The PSA response was defined as a ≥50% decrease at 3 months from baseline in patients with mCRPC. In patients treated with enzalutamide, the optimal cut-off I/N PSA value for PSA response was 531 ng/ml (sensitivity=66.7%, specificity=88.2%, area under the curve=0.73, using a receiver operating characteristic curve). The PSA response was 83.3% and 25.0% in the high and low I/N PSA groups, respectively. The median overall survival and radiographic progression-free survival from enzalutamide initiation were longer for the high compared to the low I/N PSA group. Multivariate analysis revealed I/N PSA (hazard ratio=0.275, p=0.026) as an independent risk factor for overall survival in the patients treated with enzalutamide. In contrast, I/N PSA showed no predictive ability for PSA response in patients treated with abiraterone. In patients with mCRPC, I/N PSA can be a practical predictive biomarker for response to the ARAT agent enzalutamide.

Prostate cancer cells demonstrate unique metabolism and substrate adaptability acutely after androgen deprivation therapy.

Androgen deprivation therapy (ADT) has been the standard of care for advanced hormone-sensitive prostate cancer (PC), yet tumors invariably develop resistance resulting in castrate-resistant PC. The acute response of cancer cells to ADT includes apoptosis and cell death, but a large fraction remains arrested but viable. In this study, we focused on intensively characterizing the early metabolic changes that result after ADT to define potential metabolic targets for treatment. A combination of mass spectrometry, optical metabolic imaging which noninvasively measures drug responses in cells, oxygen consumption rate, and protein expression analysis was used to characterize and block metabolic pathways over several days in multiple PC cell lines with variable hormone response status including ADT sensitive lines LNCaP and VCaP, and resistant C4-2 and DU145. Mass spectrometry analysis of LNCaP pre- and postexposure to ADT revealed an abundance of glycolytic intermediates after ADT. In LNCaP and VCaP, a reduction in the optical redox ratio [NAD(P)H/FAD], extracellular acidification rate, and a downregulation of key regulatory enzymes for fatty acid and glutamine utilization was acutely observed after ADT. Screening several metabolic inhibitors revealed that blocking fatty acid oxidation and synthesis reversed this stress response in the optical redox ratio seen with ADT alone in LNCaP and VCaP. In contrast, both cell lines demonstrated increased sensitivity to the glycolytic inhibitor 2-Deoxy- d-glucose(2-DG) and maintained sensitivity to electron transport chain inhibitor Malonate after ADT exposure. ADT followed by 2-DG results in synergistic cell death, a result not seen with simultaneous administration. Hormone-sensitive PC cells displayed altered metabolic profiles early after ADT including an overall depression in energy metabolism, induction of a quiescent/senescent phenotype, and sensitivity to selected metabolic inhibitors. Glycolytic blocking agents (e.g., 2-DG) as a sequential treatment after ADT may be promising.

IKKε Inhibitor Amlexanox Promotes Olaparib Sensitivity through the C/EBP-β-Mediated Transcription of Rad51 in Castrate-Resistant Prostate Cancer.

