Therapy For Advanced Prostate Cancer Research Articles

An unbiased seed-based RNAi selection screen identifies small RNAs that inhibit androgen signaling and prostate cancer cell growth

Blocking androgen receptor signaling is the mainstay of therapy for advanced prostate cancer (PCa). However, acquired resistance to single agents targeting this pathway results in the development of lethal castration-resistant PCa. Combination therapy approaches represent a promising strategy for the treatment of advanced disease. Here, we explore a therapeutic strategy for PCa based on the ability of shRNAs/siRNAs to function essentially as miRNAs and, via seed sequence complementarity, induce RNA interference of numerous targets simultaneously. We developed a library that contained shRNAs with all possible seed sequence combinations to identify those ones that most potently reduce cell growth and viability when expressed in PCa cells. Validation of some of these RNAi sequences indicated that the toxic effect is associated with seed sequence complementarity to the 3' UTR of AR coregulatory and essential genes. In fact, expression of siRNAs containing the identified toxic seed sequences led to global inhibition of AR-mediated gene expression and reduced expression of cell-cycle genes. When tested in mice, the toxic shRNAs also inhibited castration-resistant PCa and exhibited therapeutic efficacy in pre-established tumors. Our findings highlight RNAi of androgen signaling networks as a promising therapeutic strategy for PCa.

Quantifying the changes in body mass index and performance status during androgen deprivation therapy for advanced prostate cancer in southeast Nigeria

BackgroundAndrogen deprivation therapy (ADT) for advanced prostate cancer (aPCa) causes changes in body mass index (BMI) and in the performance status depending on the extent of cancer remission. The aim of this study is to quantify these changes.MethodsA prospective cohort study in a public tertiary urology centre in Enugu, southeast Nigeria. With appropriate sample size determined, men with aPCa for ADT, by surgical or medical modality, were recruited into a test group (TG), taking note of the Gleason score. A cohort of similar men without malignant or debilitating diseases formed the control group (CG). The age, weight and the Eastern Cooperative Oncology Group (ECOG) score were determined before ADT and at 2 monthly intervals for the TG. Same parameters were assessed for the CG at 2 monthly intervals. Additionally, total prostate-specific antigen (tPSA) was done for the TG at 3 monthly intervals.ResultsIn all, 119 men in the TG and 68 men in the CG were recruited with no differences in age (F 2.777; p 0.10) and height (F 0.409; p 0.52) at recruitment. In the TG, BMI increased from 25.20 ± 3.92 to 26.26 ± 3.90 kg/m2 (p 0.001), median tPSA dropped from 36.9 ng/ml (IQR 20.4–65.7) to 3.7 ng/ml (IQR 1.1–8.7) and ECOG score improved (χ2 34.1; df9; p < 0.001) with reduction in the proportion of men with ECOG > 1 from 84.0 to 20.4%. A secondary finding is that gains in BMI and in ECOG score are earlier in the surgical modality than in the medical modality of ADT.ConclusionsIn the first 6 months of ADT, there are gains in BMI and ECOG scores. These gains are earlier with surgical modality of ADT.

Consensus on safety management of novel hormonal therapy for advanced prostate cancer

AbstractProstate cancer (PCa) is one of the most prevalent malignant tumors in men, accompanied by high incidence and mortality rates. Novel hormonal therapy (NHT) has emerged as the primary treatment for advanced PCa, providing noticeable clinical benefits. However, the diverse range of adverse events (AEs) associated with NHT may influence both treatment efficacy and patients' quality of life. In light of the latest international clinical research evidence and recommendations from domestic and foreign guidelines, this consensus aims to provide a comprehensive overview of the common AEs experienced during NHT for advanced PCa patients. Additionally, it seeks to develop a hierarchical approach to more efficiently manage AEs, presenting valuable insights for clinical medication and adverse reaction management.

Surgical androgen deprivation therapy in advanced prostate cancer in patients of African descent: comparison of biochemical efficacy of bilateral total and subcapsular orchidectomy.

