Cardiovascular Risk in Men with Prostate Cancer: Insights from the RADICAL PC Study

Leong, Darryl P.; Fradet, Vincent; Shayegan, Bobby; Duceppe, Emmanuelle; Siemens, Robert; Niazi, Tamim; Klotz, Laurence; Brown, Ian; Chin, Joseph L.; Lavallée, Luke T.; Mousavi, Negareh; Luke, Patrick; Lukka, Himu; Gopaul, Darin; Violette, Philippe D.; Hamilton, R.; Davis, Margot K.; Karampatos, Sarah; Mian, Rajibul; Delouya, Guila; Fradet, Yves; Mukherjee, Som D.; Conen, David; Chen‐Tournoux, Annabel; Johnson, Christopher; Bessissow, Amal; Dresser, George K.; Hameed, Adnan Kazi; Abdel‐Qadir, Husam; Şener, Alp; Pal, Raveen; Devereaux, P.J.; Pinthus, Jehonathan H.

doi:10.1097/ju.0000000000000714

Cited by 73 publications

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“…Key baseline characteristics, including age, metastatic disease, a history of major adverse cardiovascular events, and other cardiovascular risk factors, were similar in the two treatment groups. Men with prostate cancer, depending on the presence of cardiovascular risk factors, are estimated to have a yearly incidence of major adverse cardiovascular events of approximately 2 to 3%, [36][37][38] similar to that observed in the relugolix group and two to three times lower than that observed in the leuprolide group. Prescribing information for LHRH agonists already contains warnings about increased risk of myocardial infarction, sudden cardiac death, and stroke.…”

Section: Discussionmentioning

confidence: 99%

Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer

et al. 2020

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Injectable luteinizing hormone-releasing hormone agonists (e.g., leuprolide) are the standard agents for achieving androgen deprivation for prostate cancer despite the initial testosterone surge and delay in therapeutic effect. The efficacy and safety of relugolix, an oral gonadotropin-releasing hormone antagonist, as compared with those of leuprolide are not known. METHODS In this phase 3 trial, we randomly assigned patients with advanced prostate cancer, in a 2:1 ratio, to receive relugolix (120 mg orally once daily) or leuprolide (injections every 3 months) for 48 weeks. The primary end point was sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks. Secondary end points included noninferiority with respect to the primary end point, castrate levels of testosterone on day 4, and profound castrate levels (<20 ng per deciliter) on day 15. Testosterone recovery was evaluated in a subgroup of patients. RESULTS A total of 622 patients received relugolix and 308 received leuprolide. Of men who received relugolix, 96.7% (95% confidence interval [CI], 94.9 to 97.9) maintained castration through 48 weeks, as compared with 88.8% (95% CI, 84.6 to 91.8) of men receiving leuprolide. The difference of 7.9 percentage points (95% CI, 4.1 to 11.8) showed noninferiority and superiority of relugolix (P<0.001 for superiority). All other key secondary end points showed superiority of relugolix over leuprolide (P<0.001). The percentage of patients with castrate levels of testosterone on day 4 was 56.0% with relugolix and 0% with leuprolide. In the subgroup of 184 patients followed for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 ng per deciliter in the relugolix group and 58.6 ng per deciliter in the leuprolide group. Among all the patients, the incidence of major adverse cardiovascular events was 2.9% in the relugolix group and 6.2% in the leuprolide group (hazard ratio, 0.46; 95% CI, 0.24 to 0.88). CONCLUSIONS In this trial involving men with advanced prostate cancer, relugolix achieved rapid, sustained suppression of testosterone levels that was superior to that with leuprolide, with a 54% lower risk of major adverse cardiovascular events. (Funded by Myovant Sciences; HERO ClinicalTrials.gov number, NCT03085095.