Simple SummaryMost men with advanced hormone-sensitive prostate cancer (HSPC) treated with androgen deprivation therapy will develop castrate resistant prostate cancer (CRPC), a lethal form of prostate cancer (PC). Our group has previously shown that IKKε expression is stronger in CRPC tumors and correlates with aggressive PC. Moreover, we have shown that IKKε depletion or inhibition (BX795, Amlexanox) decrease CRPC cell proliferation and tumor volume in an in vivo mouse model. We also demonstrate that IKKε inhibitors specifically target CRPC to induce a senescent phenotype as well as DNA damage and genomic instability. In this study, we demonstrated that IKKε depletion or inhibition block C/EBP-β recruitment on Rad51 promoter to decrease promoter activity. We have also shown that Amlexanox treatment sensitizes CRPC cells to Olaparib in vitro and in mouse models. Taken together, targeting IKKε with Amlexanox combined with Olaparib may lead to additional effective therapeutic strategies in the management of patients with CRPC.The progression of prostate cancer (PC) is often characterized by the development of castrate-resistant PC (CRPC). Patients with CRPC are treated with a variety of agents including new generation hormonal therapies or chemotherapy. However, as the cancer develops more resistance mechanisms, these drugs eventually become less effective and finding new therapeutic approaches is critical to improving patient outcomes. Previously, we have shown that IKKε depletion and IKKε inhibitors, BX795 and Amlexanox, decrease CRPC cell proliferation in vitro and in vivo and that IKKε inhibitors induce a senescence phenotype accompanied by increased DNA damage and genomic instability in CRPC cells. Here, we describe a new role for IKKε in DNA damage repair involving Rad51 and examine the therapeutic potential of Amlexanox combined with the PARP inhibitor Olaparib in CRPC cell lines. Combining Amlexanox with Olaparib decreased CRPC cell proliferation and enhanced DNA damage through the inhibition of Olaparib-induced Rad51 recruitment and expression in CRPC cells or IKKε-depleted PC-3 cells. We demonstrated that Rad51 promoter activity, measured by luciferase assay, was decreased with Amlexanox treatment or IKKε depletion and that Amlexanox treatment decreased the occupancy of transcription factor C/EBP-β on the Rad51 promoter. Our mouse model also showed that Amlexanox combined with Olaparib inhibited tumor growth of CRPC xenografts. Our study highlights a new role for IKKε in DNA damage repair through the regulation of Rad51 transcription and provides a rationale for the combination of Amlexanox and Olaparib in the treatment of patients with CRPC.

Bone biomarkers and overall survival (OS) in men with advanced hormone-sensitive prostate cancer (HSPC): Results from SWOG S1216, a phase III trial of ADT +/- orteronel.

5071 Background: Circulating bone biomarkers (BB) are strongly prognostic for OS in castration-resistant PC (CRPC). We prospectively evaluated BB in men with HSPC in S1216, a trial that established new OS benchmarks. We sought to identify patient (pt) subsets with differential OS outcomes as defined by BB. Methods: Markers of bone resorption [CTx;PYD] &amp; formation [CICP;BAP] were assessed. Pts were randomly divided into training (1/3) &amp; validation (2/3) sets. In the training set, recursive partitioning of OS was used to identify the ideal dichotomous cutpoint for each BB &amp; for a combination of biomarker split points to define prognostic groups. In the validation set, Cox PH models were used to assess impact of BB on OS, adjusted for pt &amp; tumor characteristics. Adjusted odds ratios for 3-year OS based on BB &amp; baseline clinical factors were developed using logistic regression to estimate receiver operating characteristic (ROC) curves. Results: Of 1,279 men, 949 had baseline BB. Median age–68y; median PSA-28 ng/dL; Gleason&gt;7: 60%; Zubrod PS 0/1-97%. Values of BB at the median &amp; at cutpoints maximized for OS were identified. For 3 of the BB, the cutpoint was at the ̃85th %ile; for PYD it was at the median. Recursive partitioning algorithms applied to the training set identified 4 groups with differential OS based on a dichotomous split of CTx in combination with additional CICP splits within each group. Hazard ratios (HR) for OS based on elevated BBs are shown. ROC analysis showed that only BAP &amp; PYD had significantly higher AUC(0.73;0.74) compared to AUC of baseline clinical factors(0.71) w/ p=0.02 and 0.03 respectively. There was no evidence of BB x treatment interaction (all p&gt;=0.2). Conclusions: In men initiating ADT for HSPC, elevated BB are strongly prognostic for worse OS. BB levels alone &amp; in combination with pt/tumor characteristics identify unique subsets of men with high probability of being alive at 3 years from ADT initiation. These results validate the clinical value of BB in the HSPC state, extending BB utility beyond CRPC. Clinical trial information: NCT01809691. [Table: see text]