Surgical androgen deprivation therapy (ADT) to treat advanced prostate cancer can be achieved either by bilateral total orchidectomy (BTO) or bilateral subcapsular orchidectomy (BSCO). However, biochemical and clinical equivalence between BTO and BSCO among native Africans is undocumented. To compare the biochemical response (testosterone and prostate specific antigen) in patients who had BTO and BSCO for advanced prostate cancer. A randomized single- blind study of 64 consenting patients that underwent either BTO or BSCO. Pre- and post-operative PSA and testosterone assays were done serially at intervals and compared between each treatment group. Each treatment group were similar with no statistically significant difference in terms of age (p= 0.449) or degree of tumor differentiation (p =0.714). Neither median testosterone (p= 0.515) nor the mean pre-operative PSA differ between the two groups (p = 0.482). Also, similar trends were noticed post operatively except at the 2nd month when a statistically significant difference was recorded (p = 0.003). The two techniques of orchidectomy were effective in accomplishing androgen deprivation. They produced similar biochemical (testosterone and PSA) response.

Targeting the chromatin effector Pygo2 promotes cytotoxic T cell responses and overcomes immunotherapy resistance in prostate cancer.

The noninflamed microenvironment in prostate cancer represents a barrier to immunotherapy. Genetic alterations underlying cancer cell-intrinsic oncogenic signaling are increasingly appreciated for their role in shaping the immune landscape. Recently, we identified Pygopus 2 (PYGO2) as the driver oncogene for the amplicon at 1q21.3 in prostate cancer. Here, using transgenic mouse models of metastatic prostate adenocarcinoma, we found that Pygo2 deletion decelerated tumor progression, diminished metastases, and extended survival. Pygo2 loss augmented the activation and infiltration of cytotoxic T lymphocytes (CTLs) and sensitized tumor cells to T cell killing. Mechanistically, Pygo2 orchestrated a p53/Sp1/Kit/Ido1 signaling network to foster a microenvironment hostile to CTLs. Genetic or pharmacological inhibition of Pygo2 enhanced the antitumor efficacy of immunotherapies using immune checkpoint blockade (ICB), adoptive cell transfer, or agents inhibiting myeloid-derived suppressor cells. In human prostate cancer samples, Pygo2 expression was inversely correlated with the infiltration of CD8+ T cells. Analysis of the ICB clinical data showed association between high PYGO2 level and worse outcome. Together, our results highlight a potential path to improve immunotherapy using Pygo2-targeted therapy for advanced prostate cancer.

Evaluation of a novel transcriptomic tumor signature (PROSTest) as response biomarker for 177Lu-PSMA therapy in advanced prostate cancer.

