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1st March 2023
In men with prostate cancer, an international research group has found that just over half had three or more cardiovascular risk factors which are poorly controlled, highlighting a gap in care that requires attention.
It is recognised that men with prostate cancer (PC) have an elevated cardiovascular risk, with one study of nearly 2,500 male cancer patients, finding that two-thirds were deemed to be at high risk. Other research has revealed that cardiovascular causes of death can be greater than those of the cancer itself. For instance, a study of 752,092 men with PC identified that while 17% died because of their cancer, 83% died of other causes, of which, 23% were cardiac-related. Despite evidence that men with PC have a higher risk of cardiovascular-related death, which particular risk factors are present and how well these are controlled is unclear.
In the current study, researchers used data from the RADICAL-PC trial, a longitudinal prospective cohort study of men with PC. Information of demographics and clinical factors were collected from participant’s medical records although individuals also completed several lifestyle questionnaires and were assessed for frailty. Poor risk factor control for cardiovascular disease was defined in terms of low-density lipoprotein levels, physical activity, blood pressure control and a waist: hip ratio > 0.90.
Cardiovascular risk factor control in men with prostate cancer
A total of 2,811 men with a mean age of 68.3 years were included in the study and of whom, 91% had non-metastatic PC, with just over a third (38%) in receipt of androgen deprivation therapy. In addition, 23% of participants had pre-existing cardiovascular disease and virtually all (98%) had at least one poorly controlled cardiovascular risk factor. In fact, 51% of men had > 3 risk factors that were poorly controlled.
The researchers found that men with > 3 poorly controlled risk factors were generally older, had advanced cancer and were receiving androgen deprivation therapy. In multivariable analysis, there were four factors linked to having > 3 poorly controlled risk factors. Not taking a statin (odds ratio, OR = 2.55, 95% CI 2.00 – 3.26), physical frailty (OR = 2.37), the need for blood pressure medication (OR = 2.36) and finally increasing age (OR per 10-year increase = 1.34).
The authors concluded that poor cardiovascular risk factor control in men with prostate cancer is common and requires improved interventions to target the problem.
Citation
Klimis H et al. The burden of uncontrolled cardiovascular risk factors in men with prostate cancer. A RADICAL-PC analysis. J Am Coll Cardiol CardioOnc 2023
13th February 2023
A team of UK researchers have developed a novel prostate cancer (PaC) screening test based on measurement of five chromosome conformations that were originally detected in association with advanced PaC and which, together with the prostate specific antigen (PSA) test, has a high degree of accuracy for detecting the cancer.
Prostate cancer is the second most common cancer in men and in 2020, there were just over 1.4 million new cases worldwide. Further investigations for suspected PaC are based on the results of a PSA test and the threshold has conventionally been set at 3 to 4 to differentiate between ‘normal’ and ‘abnormal’ although cancer can be present at lower PSA levels. However, while other tests have been developed, these all generally have a low positive predictive value. While imaging modalities have shown promise as screening tests, the recent PROSTAGRAM study which compared PSA test, MRI and ultrasound, found that all provided a similar level of accuracy for detecting PaC.
In the current study, researchers developed an assay based on specific chromosome conformation changes in certain genes in the blood of men with PaC. Using samples from the PROSTAGRAM study, which included men diagnosed with PaC and control patients, the team set out to establish whether their novel assay (EpiSwitch) in combination with a PSA test could improve the accuracy of PaC diagnosis.
Novel prostate cancer test performance
Samples from 109 men (88 control and 21 with PaC) were analysed. Based on a PSA cut-off level of 3 ng/mL, the test had an accuracy of 79%. The EpiSwitch test alone had an accuracy of only 64% but when the EpiSwitch test was combined with the PSA test, the accuracy was 94%.
The researchers reported that using the EpiSwitch test and the PSA level taken as a continuous variable, there was a high positive predictive (92%) and negative predictive value (94%) for the diagnosis of PaC. Although the study was based on a relatively small number of patient samples, the authors called for further studies to examine the value of the test in larger patient samples.