Selected Articles from This Issue

Histone deacetylases (HDACs) play a critical role in epigenomic regulation of cancer cell signaling. HDAC inhibitors to-date have faced challenges due to poor isoform selectivity and narrow therapeutic indices. In this first disclosure, Diamond and colleagues report the discovery and preclinical development of the novel, orally bioavailable, class I-targeting HDAC inhibitor, OKI-179 (NCT03931681). OKI-179 was active against solid tumors in preclinical cancer models with a favorable pharmacokinetic profile and on-target pharmacodynamic effects. OKI-179 is a promising next generation HDAC inhibitor suitable for combining with other targeted agents based on its potency, desirable class I HDAC inhibition profile and oral bioavailability.Most men on androgen deprivation therapy (ADT) with advanced hormone-sensitive prostate cancer (HSPC) will develop castration resistant prostate cancer (CRPC), a lethal form of prostate cancer (PC). Previously, our group has demonstrated that IKKε is overexpressed in CRPC and its expression is directly correlated with aggressive PC in patients. In this issue, Gilbert and colleagues demonstrate that IKKε inhibitors, BX795 and Amlexanox, specifically target androgen-independent PC to induce a senescent phenotype, DNA damage and genomic instability. Our in vivo study shows that androgen-independent tumor PC growth is delayed with IKKε inhibitors, providing additional effective therapeutic strategies in the management of patients with CRPC.HLRCC is notorious for being resistance to all tested therapies. A standardized treatment modality for this aggressive subtype of renal tumor is still lacking. In this issue, Kerimoglu and co-workers showed that a combination of two clinically well tolerated therapeutics, rapamycin and Cyst(e)inase®, is efficacious in suppressing HLRCC growth in vivo. The combination induces ferroptosis in tumor tissues with no observable systemic toxicity. Given that rapamycin is an FDA-approved drug, and cyst(e)inase is currently in clinical trial, the combination provides an opportunity to translate into a HLRCC treatment strategy.Pediatric osteosarcoma is an aggressive bone tumor with a poor prognostic for those patients with metastatic disease or those who do not respond to therapy. Oncolytic viruses have shown a safe toxicity profile and are becoming a real treatment option for pediatric solid tumors. In this issue, Martinez-Velez and colleagues demonstrated the therapeutic effect of Delta-24-ACT, an oncolytic adenovirus armed with the 4-1BB ligand, in local and metastatic murine osteosarcoma models. Their data show the ability of Delta-24-ACT to turn the osteosarcoma tumor microenvironment from cold to hot, underscoring its potential as a therapeutic for this disease.

Preliminary results of the "DUO" observational study: Quality of life assessment and cross-sectional follow-up of prostate cancer patients treated with degarelix.

62 Background: The use of androgen deprivation therapy (ADT), has increased over time in the treatment of prostate cancer (PCa). ATD is accompanied by side effects, some of which may increase the cardiovascular (CV) risk. The aim of this study was to evaluate the prevalence of cardiovascular risks and quality of life at the initiation of degarelix, a GnRH antagonist, and 6 months later, in patients with advanced hormone-sensitive PCa. Methods: The DUO study is a PASS, pharmaco-epidemiologic, longitudinal, multicenter observational study. It prospectively enrolled PCa patients during the first 6 months of treatment with degarelix. cohort to describe the prevalence of real-life cardiovascular co-morbidities in. The study was carried out in 46 French urology centers. At D0 and M6, the prevalence of CV, osteoporotic, metabolic, mood disorder, geriatric and sexual morbidity and risk factors were recorded using validated tools and questionnaires. EQ-5D questionnaire measured quality of life. The evolution of the disease (PSA levels) and the tolerance of the treatments were also reported. Results: A total of 124 patients with advanced hormone-dependent PCa (of whom 26.6% were metastatic) were included. At D0 57.7% of patients had a CV morbidity and CV risk factors. Metabolic co-morbidities were also present in 60.6% of patients, osteoporotic risk factors in 34%, sexual disorders in 58%, and mood disorders in 36%. ONCO-G8 score ≤ 14 was observed in 45.6% of patients aged ≥ 70 years. The percentage of patients with CV co-morbidities remained stable (56.7%). The rates of osteoporotic, metabolic, sexual, and mood-related morbidity and risk factors also remained unaltered. Likewise, quality of life remained stable between D0 and M6 (Scores: 0.765 and 0.813 respectively). At the same time, the median PSA rate decreased by -98.4% from D0 (p &lt; 0.001). 42 adverse events (AEs) were reported in 22 patients: degarelix-related AEs were reported in 4.4% of patients. Conclusions: The results of the DUO study showed high prevalence of CV co-morbidity and risk factors in patients with advanced PCa. It also showed no significant increase in CV co-morbidities and risk-factors during the first 6 months of treatment with degarelix as it was observed for osteoporotic, metabolic, sexual, and mood-related disorders. The GnRH antagonist was well tolerated without major impact on quality of life. Assessment of multiple co-morbidities at the initiation and during ADT is mandatory for the optimal management of patients.