183 Background: Radionuclide therapy targeting the prostate specific membrane antigen (177Lu-PSMA therapy) has proven to be an effective treatment in men with metastatic castration resistant prostate cancer (mCRPCs). Despite representing a significant therapeutic breakthrough, a critical unmet need in 177Lu-PSMA therapy, is a prognostic biomarker for treatment optimization. Imaging and standard biomarkers have limited value. The PROSTest is a new 27-gene algorithmic signature originally developed for prostate adenocarcinoma diagnosis (0 to 100, positive score ≥20). We hypothesized that PROSTest would be elevated in mCRPCs and could have utility as a biomarker for mCRPC management. Methods: Prospective enrollment of 113 mCRPC for 177Lu-PSMA therapy (KlbB-5338-0302021 study). Pathology, clinical and biomarker data were available as was PSMA-PET/CT. Blood samples were collected for PROSTest prior to therapy. Target genes were isolated and amplified using qPCR. PROSTest scores (0-100) were obtained following algorithmic analysis. Scores were correlated with mCRPC diagnosis and baseline information. Scores and standard clinical measures were evaluated as prognostic factors with survival as endpoint. Mann-Whitney U-test, Kaplan-Meier survival and Cox proportional hazards regression analysis were utilized. All data: median (IQ range). Results: 89 (79%) patients were evaluable. Age was 75 (68-80). Disease characteristics at time of diagnosis included Gleason scores 8-10 (70%) and TMM: T3-T4 tumors (67%), N1 (53%), M1 (45%). At the time of therapy all patients were metastatic and all exhibited PSMA-positive disease. The highest tumor SUVmax was 51 (28-78). PSA levels were 69ng/mL (18-305). The PROSTest score was 89 (81-92). PROSTest scores were weakly correlated with age (r=0.33, p=0.0015) but not with baseline histopathological parameters (e.g., Gleason score, TNM) or pretreatment imaging results (e.g., SUVmax). Twenty-four (27%) patients have perished. Treatment and follow-up (5 months, 3-18) are ongoing. The mOS was 15 months. No factors were associated with death as an outcome except for the PROSTest score. PROSTest scores ≥79 (based on ROC analysis) were associated with significantly increased risk for mortality (HR: 2.9, 95% CI: 1.5-7.4). The mOS was 14 months in patients with pre-therapy PROSTest scores &gt;79 compared to mOS not reached for PROSTest scores &lt;79 ( p=0.02). In the COX model, baseline PROSTest was confirmed to be significantly predictive of death despite therapy (β = 1.51, p=0.01). Conclusions: The PROSTest blood gene expression score is elevated in mCRPCs. Levels are not associated with baseline clinical, histopathological, pretreatment PSA or imaging parameters. Elevated expression (≥79) of this biomarker prior to treatment was associated with a lower survival and could be used to predict survival in patients undergoing 177Lu-PSMA.

Preparation and administration of androgen deprivation therapy products: Retrospective survey results

AbstractLeuprolide acetate (LA) is a gonadotropin‐releasing hormone agonist used as androgen deprivation therapy for advanced prostate cancer. LA is available in formulations intended for intramuscular (IM‐LA) or subcutaneous (SC‐LA) administration. Post‐marketing reports have noted handling errors associated with the preparation and administration of SC‐LA. This study gathered real‐world evidence on administration and management of IM‐LA and SC‐LA in large, urology‐ or oncology‐based practices. Over 200 staff were invited; 151 participated in an online survey. Main outcomes were time for each step of the ordering, inventory, mixing and administration processes. Mean values and standard errors are reported for continuous variables, and frequency and percentage are reported for categorical variables. Comparisons between groups were made with t tests and chi‐square tests as appropriate. For IM‐LA and SC‐LA, ease of ordering and time to place an order (10.8 ± 1.3 vs. 10.6 ± 1.4 min, respectively) were similar. IM‐LA was associated with a shorter time to complete preparation (2.5 ± 0.2 vs. 6.1 ± 0.6 min, P &lt; 0.001) compared with SC‐LA. This difference of 3.6 min per preparation could result in substantial time savings annually ranging from 120 h per year to 240 h per year in clinical practices administering 2000 injections per year or 4000 injections per year, respectively. For IM‐LA vs. SC‐LA, greater ease of preparation was reported by 64% vs. 43% of respondents, respectively. Over 15% of respondents used injection sites inconsistent with prescribing information, regardless of the type of injection. This study found that it takes a significantly shorter time to prepare and administer IM‐LA than SC‐LA in large urology‐ and oncology‐based practices. The time saved could be utilized for other tasks such as seeing additional patients. Use of injection sites inconsistent with prescribing information suggests a need for more training of nursing staff in the proper administration of these drugs to ensure adequate testosterone suppression and patient safety.

Adherence to oral hormonal therapy in advanced prostate cancer: a scoping review.