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Section: Discussionmentioning

confidence: 99%

Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer

et al. 2020

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“…We undertook an analysis of baseline data from the Role of Androgen Deprivation Therapy in Cardiovascular Disease -A Longitudinal Prostate Cancer (RADICALPC) study, which is an ongoing, prospective cohort study that has recruited participants from 16 academic and community cancer sites in Canada 7 .…”

Section: Methodsmentioning

confidence: 99%

Psychological morbidity associated with prostate cancer: Rates and predictors of depression in the RADICAL PC study

Fervaha

Izard²,

Tripp³

et al. 2020

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Introduction: Across all cancer sites and stages, prostate cancer has one of the greatest median five-year survival rates, highlighting the important focus on survivorship issues following diagnosis and treatment. In the current study, we sought to evaluate the prevalence and predictors of depression in a large, multicenter, contemporary, prospectively collected sample of men with prostate cancer. Methods: Data from the current study were drawn from the baseline visit of men enrolled in the RADICAL PC study. Men with a new diagnosis of prostate cancer or patients initiating androgen deprivation therapy for prostate cancer for the first time were recruited. Depressive symptoms were evaluated using the nine-item version of the Patient Health Questionnaire (PHQ-9). To evaluate factors associated with depression, a multivariable logistic regression model was constructed, including biological, psychological, and social predictor variables. Results: Data from 2445 patients were analyzed. Of these, 201 (8.2%) endorsed clinically significant depression. Younger age (odds ratio [OR] 1.38; 95% confidence interval [CI] 1.16–1.60 per 10-year decrease), being a current smoker (OR 2.77; 95% CI 1.66–4.58), former alcohol use (OR 2.63; 95% CI 1.33–5.20), poorer performance status (OR 5.01; 95% CI 3.49–7.20), having a pre-existing clinical diagnosis of depression or anxiety (OR 3.64; 95% CI 2.42–5.48), and having high-risk prostate cancer (OR 1.49; 95% CI 1.05–2.12) all conferred independent risk for depression. Conclusions: Clinically significant depression is common in men with prostate cancer. Depression risk is associated with a host of biopsychosocial variables. Clinicians should be vigilant to screen for depression in those patients with poor social determinants of health, concomitant disability, and advanced disease.

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“…For men with non‐metastatic disease who require treatment, local therapy is not always curative. While systemic therapies, such as chemotherapy and novel hormonal agents, that improve overall survival in late‐stage PC 3,4 are being used in earlier stages, these therapies can have significant side effects including elevated risk for cardiovascular diseases 5 . Moreover, the backbone of systemic treatment for PC remains androgen deprivation therapy (ADT) by decreasing male hormone levels to reduce tumor growth.…”

Section: Introductionmentioning

confidence: 99%

The influence of low‐carbohydrate diets on the metabolic response to androgen‐deprivation therapy in prostate cancer

et al. 2021

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Background: Prostate cancer (PC) is the second most lethal cancer for men. For metastatic PC, standard first-line treatment is androgen deprivation therapy (ADT).While effective, ADT has many metabolic side effects. Previously, we found in serum metabolome analysis that ADT reduced androsterone sulfate, 3-hydroxybutyric acid, acyl-carnitines but increased serum glucose. Since ADT reduced ketogenesis, we speculate that low-carbohydrate diets (LCD) may reverse many ADT-induced metabolic abnormalities in animals and humans.Methods: In a multicenter trial of patients with PC initiating ADT randomized to no diet change (control) or LCD, we previously showed that LCD intervention led to significant weight loss, reduced fat mass, improved insulin resistance, and lipid profiles. To determine whether and how LCD affects ADT-induced metabolic changes, we analyzed serum metabolites after 3-, and 6-months of ADT on LCD versus control.Results: We found androsterone sulfate was most consistently reduced by ADT and was slightly further reduced in the LCD arm. Contrastingly, LCD intervention increased 3-hydroxybutyric acid and various acyl-carnitines, counteracting their reduction during ADT. LCD also reversed the ADT-reduced lactic acid, alanine, and S-adenosyl methionine (SAM), elevating glycolysis metabolites and alanine. While the degree of androsterone reduction by ADT was strongly correlated with glucose and indole-3-carboxaldehyde, LCD disrupted such correlations.Conclusions: Together, LCD intervention significantly reversed many ADT-induced metabolic changes while slightly enhancing androgen reduction. Future research is needed to confirm these findings and determine whether LCD can mitigate ADT-linked comorbidities and possibly delaying disease progression by further lowering androgens.

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Cardiovascular Risk in Men with Prostate Cancer: Insights from the RADICAL PC Study

Cited by 73 publications

References 0 publications

Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer

Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer

Psychological morbidity associated with prostate cancer: Rates and predictors of depression in the RADICAL PC study

The influence of low‐carbohydrate diets on the metabolic response to androgen‐deprivation therapy in prostate cancer

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