HOW TO OPTIMALLY SEQUENCE AVAILABLE THERAPY LINES IN ADVANCED PROSTATE CANCER.

Optimal sequencing of available therapy lines in patients with advanced prostate cancer often poses quite a challenge. The guidelines are sometimes equivocal and clinical trial data are not always applicable to a particular patient. There is a difference in availability of therapy options throughout the world. In decision making, a patient as a whole should be taken into consideration, not just the stage and biology of the disease, but also patient's age, performance status, comorbidities, previous therapy lines, drug's safety profile and patient's preferences. This review article will show certain therapeutic options in the treatment of advanced hormone-sensitive prostate cancer and castration resistant prostate cancer: non- metastatic and metastatic. An attempt will be made to clarify the optimal sequencing.

Degarelix for treating advanced hormone-sensitive prostate cancer.

Degarelix is a gonadotropin-releasing hormone antagonist that leads to medical castration used to treat men with advanced or metastatic prostate cancer, or both. It is unclear how its effects compare to standard androgen suppression therapy. To assess the effects of degree compared with standard androgen suppression therapy for men with advanced hormone-sensitive prostate cancer. We searched multiple databases (CENTRAL, MEDLINE, Embase, Scopus, Web of Science, LILACS until September 2020), trial registries (until October 2020), and conference proceedings (until December 2020). We identified other potentially eligible trials by reference checking, citation searching, and contacting study authors. We included randomized controlled trials comparing degarelix with standard androgen suppression therapy for men with advanced prostate cancer. Three review authors independently classified studies and abstracted data from the included studies. The primary outcomes were overall survival and serious adverse events. Secondary outcomes were quality of life, cancer-specific survival, clinical progression, other adverse events, and biochemical progression. We used a random-effects model for meta-analyses and assessed the certainty of evidence for the main outcomes according to GRADE. We included 11 studies with a follow-up of between three and 14 months. We also identified five ongoing trials. Primary outcomes Data to evaluate overall survival were not available. Degarelix may result in little to no difference in serious adverse events compared to standard androgen suppression therapy (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.62 to 1.05; low-certainty evidence; 2750 participants). Based on 114 serious adverse events in the standard androgen suppression group, this corresponds to 23 fewer serious adverse events per 1000 participants (43 fewer to 6 more). We downgraded the certainty of evidence for study limitations and imprecision. Secondary outcomes Degarelix likely results in little to no difference in quality of life assessed with a variety of validated questionnaires (standardized mean difference 0.06 higher, 95% CI 0.05 lower to 0.18 higher; moderate-certainty evidence; 2887 participants), with higher scores reflecting better quality of life. We downgraded the certainty of evidence for study limitations. Data to evaluate cancer-specific survival were not available. The effects of degarelix on cardiovascular events are very uncertain (RR 0.15, 95% CI 0.04 to 0.61; very low-certainty evidence; 80 participants). We downgraded the certainty of evidence for study limitations, imprecision, and indirectness as this trial was conducted in a unique group of high-risk participants with pre-existing cardiovascular morbidities. Degarelix likely results in an increase in injection site pain (RR 15.68, 95% CI 7.41 to 33.17; moderate-certainty evidence; 2670 participants). Based on 30 participants per 1000 with injection site painwith standard androgen suppression therapy, this corresponds to 440 more injection site pains per 1000 participants (192 more to 965 more). We downgraded the certainty of evidence for study limitations. We did not identify any relevant subgroup differences for different degarelix maintenance doses. We did not find trial evidence foroverall survival or cancer-specific survival comparing degarelix to standard androgen suppression, but serious adverse events and quality of life may be similar between groups. The effects of degarelixon cardiovascular events are very uncertain as the only eligible study had limitations, was small withfew events, and was conducted in a high-risk population.Degarelix likely results in an increase in injection site pain compared to standard androgen suppression therapy. Maximum follow-up of included studies was 14 months, which is short.There is a need for methodologically better designed and executed studies with long-term follow-up evaluating men with metastatic prostate cancer.