Orally administrated agents play a key role in the management of prostate cancer, providing a convenient and cost-effective treatment option for patients. However, they are also associated with adherence issues which can compromise therapeutic outcomes. This scoping review identifies and summarizes data on adherence to oral hormonal therapy in advanced prostate cancer and discusses associated factors and strategies for improving adherence. PubMed (inception to 27 January 2022) and conference databases (2020-2021) were searched to identify English language reports of real-world and clinical trial data on adherence to oral hormonal therapy in prostate cancer using the key search terms 'prostate cancer' AND 'adherence' AND 'oral therapy' OR respective aliases. Most adherence outcome data were based on the use of androgen receptor pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Self-reported and observer-reported adherence data were used. The most common observer-reported measure, medication possession ratio, showed that the vast majority of patients were in possession of their medication, although proportion of days covered and persistence rates were considerably lower, raising the question whether patients were consistently receiving their treatment. Study follow-up for adherence was generally around 6 months up to 1 year. Studies also indicate that persistence may drop further with longer follow-up, especially in the non-mCRPC setting, which may be a concern when years of therapy are required. Oral hormonal therapy plays an important role in the treatment of advanced prostate cancer. Data on adherence to oral hormonal therapies in prostate cancer were generally of low quality, with high heterogeneity and inconsistent reporting across studies. Short study follow-up for adherence and focus on medication possession rates may further limit relevance of available data, especially in settings that require long-term treatment. Additional research is required to comprehensively assess adherence.

Understanding Prescribing Differences Between Urologists and Medical Oncologists in the Management of Advanced Prostate Cancer

The availability of oral therapies for advanced prostate cancer allows urologists to continue to care for their patients who develop castration resistance. We compared the prescribing practices of urologists and medical oncologists in treating this patient population. The Medicare Part D Prescribers data sets were utilized to identify urologists and medical oncologists who prescribed enzalutamide and/or abiraterone from 2013 to 2019. Each physician was assigned to one of 2 groups: enzalutamide prescriber (physicians that wrote more 30-day prescriptions for enzalutamide than abiraterone) or abiraterone prescriber (opposite). We ran a generalized linear regression to determine factors influencing prescribing preference. In 2019, 4,664 physicians met our inclusion criteria: 23.4% (1,090/4,664) urologists and 76.6% (3,574/4,664) medical oncologists. Urologists were more likely to be enzalutamide prescribers (OR 4.91, CI 4.22-5.74, P < .001) and this held in all regions. Urologists with greater than 60 prescriptions of either drug were not shown to be enzalutamide prescribers (OR 1.18, CI 0.83-1.66, P = .349); 37.9% (5,702/15,062) of abiraterone fills by urologists were for generic compared to 62.5% (57,949/92,741) of abiraterone fills by medical oncologists. There are dramatic prescribing differences between urologists and medical oncologists. A greater understanding of these differences is a health care imperative.

This Month in Adult Urology.

This Month in Adult Urology.

Tumor-derived OBP2A promotes prostate cancer castration resistance.

Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa); although most patients initially respond to ADT, almost all cancers eventually develop castration-resistant PCa (CRPC). Currently, most research focuses on castration-resistant tumors, and the role of tumors in remission is almost completely ignored. Here, we report that odorant-binding protein (OBP2A) released from tumors in remission during ADT catches survival factors, such as CXCL15/IL8, to promote PCa cell androgen-independent growth and enhance the infiltration of myeloid-derived suppressor cells (MDSCs) into tumor microenvironment, leading to the emergence of castration resistance. OBP2A knockdown significantly inhibits CRPC and metastatic CRPC development and improves therapeutic efficacy of CTLA-4/PD-1 antibodies. Treatment with OBP2A-binding ligand α-pinene interrupts the function of OBP2A and suppresses CRPC development. Furthermore, α-pinene-conjugated doxorubicin/docetaxel can be specifically delivered to tumors, resulting in improved anticancer efficacy. Thus, our studies establish a novel concept for the emergence of PCa castration resistance and provide new therapeutic strategies for advanced PCa.

Testosterone Therapy in Advanced Prostate Cancer.