Citation
Pchejetski D et al. Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection. Cancers 2023
20th January 2023
A randomised trial by Californian researchers has shown that magnetic resonance imaging (MRI) guided stereotactic body radiation, significantly reduced grade 2 or higher acute physician-scored genitourinary and gastrointestinal toxic effects as well as patient self-reported prostate cancer symptom scores, compared to computed tomography (CT) guided radiotherapy.
Stereotactic radiotherapy delivers treatment with high precision from a number of different angles around the body and is designed to reduce adverse effects on the tissue surrounding a tumour. Furthermore, results from several trials, indicate that this approach does not increase gastrointestinal or genitourinary acute toxicity. While stereotactic radiotherapy has traditionally been delivered using linear accelerators and guided by computed tomography (CT) imaging, MRI guided adaptive radiotherapy is seen as an emerging and alternative approach. Moreover, it may also be possible using MRI to reduce the radiotherapy planning target volume (PTV) which encompasses the clinical target volume to account for possible uncertainties in beam alignment, patient positioning, organ motion, and organ deformation.
In the present study, the US researchers undertook a phase 3 study, with a view to demonstrating a reduced PTV with MRI compared to CT guidance, following stereotactic body radiotherapy for men with localised prostate cancer. Eligible men were randomised 1:1 to either MRI or CT guided stereotactic radiotherapy although neither the treating physician or patient were blinded to the treatment allocation. The primary outcome was set as the incidence of acute (defined by occurring less than 90 days after stereotactic therapy) grade 2 or higher genitourinary (GU) toxic effects, whereas secondary outcomes included gastrointestinal toxic effects. Other measures assessed included changes in the international prostate symptom score (IPSS) and for which increases of 15 points or more are considered to be clinically relevant.
MRI guided stereotactic therapy and GU toxicity
A total of 156 men with a mean age of 71 years were randomised to the MRI arm (77) or the CT arm.
The proportion of GU toxic effects of grade 2 or higher was significantly lower among those receiving MRI guided stereotactic therapy (24.4% vs 43.4%, p = 0.01). There were no reported gastrointestinal toxic effects at grade 2 or higher compared to 10.5% in the CT guided group (p = 0.003).
The researchers also observed a significantly lower proportion of men with an IPSS score increase of 15 points or more after 4 weeks (6.8% vs 19.4%, p = 0.01).
The authors concluded on how MRI guided stereotactic radiotherapy reduced physician reported toxic GU and gastrointestinal adverse effects and called for future studies to examine the sustainability of these benefits.
Citation
Kishan AU et al. Magnetic Resonance Imaging-Guided vs Computed Tomography-Guided Stereotactic Body Radiotherapy for Prostate Cancer: The MIRAGE Randomized Clinical Trial. JAMA Oncol 2023
7th November 2022
The use of an inherited polygenic risk score and an individual’s family history of prostate or breast cancer provides a much better method for risk stratification for disease mortality according to the findings of a study by US researchers.
Prostate cancer is the second most frequent cancer diagnosis made in men and the fifth leading cause of death worldwide. Moreover, global data suggests that in 2020 there were 1,414,259 new cases and 375,304 deaths from the cancer. The importance of family history as a risk factor has been known for several decades and a 1990 case-control study found that men with a father or brother affected by the cancer were twice as likely to develop prostate cancer compared to men without affected relatives. Given the higher risk for men with a family history of the cancer, in recent years, genome-wide association studies have been used to identify a polygenic risk score (PRS) and which influences prostate cancer susceptibility. In fact, the PRS can be used to identify a substantial proportion of men at high-risk for prostate cancer. Interestingly, some evidence indicates that men with a family history of breast or prostate cancer had elevated prostate cancer risks, including the risk of lethal disease. With both a PRS and the presence of a family history able to evaluate an individual’s risk of developing prostate cancer, for the present study, the US researchers wondered about the prognostic value of combining these two risk scores.
