1: Trial identifies earlier clinical endpoint that can predict the effectiveness of treatments for localised prostate cancer

Results from a meta-analysis, published in the Journal of Clinical Oncology, show that metastasis-free-survival (MFS) is a valid surrogate for overall survival (OS) and, if used, could shorten the length of clinical trials. Currently, trials involving men with intermediate or high risk localised prostate cancer can take over 10 years before differences in OS are seen. The ICECaP working group looked at individual patient and trial data from 28 randomly controlled trials (28,905 patients) with a median follow up of 10 years. The study analysed four intermediate clinical end points (ICEs): MFS, disease-free survival, time to disease recurrence and time to metastasis. The ICE were tested for two criteria: 1) Was the ICE correlated with OS at patient level? 2) Was the treatment effect the same for the ICE as for OS at trial level?  

While a correlation was seen between all 4 ICEs and OS, the strongest correlation was with MFS at both the patient level (0.91 [95% CI, 0.91-0.91]) and trial level (0.92 [95% CI, 0.81-0.95]). Similar results were seen when the analysis was done with sub-groups, such as high-risk populations. Of note, the majority of patients (90%) in the MFS analysis were enrolled in radiation trials.  

This study is the first to identify a valid surrogate for OS in trials involving men with localised prostate cancer. However, this doesn’t mean that a surrogate endpoint will always be the best measure. This depends on a number of factors, including size and length of the trial and the magnitude of the effect that clinicians are hoping to see. Since MFS will clearly not be as good at predicting OS as actually measuring OS itself, there are times - i.e. if you are looking for a small impact on OS - where OS would be a more appropriate endpoint then MFS.   

So what does this mean for clinical trial design? This study suggests that using metastasis-free survival as a surrogate endpoint could shorten clinical trials by months or even years. We look forward to continuing analysis by the ICECaP working group which will be testing the reproducibility of these results with more recent trial data involving newer and more relevant prostate cancer therapies. 

2: Quality of life analysis for immediate vs. delayed ADT in patients with non-curable prostate cancer

The phase 3 randomised TOAD trial, published in 2016, showed that men with non-curative disease had modest but improved survival when they received immediate androgen deprivation therapy (ADT) compared to delayed treatment (HR, 0.55 [95% CI, 0.30-1.00]; p=0·05). This month, a follow-up study was published that looked in detail at quality of life for men in the two arms. For men who relapse with rising PSA (PSA-only relapse) or have non-curable but asymptomatic disease, treatment is non-curative and it is important that risks (side-effects and symptoms) and benefits (survival) are properly weighed. 

In the initial analysis, there was no difference in global quality of health between immediate and delayed ADT arms. To look more closely at treatment specific side-effects, which may have been masked in the global analysis, the researchers examined a number of outcomes with a 5 year follow up. There was a significant decrease in sexual activity up to 2 years after randomisation, in men who received immediate ADT compared to men in the delayed treatment group (At 2yrs, 10.24 vs 25.88, p=0.0024). In addition, hormone-therapy related symptoms increased in the first 12 months in the immediate treatment group, with the most significant side-effect being increased hot flushes (OR, 2.87, [95% CI, 1.96-4.21]). 

Interestingly, these effects did not appear to decrease overall quality of life measures, and there was also no difference seen for measures such as physical, role or emotional functioning, fatigue, insomnia or pain. In addition, approximately 20% of men in both arms did not report any symptoms at all, while 40% of men in the delayed treatment arm avoided ADT for the entirety of the study. 

Taken together, this study may be important when deciding on a treatment plan for men with incurable but asymptomatic prostate cancer. While there was a significant difference in sexual functioning, sexual activity was already low at the beginning of the trial - partially reflecting the fact that the majority of men had already been treated for prostate cancer. Therefore, an individual man’s lifestyle and level of sexual activity will be important in deciding whether to have immediate or delayed treatment. Future research to identify men who are most at risk for progression, or those who may be less susceptible to ADT side-effects, may help determine who will benefit the most from early ADT treatment.

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3: Cochrane Review: decision aids improve people’s knowledge and perception of risk

A new Cochrane review, involving 31,043 participants from over 100 studies, has looked at the impact of decision aids on people facing treatment or screening decisions. The study found that there was high-quality evidence that decision aids increased participants’ knowledge and decreased uncertainty about which choice to make. There was also moderate-quality evidence that people who used decision aids had a more accurate perception of their risk and were less passive about the decision in question. Finally, patients also felt either equally or more satisfied with the process and their decision after using a decision aid.  

Of particular relevance to prostate cancer, decision aids reduced the number of people choosing invasive surgery (RR, 0.86 [95% CI 0.75-1.00]) or PSA testing (RR, 0.88 [95% CI 0.80-0.98]), while, from a clinical perspective, use of decision aids led to a small increase in appointment time (less than 3 minutes) and were either cost-neutral or cost-saving. In summary, decision aids may be cost-effective tools to increase patient knowledge and improve health-related decision making.

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