Cardiovascular Risk in Prostate Cancer Patients Using Luteinizing Hormone-Releasing Hormone Agonists or a Gonadotropin-Releasing Hormone Antagonist.

PURPOSE: Luteinizing hormone-releasing hormone (LHRH) agonists are believed to have higher cardiovascular risk relative to gonadotropin-releasing hormone (GnRH) antagonists. However, previous studies have not consistently demonstrated this. We used real-world clinical practice data to evaluate differences in major adverse cardiovascular events (MACE) risk between LHRH agonists compared to a GnRH antagonist following androgen deprivation therapy (ADT) initiation. MATERIALS AND METHODS: We performed a retrospective analysis of data in the Decision Resources Group (now Clarivate) Real World Evidence repository, which represents >300 million US patients from 1991 to 2020 across all US regions. Patients with prostate cancer who received at least 1 injection of ADT were included. The risks of MACE and all-cause mortality as independent endpoints were evaluated, Kaplan-Meier curves were constructed, and associations between MACE and all available confounding risk factors were evaluated by Cox regression analysis using Statistical Package for the Social Sciences. RESULTS: A total of 45,059 men with prostate cancer treated with ADT were analyzed. Overall, the risks of MACE and all-cause mortality were slightly lower in the first year after ADT initiation compared to subsequent years. MACE risk was higher for the GnRH antagonist compared to LHRH agonists (HR=1.62; 95% CI 1.21-2.18, P = .001). The risk of all-cause mortality was also higher for the GnRH antagonist vs LHRH agonists (HR=1.87; 95% CI 1.39-2.51, P < .001). CONCLUSIONS: The adjusted incidence of MACE was higher for men treated with the GnRH antagonist compared to the LHRH agonists. The demographic and risk factors with the greatest impact on MACE risk were higher age, baseline metastasis, oncology (vs urology) setting, personal MACE history, antagonist (vs agonist), tobacco history, White (vs Black) race, and lower BMI.

Optimizing outcomes in men with prostate cancer: the cardiovascular event lowering (CaELo) pathways.

INTRODUCTION: Risk of cardiovascular disease is higher among men with prostate cancer than men without, and prostate cancer treatments (especially those that are hormonally based) are associated with increased cardiovascular risk. MATERIALS AND METHODS: An 11-member panel of urologic, medical, and radiation oncologists (along with a men's health specialist and an endocrinologist/preventive cardiologist) met to discuss current practices and challenges in the management of cardiovascular risk in prostate cancer patients who are taking androgen deprivation therapies (ADT) including LHRH analogues, alone and in combination with androgen-targeted therapies (ATTs). RESULTS: The panel developed an assessment algorithm to categorize patients by risk and deploy a risk-adapted management strategy, in collaboration with other healthcare providers (the patient's healthcare "village"), with the goal of preventing as well as reducing cardiovascular events. The panel also developed a patient questionnaire for cardiovascular risk as well as a checklist to ensure that all aspects of cardiovascular disease risk reduction are completed and monitored. CONCLUSIONS: Prostate cancer patients receiving ADT with or without ATT need to be more zealously assessed for prevention and aggressively managed to reduce cardiovascular events. This can and should include participation from the entire multidisciplinary healthcare team.

A Proposal for the Comprehensive Care of Men on Androgen Deprivation Therapy: Recommendations From the Multidisciplinary Prostate Cancer 360 Working Group.