The researchers used data from the Health Professionals Follow-up Study (HPFS) in which information on a family history of prostate and breast cancer had been collected. In addition, men in the HPFS study were invited to provide a blood or buccal sample for genotyping. The US team then collated data for men who had genotyped samples and who were prostate cancer free. They defined genetic risk in terms of a family history (Yes/No) of either prostate or breast cancer and divided the polygenic risk score into quartiles. The primary outcomes were prostate cancer and prostate cancer-specific death and the researchers used regression models to assess the association between PRS, family history and the risk of developing prostate cancer and of dying from the cancer.
Polygenic risk score and prostate cancer
Data were available for 10,120 men with a median age of 65.3 years at entry into the study of whom 49.9% reported a family history of prostate cancer and 7.7% had a history of both prostate and breast cancer.
A total of 1,915 cases of prostate cancer and 166 fatal prostate cancers were detected during a median follow-up of 18.3 and 23.2 years respectively.
When researchers considered a family history of prostate cancer, this was associated with a 58% higher risk of developing the cancer (Hazard ratio, HR = 1.58, 95% CI 1.38 – 1.81) and a 60% higher risk of prostate cancer-related death (HR = 1.60, 95% CI 1.06 – 2.42). In addition, using the top quartile polygenic risk score, the hazard ratio for prostate cancer was 5.29 (95% CI 4.47 – 6.27) and 3.68 (95% CI 2.29 – 5.90) for mortality.
But when both the PRS and a family history of prostate or breast cancer were included in a model, the hazard ratio increased to 6.95 (95% CI 5.57 – 8.66) and the associated hazard ratio for prostate cancer mortality was 4.84 (95% CI 2.59 – 9.03) compared to men in the lowest quartile and without a family history of either prostate or breast cancer. Overall, men within the upper two PRS quartiles (i.e., 50 to 100%) and who had a family history or prostate, or breast cancer accounted for 97.5% of prostate cancer deaths by age 75.
The authors concluded that using both the polygenic risk score and the presence of a family history, can enable the identification of men who at the highest risk of dying from prostate cancer before the age of 75.
Citation
Plym A et al. Family history of prostate and breast cancer integrated with a polygenic risk score identifies men at highest risk of dying from prostate cancer before age 75 years. Clin Cancer Res 2022
24th October 2022
A gallium positron emission tomography/computed tomography (Ga PET-CT) scan-based radiomics model was better able to distinguish between benign prostate disease and prostate cancer than radiologists according to a retrospective study by Chinese researchers.
Prostate cancer is the 2nd most commonly occurring cancer in men and the 4th most common cancer overall with more than 1.4 million new cases reported in 2020 cancer and 375,304 recorded deaths. Prostate specific membrane antigen (PSMA) is a transmembrane protein that is expressed by virtually all prostate cancers and molecules targeting PSMA can be labelled with radionuclides to become both diagnostic and/or therapeutic agents. Gallium-68 prostate-specific membrane antigen (PSMA) positron emission tomography (PET) has increasingly been utilised globally to assess the local and metastatic burden of prostate cancer. Moreover, a meta-analysis of 37 studies concluded that Ga-68-PSMA PET improves detection of metastases with biochemical recurrence, particularly at low pre-PET PSA levels. A Ga PET-CT scan is normally interpreted by nuclear medicine specialists although there is some evidence to suggest that lesions can be missed. The use of radiomics focuses on improvements in image analysis, using an automated high-throughput extraction of large amounts (200+) of quantitative features of medical images. To date however, the predictive value of a Ga PET-CT scan radiomics model has not been explored for patients with prostate cancer and was the subject of the present study.
The Chinese team retrospectively examined patients who underwent a Ga PET-CT scan and who had pathologically proven prostate cancer or biopsy benign prostate disease. Radiomics prostate cancer features were extracted from the scans and a model created and the ability of the model to differentiate between prostate cancer and benign disease tested. The sensitivity, specificity, positive and negative predictive values of the model were calculated and compared with those of two radiologists who visually inspected the scans.
Ga PET-CT scan radiomics model performance
A total of 125 patients were included and split into a training set (87) and a test set (38). All patients underwent biopsy or surgery and their pathological examination results were assessed.