Copy number profiles of primary tumors for risk stratification of advanced prostate cancer: A biomarker study embedded in the multicenter STAMPEDE trial.

5021 Background: Men with advanced hormone-sensitive prostate cancer (HSPC) starting long term androgen deprivation therapy (ADT) follow a highly variable clinical course. Treatment intensification with docetaxel or AR targeted therapies improves outcomes but there is a risk of overtreatment, especially in non-metastatic (M0) or metastatic (M1) low volume disease. We established a framework for biomarker evaluation in the STAMPEDE trial. We aimed to evaluate the feasibility and clinical utility of assessing the burden of copy number (CN) aberrations in newly diagnosed advanced HSPC. We hypothesised that increased percentage genome altered (PGA) would associate with higher disease burden and worse prognosis. Methods: We implemented a scalable strategy using low coverage whole genome sequencing (lpWGS) of formalin fixed paraffin embedded (FFPE) diagnostic core biopsies from STAMPEDE participants randomised to the standard of care ADT arm, between 2005 and 2016. Tissue was retrieved from 136 trial sites. 315 cases were randomly selected, aiming for a biomarker population of 300, anticipating an assay failure rate ̃5%. We defined 40% as the minimum histopathologically determined tumor cellularity (TC) for inclusion. We performed a survival analysis investigating PGA at diagnosis as a continuous measure with fractional polynomial specification in Cox models adjusting for disease burden, Gleason grade, pre-ADT PSA (log-transformed), age at randomisation and TC. We pre-specified that all hypothesis tests required evidence at the 5% significance level to consider rejecting the null hypothesis. Results: We successfully CN profiled 300/315 cases. There were no significantly different baseline clinico-pathological features between the full trial comparison n = 3106 and final biomarker population n = 300, 290/300 cases were de novo presentations. PGA in the core with highest Gleason grade and TC was median 18% (range 0%-75%; n = 300). PGA was significantly higher in M1 (n = 169) compared to M0 (n = 131) cases (median: 21% vs 14%; p = 0.00006). 284/300 were subclassified by disease burden into M0 node negative and node positive, and M1 low and high volume. PGA was significantly associated with increased disease burden (p = 0.00002). Increased PGA was significantly and non-linearly associated with an increased hazard of failure-free survival (p = 0.004), progression-free survival (p = 0.002), metastatic progression-free survival (p = 0.003), overall survival (p = 0.045) and prostate cancer-specific survival (p = 0.011). Conclusions: Evaluation of the burden of CN aberrations in archival, poor quality FFPE diagnostic tissue from men randomised in the STAMPEDE trial is feasible using lpWGS and has potential clinical utility to identify better prognosis advanced HSPC patients, who may not require treatment intensification.

Living with Advanced Hormone-Sensitive Prostate Cancer and Treatment with Abiraterone and Androgen Deprivation Therapy: The Patient, Nursing and Physician Perspective.

This article is co-authored by a patient with metastatic hormone-sensitive prostate cancer who is receiving abiraterone and androgen deprivation therapy treatment in Manchester, UK. The patient relates his personal experiences struggling with the diagnosis, his experience with treatment and the physical, emotional and psychosexual impact on his life. After his diagnosis, the patient has become an outspoken advocate and fundraiser for prostate cancer awareness and wants to ensure that novel treatments with proven efficacy and tolerability, such as abiraterone, are available for all men in his condition. The specialist nursing and physician perspectives, provided by healthcare professionals based in London who are not directly involved in this patient’s care, were written in response to the challenges and concerns highlighted by this patient. The role of the specialist nurse as a key healthcare professional in the cancer patient journey, particularly in managing the complex physical and emotional side effects of treatment, is highlighted in this perspective piece. The physician reviews the current difficulties of establishing an effective screening programme in prostate cancer, the common side effects of hormone treatment and the significant progress and challenges in novel drug development and prescription in metastatic hormone-sensitive prostate cancer. While written primarily from the perspective of a patient and healthcare professionals in England, many messages in this commentary would resonate with patients and professionals involved in the care of prostate cancer worldwide.