Androgen deprivation therapy is a mainstay of advanced prostate cancer (PCa) but the resulting low testosterone levels leave men susceptible to a multitude of adverse effects. These can include vasomotor symptoms, reduced sexual desire and performance, and mood changes. Testosterone therapy (TTh) in advanced PCa has historically been contraindicated since Huggins and Hodges reported that testosterone activates PCa. Although TTh has been demonstrated to be safe in patients who have undergone treatment for localized PCa, there is extremely limited evidence on its safety in advanced PCa. Despite the lack of evidence, some men with advanced PCa still inquire about TTh, and recent publications have described its use. In this article, we review the potential implications of TTh in men with advanced PCa, defined here as biochemical recurrence after localized therapy or metastatic PCa that is either hormone sensitive or castration resistant.

Statin Use and Survival Among Men Receiving Androgen-Ablative Therapies for Advanced Prostate Cancer

Epidemiological evidence supports a role for statins in improving survival in advanced prostate cancer, particularly among men receiving androgen-ablative therapies. To study the association between statin use and survival among men with prostate cancer receiving androgen deprivation therapy (ADT) or androgen receptor axis-targeted therapies (ARATs). This systemic review and meta-analysis used sources from MEDLINE, EMBASE, Epub Ahead of Print, Cochrane Clinical Trials, Cochrane Systematic Reviews, and Web of Science from inception to September 6, 2022. Observational studies reporting associations of concurrent statin use and survival outcomes (in hazard ratios [HRs]). Two authors independently abstracted all data. Summary estimates pooled multivariable HRs with 95% CIs using the generic inverse variance method with random-effects modeling. A priori specified subgroup and sensitivity analyses were undertaken, and heterogeneity, study quality, and publication bias were evaluated. Confidence in the evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Overall mortality and prostate cancer-specific mortality (PCSM). Twenty-five cohorts of 119 878 men (65 488 statin users [55%]) with more than 74 416 deaths were included. Concurrent statin use was associated with a 27% reduction in the risk of overall mortality (HR, 0.73 [95% CI, 0.66-0.82]; I2 = 83%) and a 35% reduction in the risk of PCSM (HR, 0.65 [95% CI, 0.58-0.73]; I2 = 74%), with substantial heterogeneity in both estimates. Subgroup analyses identified a PCSM advantage associated with statins for men receiving ARATs compared with ADT alone (HR, 0.40 [95% CI, 0.30-0.55] vs 0.68 [95% CI, 0.60-0.76]; P = .002 for difference). Confidence in the evidence was rated low for both outcomes. The findings of this meta-analysis show that concurrent statin use was associated with reduced overall mortality and PCSM among men receiving androgen-ablative therapies for advanced prostate cancer. These findings are limited by the observational nature of the data and residual unexplained interstudy heterogeneity. Randomized clinical trials are warranted to validate these results.

A New Targeted Therapy for Advanced Prostate Cancer

A New Targeted Therapy for Advanced Prostate Cancer

P081 - Oral relugolix for androgen deprivation therapy in advanced prostate cancer: Detailed safety analysis from the randomized phase 3 HERO study

P081 - Oral relugolix for androgen deprivation therapy in advanced prostate cancer: Detailed safety analysis from the randomized phase 3 HERO study