On the test set, the radiomics model had a sensitivity of 84%, specificity of 77% and and a positive predictive value of 88% for distinguishing between cancer and benign disease.
The agreement between the two radiologists for visual inspection of the scans were very close (kappa = 0.81). However, the corresponding sensitivity for the radiologists on the test set were 74% and specificity was 55% and both were significantly different to the radiomics model (p = 0.036 and 0.002 respectively).
The authors concluded that they had successfully developed and validated a radiomics model based on data extracted from a Ga PET-CT scan and that this non-invasive model was able to predict intraprostatic lesions in men with prostate cancer.
Citation
Zang S et al. Development and validation of 68Ga-PSMA-11 PET/CT-based radiomics model to detect primary prostate cancer EJNMMI Res 2022
29th September 2022
A caffeine genotype is associated with a longer prostate cancer specific survival among men who drink higher amounts of coffee in comparison to other genotypes, according the findings of a study by an international team of researchers.
Prostate cancer the 2nd most common cancer in men worldwide and there were more than 1.4 million new cases in 2020. One possible lifestyle factor that may have a protective role against the development of prostate cancer is intake of coffee. In fact, a 2015 meta-analysis of 13 cohort studies including 539,577 participants concluded that coffee consumption may be associated with a reduced risk of prostate cancer and it that there was also has an inverse association with non-advanced prostate cancer.
Caffeine is metabolised by the polymorphic cytochrome P450 1A2 (CYP1A2) enzyme although single nucleotide polymorphisms (SNPs) have been identified which impact on the speed with which caffeine is metabolised giving rise to differences in caffeine genotype. For example, rs762551 (also known as -164A>C or -163C>A) is a SNP encoding the CYP1A2*1F allele of the CYP1A2 gene (which metabolises caffeine). Furthermore, rs762551 SNP can affect CYP1A2 enzyme activity and has been used to categorise individuals as either ‘fast’ (AA genotype) or ‘slow’ (AC or CC genotype) caffeine metabolisers. Moreover, there is some data to suggest that individuals with a ‘fast’ caffeine genotype with localised prostate cancer and a low to moderate coffee intake, are less likely to experience grade progression than non-consumers. Based on this earlier work, suggesting that a caffeine genotype may affect prostate cancer survival, for the present study, researchers examined the association between coffee intake, rs762551 genotype and survival among men with prostate cancer. Using data from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium, researchers included individuals with the caffeine genotype of interest (i.e., -163C>A rs762551). Coffee consumption before their diagnosis of prostate cancer was categorised as none/very low (0 to 3 or more cups/week); low’ (3 or more cups/week) or high (2 or more cups/day). The low consumption level was used as the reference point for statistical analysis.
Caffeine genotype and prostate cancer survival
The whole cohort comprised 5,727 men with a median age of 63 years and who consumed a median of 2.5 cups of coffee/day. Individuals were followed for a median of 5.1 years. In the overall cohort there were 906 deaths including 481 due to prostate cancer.
A high intake of coffee was associated with a 15% lower (but non-significant) reduction in prostate cancer-specific survival in the overall cohort (Hazard ratio, HR = 0.86, 95% CI 0.68 – 1.08, p = 0.19). A similar, non-significant reduction was also observed for overall survival (HR = 0.90, 95% CI 0.77 – 1.07, p = 0.24).
For men in the group with localised disease, a higher intake of coffee was associated with a significantly longer prostate cancer-specific survival (HR = 0.66, 95% CI 0.44 – 0.98, p =0.04). However, among those with more advanced disease (e.g., node positive, distant metastases), higher coffee intake was not associated with better survival (HR = 0.92, 95% CI 0.69 – 1.27, p = 0.60).
When researchers considered survival among those with different caffeine genotypes, those with the AA genotype (i.e., the fast metabolisers), there was a significantly longer prostate cancer specific survival (HR = 0.67, 95% CI 0.49 – 0.93, p = 0.017) for the highest level of coffee intake. In contrast, this relationship was non-significant for the other genotype (AA/CC) examined (HR = 1.04, 95% CI 0.74 – 1.47, p = 0.8).