INTRODUCTION: To promote comprehensive care of patients throughout the androgen deprivation therapy (ADT) prescribing process, the Prostate Cancer 360 (PC360) Working Group developed monitoring and management recommendations intended to mitigate or prevent ADT-associated adverse events. METHODS: The PC360 Working Group included 14 interdisciplinary experts with a dedicated clinical interest in prostate cancer and ADT management. The working group defined challenges associated with ADT adverse event management and then collaboratively developed comprehensive care recommendations intended to be practical for ADT prescribers. RESULTS: The PC360 Working Group developed both overarching recommendations for ADT adverse event management and specific recommendations across 5 domains (cardiometabolic, bone, sexual, psychological, and lifestyle). The working group recommends an interdisciplinary, team-based approach wherein the ADT prescriber retains an oversight role for ADT management while empowering patients and their primary and specialty care providers to manage risk factors. The PC360 recommendations also emphasize the importance of proactive patient education that involves partners or other support providers. Recommended monitoring and assessment tools, risk factor management, and patient counseling points are also included for the 5 identified domains, with an emphasis on lifestyle and behavioral interventions that can improve quality of life and reduce the risk for ADT-associated complications. CONCLUSIONS: Comprehensive care of patients receiving ADT requires early and ongoing coordinated management of a variety of health domains, including cardiometabolic, bone, sexual, psychological health. Patient education and primary care provider involvement should begin prior to ADT initiation and continue throughout treatment to improve patient and partner quality of life.

The utility of prostate-specific antigen in the management of advanced prostate cancer.

To review current prostate-specific antigen (PSA) metrics used in monitoring treatment of advanced prostate cancer, with a specific focus on castration-resistant prostate cancer (CRPC) therapies. Explore what is known about the correlation between PSA and androgen levels as well as underlying reasons for persistent PSA expression and serum elevation in CRPC, and outline suggestions for use of PSA in managing patients with advanced prostate cancer. A comprehensive search of the PubMed database for English language articles through April 2012 was performed using the following Medical Subject Headings (MeSH) keywords or terms, alone or in combination: 'prostate cancer'; 'prostate cancer treatment'; 'prostate cancer outcomes'; 'prostate-specific antigen'; 'androgen receptor'; 'advanced prostate cancer'; 'castration-resistant prostate cancer'; 'biomarkers'. Bibliographies of relevant articles were searched for additional references. Relevant medical society and regulatory agency web sites from the USA and Europe were accessed for issued guidance on PSA use. PSA doubling time (PSADT) is a useful metric for determining which patients should be considered for androgen-deprivation therapy (ADT) after failing local treatment or for second-line therapies after failing ADT. However, it is not a validated surrogate for survival and no therapy has received regulatory approval based upon PSADT characteristics. PSA nadir and time-to-nadir have been identified as possible prognostic markers for patients receiving ADT. There is no universally accepted definition for PSA progression, nor is PSA progression a regulatory-approved surrogate for clinical progression in drug approval trials. PSA responses to second-line therapies can vary and are not considered by regulatory agencies as valid surrogates for clinical endpoints, so they must be assessed in the context of each individual therapy and trial design. PSA expression in CRPC is often a reflection of persistent androgen receptor activity. While we can provide guidance for use of PSA monitoring in managing patients with advanced prostate cancer based on the data at hand, there is an urgent need for prospective analyses of refined PSA metrics in conjunction with newer prostate cancer biomarkers in clinical trials to provide stronger evidence for their roles as surrogate endpoints.

New treatment paradigm for prostate cancer: abarelix initiation therapy for immediate testosterone suppression followed by a luteinizing hormone-releasing hormone agonist.