Selected Articles from This Issue

Glioblastoma (GBM) is one of the most aggressive cancers and it is usually refractory to immunotherapies. EGFR variant III (EGFRvIII) is an EGFR mutation commonly present in GBM that generates a unique cell surface neoantigen in tumor cells. Here, Iurlaro and colleagues have designed and developed a novel T cell bispecific antibody (TCB) with specificity for EGFRvIII and CD3. The EGFRvIII-TCB promoted T cell activation and tumor cell killing in EGFRvIII-expressing patient-derived models, and induced tumor regression in GBM patient-derived xenografts (PDX). These results led to the clinical testing of the EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.Comparative oncology clinical trials, carried out in pet dogs with spontaneously occurring cancers, are increasingly recognized a valuable component of the anti-cancer drug discovery and development pathway. In this report, LeBlanc and colleagues conducted a clinical study of a novel orally bioavailable inhibitor of valosin-containing protein (VCP), CB-5339, in pet dogs with a variety of malignancies. This canine trial generated key pharmacokinetic and pharmacodynamic data, defined a tolerable dose and schedule, and discovered an efficacy signal in multiple myeloma. The data generated herein provided a foundation for future studies of this drug in humans with multiple myeloma as well as other tumor types.Glutamine metabolism has been considered an important mechanism for control of tumor growth and survival. Here, Yokoyama and colleagues describe the preclinical pharmacology and mechanism of action of the novel clinical stage glutamine antagonist, DRP-104 (sirpiglenastat). Broadly targeting all 10 glutamine metabolizing enzymes, DRP-104 leads to profound anti-tumor activity related to both direct effects on tumor metabolism as well as immune mediated activity via remodeling of the tumor microenvironment and induction of both innate and adaptive anti-tumor immunity. This unique activity shows promise for the treatment of various tumors including those resistant to immune checkpoint inhibitors.Prostate cancer is the second leading cause of cancer related deaths and most commonly diagnosed cancer in US males. Although androgen receptor-targeted therapies such as enzalutamide are initially effective for the treatment of advanced prostate cancer, resistance occurs frequently. Here, Ning and colleagues have demonstrated that Wnt5A/FZD2 signaling plays vital roles in conferring resistance to enzalutamide and the levels of their expression correlates with aggressive prostate cancer with shortened disease-free survival. Furthermore, a novel bioengineered BERA-Wnt5A siRNA construct significantly suppressed tumor growth and enhanced enzalutamide treatment, suggesting targeting Wnt5A could be developed as a potential therapy for advanced prostate cancer.

Estetrol Prevents Hot Flushes and Improves Quality of Life in Patients with Advanced Prostate Cancer Treated with Androgen Deprivation Therapy: The PCombi Study

BackgroundAndrogen deprivation therapy (ADT) for prostate cancer (PCa) is accompanied by side effects affecting health-related quality of life (HRQL). ObjectiveTo assess the effects of the fetal estrogen estetrol (E4) on symptoms related to estrogen and androgen deficiency, and on HRQL measured using the validated Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Design, setting, and participantsThis was a phase 2, double-blind, randomized, placebo-controlled study in patients with advanced PCa. InterventionPatients receiving ADT were randomly assigned at a 2:1 ratio to daily treatment with a high dose of E4 (HDE4; n = 41) or placebo (n = 21) for 24 wk. Outcome measurements and statistical analysisThe primary outcome was the effect of HDE4 cotreatment on hot flushes (HFs). Secondary outcomes were the Q-Man questionnaire for evaluation of the effect on estrogen and androgen deficiency symptoms, and the FACT-P questionnaire for evaluating HRQL. Results and limitationsAt 24 wk, the number of patients experiencing HFs was significantly lower in the HDE4 group than in the placebo group (14.3% vs 60.0%; p < 0.001). HDE4 treatment was associated with lower incidence of night sweats, arthralgia, and fatigue, but more nipple tenderness and gynecomastia. At 24 wk, the mean HRQL score favored HDE4 over placebo for the FACT-P total score (122.2 ± 12.3 vs 118.7 ± 19.7) and for several other FACT subscales. ConclusionsDaily HDE4 coadministration almost completely prevented HFs in patients with advanced PCa treated with ADT. HDE4 also had positive effects on HRQL and counteracted other estrogen deficiency symptoms caused by ADT. These data support the dual efficacy concept of ADT and HDE4 to improve HRQL and increase the antitumor effect of ADT. Patient summaryFor patients on androgen deprivation therapy for advanced prostate cancer, cotreatment with a high dose of estetrol almost completely prevents the occurrence of hot flushes and improves quality of life and well-being, but nipple sensitivity and an increase in breast size may occur.

Out-of-Pocket Cost Burden Associated With Contemporary Management of Advanced Prostate Cancer Among Commercially Insured Patients.