The authors concluded that coffee intake was associated with longer prostate cancer specific survival among men with a CYP1A2 -163AA genotype and suggested that this finding would require further replication.
Citation
Gregg JR et al. Coffee Intake, Caffeine Metabolism Genotype, and Survival Among Men with Prostate Cancer. Eur Urol Oncol 2022
19th August 2022
Use of a genetic risk score (GRS) in men with symptoms suggestive of prostate cancer could enable the identification of those at risk and fast track them for further investigation according to the results of a study by UK researchers using a cohort from the UK Biobank database.
Prostate cancer was responsible for 1.4 million global cases in 2020 and is the 2nd most commonly occurring cancer in men. Screening for the cancer may help to save lives and a European study which followed-up on men for 13 years found that one prostate cancer death was averted per 781 men invited for screening although the authors concluded that ‘despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening.’ Symptoms potentially suggestive of prostate cancer include lower urinary tract symptoms (LUTS) including nocturia, urinary frequency or poor stream but these are often present at the time of a prostate cancer diagnosis. The use of prostate-specific antigen (PSA) in men with LUTS is another means of screening though a 2022 systematic review concluded that the available evidence suggests PSA is highly sensitive but poorly specific for prostate cancer detection in symptomatic patients. Prostate cancer is a highly heritable disease and there are 269 known genetic risk variants such that the use of a genetic risk score offers an approach for personalised risk prediction. Moreover, it has been suggested that the use of a GRS provides additional information to improve upon current practices in prostate cancer screening by risk-stratifying patients before initial prostate-specific antigen testing. However, to date, GRS is not routinely used and for the present study, researchers set out to assess whether a GRS was able to predict a new diagnosis of prostate cancer in men with LUTS over the next 2 years.
The team used information held in the UK Biobank and included men with LUTS but no recorded diagnosis of prostate cancer and a GRS was calculated for each participant based on the known genetic variants. The association between the GRS and prostate cancer diagnosis within 2 years of symptom onset was calculated using logistic regression and GRS scores were split into quintiles for analysis.
Genetic risk score and prostate cancer
A total of 6777 men with prostate cancer symptoms were included and of whom, 247 men had a record of prostate cancer within 2 years. For the remaining 6530 men, 62 died during the 2-year follow-up period, leaving 6448 as control patients.
Among men with symptoms, the GRS was associated with the development of symptoms over the next 2-years (odds ratio, OR = 2.12, 95% CI 1.86 – 2.41). The risk of prostate cancer was also age dependent such that men in the highest GRS quintile had a 13% greater incidence than those in the lowest (2.3%).
When researchers added age to the GRS score, the predictive power of the model improved with an area under (AUC) the receiver operating characteristic curve of 0.77 (95% CI 0.74 – 0.80) which was higher than either the GRS (AUC = 0.70) or age (AUC = 0.68) alone.
The authors discussed how the results of the study could be used to enable identification of men at low risk of prostate cancer and therefore avoid further testing but also to fast track those with the highest risk. A recognised limitation of the study was that genetic sequencing is not currently available in the UK so that the GRS approach cannot be implemented at present.
Citation
Green HD et al. Applying a genetic risk score for prostate cancer to men with lower urinary tract symptoms in primary care to predict prostate cancer diagnosis: a cohort study in the UK Biobank Br J Cancer 2022
12th May 2022
A higher body fat level in men is associated with an elevated risk of prostate cancer death according to a meta-analysis of prospective studies by researchers from the Nuffield Department of Population Health, Cancer Epidemiology Unit, University of Oxford, Oxford, UK.
Prostate cancer is the second most frequent cancer diagnosis made in men and the fifth leading cause of death worldwide and in 2020 there were more than 1.4 million new cases of prostate cancer. Prior evidence indicates that there is a positive association between height and the risk of prostate cancer, with taller men being at a greater risk but also that those with greater adiposity, have an elevated risk of high-grade prostate cancer and prostate cancer death. Moreover, other work suggests that a higher body fat level, based on central adiposity is a more relevant factor and that a higher waist circumference was an important risk factor for prostate cancer.