UNLABELLED: Study Type - Therapy (prospective cohort). Level of Evidence 2a. What's known on the subject? and What does the study add? The sequential administration of a GnRH antagonist followed by an LHRH agonist in the management of prostate cancer patients has not been studied, but such a program would provide a more physiologic method of achieving testosterone suppression and avoid the obligatory testosterone surge and need for concomitant antiandrogens that accompany LHRH agonist therapy. The current study which uses abarelix initiation therapy for 12 weeks followed by either leuprolide or goserelin demonstrates the ability to more rapidly achieve testosterone suppression, avoid the obligatory LHRH induced testosterone surge, avoid the necessity of antiandrogens, all of which were accomplished safely, without inducing either additional or novel safety issues. OBJECTIVE: • To demonstrate the safety and endocrinological and biochemical efficacy of initiating treatment with the gonadotropin-releasing hormone (GnRH) antagonist, abarelix, followed by administration of an luteinizing hormone-releasing hormone (LHRH) agonist in patients with advanced and metastatic prostate cancer. PATIENTS AND METHODS: • A multicentre, open-label design study was conducted at 22 centres in the US involving patients with: localized, locally advanced or metastatic disease; with a rising prostate-specific antigen (PSA) after definitive local treatment; patients undergoing neoadjuvant hormonal therapy before local therapy (radical prostatectomy, radiation therapy or cryosurgery); and patients in whom intermittent therapy was the planned treatment. • All patients received abarelix for 12 weeks followed by an LHRH agonist (either leuprolide or goserelin) for 8 weeks • The primary efficacy endpoint was achievement and maintenance of castration defined as testosterone <50 ng/dL from day 29 through to day 141 and whether abarelix initiation therapy could eliminate the testosterone surge after two consecutive doses of LHRH agonist therapy. • PSA, LH and follicle-stimulating hormone (FSH) levels were measured and adverse events were monitored. RESULTS: • A total of 176 patients were enrolled into the present study, the majority of whom had localized prostate cancer (82%) and a PSA level <10 ng/mL (62%). • At the end of the abarelix treatment period (day 85), 93.8% of patients achieved castrate levels; during the first week of switch over to the LHRH agonist therapy (days 85-92) the rate was 86.5% and during the week after the second LHRH agonist injection (days 114-12) it was 93.3%. • A small, transient increase in testosterone occurred during the first injection of the LHRH agonist; mean (standard deviation [sd]) values increased from 17 (17.8) ng/dL at day 85 to 37.3 (51.07) ng/dL at day 86. • Mean (sd) PSA levels decreased from 20.5 (56.6) ng/mL at baseline to 3.7 (23.5) ng/mL on day 85 and remained stable throughout the LHRH agonist treatment phase. • Treatment-related adverse events occurred in 84% of patients overall; a similar incidence was reported during the two treatment phases. CONCLUSIONS: • Abarelix initiation therapy results in the desired effect of achieving rapid testosterone suppression; testosterone surges after subsequent LHRH agonist therapy are greatly abrogated or completely eliminated. • This treatment paradigm (abarelix initiation followed by agonist maintenance) obviates the need for an antiandrogen. • Abarelix was well tolerated and no clinically meaningful or novel adverse events were observed during abarelix treatment or in the transition to LHRH agonist maintenance therapy.

Risk stratification and validation of prostate specific antigen density as independent predictor of progression in men with low risk prostate cancer during active surveillance.

PURPOSE: We assessed risk stratification in patients with low grade prostate cancer managed by active surveillance using a 20-core saturation biopsy technique. MATERIALS AND METHODS: A total of 135 consecutive patients with low risk prostate cancer were prospectively entered in an active surveillance program in a 10-year period. The study entrance requirement and progression definition followed Epstein criteria using only pathological parameters, ie fewer than 3 positive cores, Gleason score 6 or less and 50% or less of any single core involved. All patients were monitored by restaging 20-core saturation biopsy every 12 to 18 months. A total of 120 patients with at least 1 rebiopsy form the basis of this report. RESULTS: Of the cohort 30% progressed during a median of 2.4 years. Three multivariate analyses were performed. The first analysis used variables only at diagnosis biopsy and revealed that prostate specific antigen density greater than 0.08 ng/ml/cc and prostate cancer family history were significant predictors of progression. When combined in a 3-level risk factor score, they were significant (p = 0.003). The second multivariate analysis considered changes in characteristics between diagnosis biopsy and first rebiopsy. Prostate specific antigen velocity along with prostate specific antigen density and family history highly predicted progression according to a 4-level risk factor score (p <0.0001). The third multivariate analysis validated the previously reported prostate specific antigen density cutoff of 0.08 ng/ml/cc at first rebiopsy as a significant predictor of subsequent progression (HR 3.16, 95% CI 1.12, 8.93; p = 0.03). CONCLUSIONS: Risk factor stratification can be used to significantly predict the outcome in patients on active surveillance. Prostate specific antigen density 0.08 ng/ml/cc at first rebiopsy was validated as a significant predictor of subsequent progression.