Out-of-pocket costs represent an important component of financial toxicity and may impact patients' receipt of care. Herein, we evaluated patient-level factors associated with out-of-pocket costs for contemporary advanced prostate cancer treatment options. We identified all commercially insured men receiving treatment for advanced prostate cancer between 2007 and 2019 within the OptumLabs Data Warehouse®. Patients were categorized into 3 treatment groups: androgen deprivation monotherapy, novel hormonal therapy, and nonandrogen systemic therapy. The primary outcome was out-of-pocket costs in the first year of treatment. The associations of treatment and patient variables with out-of-pocket costs were assessed using multivariable regression models. All costs were adjusted to reflect 2019 U.S. dollars using the Consumer Price Index. In a cohort of 13,409 men 81% (n = 10,926) received androgen deprivation monotherapy, 6% (n = 832) novel hormonal therapy, and 12% (n = 1,651) nonandrogen systemic therapy. Mean treatment-related out-of-pocket costs in the first year were $165, $4,236, and $994 for androgen deprivation monotherapy, novel hormonal therapy, and nonandrogen systemic therapy, respectively. The adjusted difference in annual treatment-related out-of-pocket costs for novel hormonal therapy and nonandrogen systemic therapy were $2,581 (95% CI: $1,923-$3,240) and $752 (95% CI: $600-$903) higher than androgen deprivation monotherapy, respectively. Patient characteristics associated (P < .05) with higher treatment-related out-of-pocket costs included older age (65-74 years), Black race, lower comorbidity scores, and lower household income. Patients receiving novel hormonal therapy for advanced prostate cancer had substantially higher treatment-related out-of-pocket costs. In addition to raising awareness among prescribers, these data support the inclusion of treatment associated financial toxicity in shared decision making for advanced prostate cancer and call attention to subgroups of patients particularly vulnerable to financial toxicity.

Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer.

The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial. Germline DNA from 549 Japanese men with metastatic and/or castration-resistant PCa was sequenced for 27 cancer-predisposing genes. The associations between pathogenic variants and clinical outcomes were examined. Further, for comparison, DNA from prostate biopsy tissue samples from 80 independent patients with metastatic PCa were analysed. Forty-four (8%) patients carried germline pathogenic variants in one of the analysed genes. BRCA2 was most frequently altered (n = 19), followed by HOXB13 (n = 9), PALB2 (n = 5) and ATM (n = 5). Further, the BRCA1, BRCA2, PALB2 and ATM variants showed significant association with a short time to castration resistance and overall survival (hazard ratio = 1.99 and 2.36; 95% CI, 1.15-3.44 and 1.23-4.51, respectively), independent of other clinical variables. Based on log-rank tests, the time to castration resistance was also significantly short in patients with BRCA1, BRCA2, PALB2 or ATM somatic mutations and TP53 mutations. Germline variants in BRCA1, BRCA2, PALB2 or ATM are independent prognostic factors of the short duration of response to hormonal therapy in advanced PCa.

Advanced delivery of leuprorelin acetate for the treatment of prostatic cancer

ABSTRACT Introduction Androgen-deprivation therapy (ADT) is the main therapy for patients with advanced and metastatic prostate cancer (PCa) and, in combination with radiotherapy, for patients with localized high-risk PCa. Due to its favorable tolerability among different treatments available for ADT, leuprorelin acetate is well established as the leading luteinizing hormone-releasing hormone (LHRH) analog. The development of second-generation leuprorelin acetate (LA) depot formulation (Eligard®, Recordati S.p.A) allowed a consistent and controlled release of leuprorelin between injections and a more efficient reduction of testosterone levels with respect to conventional LHRH agonists. Areas covered This work provides a summary of the biological and clinical rationale for using LA to manage PCa and presents the current evidence about the therapeutic activity of the LA gel depot formulation, used as an advanced leuprorelin acetate delivery method. Expert opinion Results of the registration studies and post-marketing clinical trials demonstrate that the LA gel depot provides long-term efficacy in the clinical practice and a good degree of tolerability. Overall, collected data suggest that the LA gel depot can represent the ADT reference therapy in advanced PCa.