For the present study, the Oxford team use data from the UK Biobank and focused on men who had originally undergone anthropometric measurements (e.g., height, weight, waist and hip circumference). A subgroup of these men also underwent abdominal MRI and a dual-energy X-ray absorptiometry (DXA) scan and for whom body mass index (BMI), waist and hip circumferences were re-assessed. The primary outcome of interest was prostate cancer as the underlying cause of death. In addition, the researchers combined their Biobank data with other published prospective studies to undertake a dose response meta-analysis.
Higher body fat levels and prostate cancer death
Among a cohort of 21,8237 men with a mean age at recruitment of 56.5 years, over a follow-up period of 11.6 years, 661 men (mean age = 63.1 years), died of prostate cancer.
In a multivariable-adjusted model, there was no statistically significant association of BMI, body fat percentage and waist circumference and prostate cancer mortality. However, for the waist to hip ratio (WHR), this association was significant per 0.05 unit increase (hazard ratio, HR = 1.07, 95% CI 1.01 – 1.14, P for trend = 0.028) when comparing the highest to lowest WHR quartiles.
In the meta-analysis, the hazard ratio was 1.10 (95% CI 1.07 – 1.12) for every 5kg/m2 increase in BMI, 1.03 for every 5% increase in body fat percentage, and 1.06 for every 0.05 increase in WHR.
Using the estimate for the effect of BMI from the meta-analysis, the authors estimated that as approximately 11,900 men died from prostate cancer each year (averaged between 2016 – 2018) and if their estimate was accurate, a reduction in mean BMI of 5kg/m2 would potentially lead to 1309 fewer prostate cancer deaths every year in the UK.
They concluded that men with higher body fat (both total and central) were at a higher risk of death from prostate cancer and that these findings provided a reason for men to maintain a healthy weight.
Citation
Perez‐Cornago A et al. Adiposity and risk of prostate cancer death: a prospective analysis in UK Biobank and meta-analysis of published studies BMC Med 2022
11th March 2022
Multi-parametric ultrasound is a useful alternative to magnetic resonance imaging (MRI) for the detection of prostate cancer although detection rates would be improved by using both imaging modalities. This was the conclusion of a comparative study by a team from the Division of Surgical and Interventional Sciences, University College London, London, UK.
Prostate cancer has been found to be the second most frequent cancer diagnosis made in men and the fifth leading cause of death worldwide. According to the World Cancer Research Fund, there were 1.3 million new cases in 2018 and which resulted in 358,989 deaths (3.8% of all deaths caused by cancer in men) in 2018. Among men who present with an elevated prostate specific antigen (PSA) level or a palpable abnormality after a digital-rectal examination, there is an increased potential for the diagnosis of prostate cancer.
According to a 2019 Cochrane systematic review, the use of a magnetic resonance imaging pathway has the most favourable diagnostic accuracy in clinically significant prostate cancer detection. Nevertheless, multi-parametric MRI is not universally used and multi-parametric ultrasound appears to be a promising alternative approach with the available evidence confirming that combining different ultrasound scans significantly improves diagnostic performance in prostate cancer.
For the present study and given the widespread availability of multi-parametric ultrasound, the UK team sought to compare the overall level of agreement between ultrasound and MRI scanning for the diagnosis of clinically significant prostate cancer. They undertook a prospective, multi-centre, paired-cohort study, in which patients with an elevated PSA or a digital-rectal examination abnormality, underwent both multi-parametric ultrasound (MPUS) and multi-parametric MRI (MPMRI). In cases where either modality identified positive findings, patients were referred for targeted biopsies. The study had two primary endpoints: the proportion of positive results from both imaging tests and the level of agreement between them. The second outcome was the detection of clinically significant prostate cancer after biopsy defined as Gleason >4+3 of any length and/or maximum cancer core length of >6mm of any grade.
Multi-parametric ultrasound and cancer detection
A total of 370 men with a mean age of 64.5 years were included in the trial, of whom, 306 had both imaging scans and 257 underwent a subsequent prostate biospy.
MPUS was positive for 89 % of patients and MRMRI in 78% (difference 11.1%, 95% CI 5.1 – 17.1). In addition, the agreement in lesion detection between MPUS and MRMRI was 73.2%.
Any cancer was detected in 52% of the 257 patients with 32% being clinically significant. However, there were differences between the two modalities. Overall, MPUS detected 4.3% fewer clinically significant cancers than MRMRI although MPUS detected 7.2% (6/83) significant cancers missed by MRMRI but the latter detected 20.5% of significant cancers missed by MPUS. Nevertheless, there was a 91.1% agreement between the two modalities on the detection of clinically significant cancer.
The authors determined that combining MPUS and MPMRI would have led to the detection of 99 clinically significant cancers. They added that while MPUS detected 4.3% few significant cancers and would have resulted in 11.3% more patients being referred for a biopsy, both imaging modalities had missed cancers detected by the other technique. As a final point, they added that using both modalities would increase the detection of clinically significant cancers to either test alone.
Citation
Grey ADR et al. Multiparametric ultrasound versus multiparametric MRI to diagnose prostate cancer (CADMUS): a prospective, multicentre, paired-cohort, confirmatory study Lancet Oncol 2022
28th February 2022
Darolutamide combined with androgen-deprivation therapy and docetaxel, provides a better overall survival in men with metastatic, hormone-sensitive prostate cancer compared not using the drug. This was the findings of a randomised trial by researchers from the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, US.
Prostate cancer is the second most frequent malignancy in men worldwide and in 2018, there were 1,276,106 new cases and 358,989 deaths, representing 3.8% of all male cancer deaths. Among men with metastatic, hormone-naive, prostate cancer the addition of an androgen-receptor pathway inhibitor such as abiraterone, apalutamide, enzalutamide or docetaxel improves overall survival compared to androgen-deprivation therapy alone.
Darolutamide is an androgen-receptor inhibitor and in the Phase III ARAMIS study, it was found that for men with non-metastatic, castration-resistant prostate cancer, darolutamide treatment, metastasis-free survival was significantly longer with darolutamide than with placebo. However, whether combining darolutamide, androgen-deprivation therapy and docetaxel, would increase survival among patients with metastatic, hormone-sensitive prostate cancer is currently unclear and was the rational for the current study by the US team.
The researchers included adults (> 18 years of age) with an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 1 (where higher scores, reflect a greater disability). All received androgen-deprivation therapy, in the form of a luteinising hormone-releasing hormone or analogue) or underwent orchiectomy within 12 weeks before randomisation. Participants were randomised 1:1 to darolutamide 600 mg twice daily or matching placebo and received six cycles of docetaxel with prednisolone within 6 weeks after randomisation. The primary endpoint of the trial was overall survival, defined as the time from randomisation until any cause of death. Secondary outcomes included time to castration-resistant prostate cancer and time to pain progression and participants were assessed every 12 weeks.
Darolutamide and overall survival
A total of 1305 men with metastatic disease and a median age of 67 years were included in the final dataset, with most (71.1%) having an ECOG score of 0.
The risk of death was 32.5% lower in the darolutamide group (hazard ratio, HR = 0.68, 95% CI 0.57 – 0.80, p < 0.001). After 4 years, the overall survival was 62.7% in the darolutamide group compared to 50.4% in the placebo arm.
With respect to the secondary outcomes, the time to castration-resistant prostate cancer was significantly lower in the darolutamide group (HR = 0.36, 95% CI 0.30 – 0.42, p < 0.001) as was the time to pain progression (HR = 0.79, 95% CI 0.66 – 0.95, p = 0.01).
In terms of safety, the incidence of adverse effects was similar in both groups (99.5 vs 98.9, darolutamide vs placebo) as was the incidence of a serious adverse event (44.8% vs 42.3%).
Based on these findings, the authors concluded that darolutamide combined with androgen-deprivation therapy and docetaxel in men with metastatic, hormone-sensitive prostate cancer, led to a significantly longer overall survival.
Citation
Smith MR et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer New Engl J Med 2022
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