ADT for Castration-Naive Disease A Review of the NCCN Prostate Cancer Guidelines – Christopher Wallis and Zachary Klaassen

September 13, 2021

In this UroToday discussion between Zachary Klaassen and Christopher Wallis, the pair discuss the NCCN clinical practice guidelines in oncology, specifically looking at prostate cancer. This part of the conversation specifically looks at androgen deprivation therapy (ADT) for castration-naive disease. Dr. Klaassen begins by discussing the different categories that ADT has been categorized into recently. Dr. Klaassen then goes into a discussion on ADT when local therapy fails and how some believe that early ADT is best. About halfway through the conversation, Dr. Wallis joins to discuss key trials in the M1 castration-naïve disease space. The trials that Dr. Wallis discusses are the GETUG-15 trial, the CHAARTED trial, and the STAMPEDE trial. This conversation wraps up with a discussion on treatment options for castration-naïve disease patients.


Christopher J.D. Wallis, MD, Ph.D., Assistant Professor in the Division of Urology at the University of Toronto

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center

Read the Full Video Transcript

Zachary Klaassen: Hello, and thank you for joining us for this UroToday discussion of the NCCN Clinical Practice Guidelines in oncology, specifically looking at prostate cancer, which was updated by the NCCN in February 2021. Today, we will be discussing androgen deprivation therapy, and you can see that the NCCN Guidelines have divided androgen deprivation therapy into several groups, including ADT for clinically localized N0M0 disease, ADT for regional disease, palliative ADT, ADT for castration-naive disease, intermittent vs continuous ADT, and adverse events for traditional ADT. We previously discussed the first three on this list in a previous UroToday recording and so today we will focus on ADT for castration-naive disease.

So several important introductory points for ADT in the castration-naive setting.  The term castration-naive is used to define patients who are not on ADT at the time of disease progression. And the NCCN panel also uses the term castration-naive in patients that have had neoadjuvant concurrent and/or adjuvant ADT as part of radiotherapy provided that the patient has recovered their testicular function. Importantly, LHRH agonists and LHRH antagonists appear equally effective in patients with advanced prostate cancer. And they note that antiandrogen monotherapy appears to be less effective for medical than medical or surgical castration and is not recommended for primary androgen deprivation therapy.

There's been a new LHRH antagonist, which goes by the name of relugolix, which has been studied as ADT in patients with advanced prostate cancer, and the randomized phase 3 HERO trial, which we will dig into a little bit further here. This trial was published in 2020 in the New England Journal of Medicine led by Neal Shore and colleagues. In the bottom left, you can see the trial design. This is 934 men with advanced prostate cancer that were randomized two to one to either relugolix or traditional Lupron where the primary endpoint at 48 weeks of testosterone recovery and important secondary endpoints we will discuss as well.

So this is the primary endpoint of sustained castration rate. We can see that 88.8% of patients in the leuprolide group had a sustained castration rate compared to 96.7% of patients in the relugolix arm, which was higher than the success criteria for the primary endpoint of the lower boundary of the 95% confidence interval in the relugolix group of greater than 90%. There were several key secondary endpoints that all favor relugolix, including non-inferiority analysis for sustained castration rates of 96.7% in the relugolix arm and 88.8% in the leuprolide arm, which we showed in the previous slides. The cumulative probability of testosterone suppression to less than 50, 56.0% in the relugolix arm, and 0% in the Leuprolide arm at day four.

Cumulative probability of testosterone suppression to less than 50 on day 15, which was an impressive 98.7% in the relugolix arm and 12% in the leuprolide arm. PSA response at day 15 followed by confirmation at day 29, 79% in the relugolix arm and 19.8% in the leuprolide arm. As well as cumulative probability of profound testosterone suppression to less than 20 on day 15, which was 78.4% in the relugolix arm, and 1.0% in the leuprolide arm. The NCCN Guidelines make note of adverse events, specifically, they were noting the major adverse cardiovascular event rate, which was any grade in 2.9% of the relugolix patients and 6.2% in the leuprolide patients. And importantly, in a patient with a history of major adverse cardiac events, the number for the relugolix arm or the percentage was 3.6% of patients, and up to 17.8% of patients in the leuprolide arm. So specifically in a patient with cardiac risk factors from this study, relugolix looks like a safe option for these patients.

We will now focus on some of our discussions on ADT for M0 biochemical recurrence. And certainly, there is controversy about the timing and duration of ADT when local therapy fails and many believe that early ADT is best, but cancer control must be balanced against some of the side effects we know for ADT. Early ADT is associated with an increased side effect profile and the potential development of metabolic syndrome. And the timing of ADT for patients whose only evidence of cancer is increasing PSA is influenced by several factors, including PSA doubling time, patient and physician anxiety, short and long-term side effects of ADT, as well as underlying comorbidities of the patient. However, early ADT is acceptable and an alternative approach is a close observation until progression of cancer, whereas earlier ADT may be better than delayed therapy. The definition of early versus late in terms of what PSA level we should be looking at does remain controversial.

The phase 3 TOAD trial is one trial that looked at this, looking at randomizing 293 men with PSA relapse after radical prostatectomy or radiotherapy or those who were not considered for curative treatment to immediate ADT or ADT delayed by a recommended interval of greater than or equal to two years. So looking closer at the TOAD trial, we can see that the five-year overall survival was improved in the immediate therapy arm compared with the delayed therapy arm with 91.2% in the immediate arm and 86.4% in the delayed arm. And this is displayed in the overall survival Kaplan-Meier curve on the right where we have delayed ADT arm in red and the immediate ADT arm in blue. And so we can see that the curves are pretty consistent until about year five when we see a split in the curves, favoring the immediate ADT arm. However, there were no significant differences seen in the secondary endpoint of global health-related quality of life at two years. Although sexual activity was lower and the hormone treatment-related symptoms score was higher in the immediate ADT arm.

So the panel recommendation for early ADT is that early ADT is uncertain and must be balanced against the risk of ADT side effects. Patients that have an elevated PSA and/or a short PSA doubling time with a long life expectancy should be encouraged to consider ADT earlier. However, this should be given in an intermittent ADT approach. Men with prolonged PSA doubling times who are older are excellent candidates for observation according to the panel recommendations by the NCCN.

For the remainder of our discussion in this section, we will talk about primary ADT for M1 castration-naive prostate cancer. And we know that ADT is the gold standard for the initial treatment of patients with metastatic disease at presentation. And additionally, there are several options for M1 castration-naive disease, which we will talk about in the subsequent slides as well, including orchiectomy +/- docetaxel, LHRH agonist alone +/- docetaxel, LHRH agonist + first-generation antiandrogen +/- docetaxel, LHRH antagonist +/- docetaxel, orchiectomy + abiraterone, apalutamide or enzalutamide, LHRH agonist + abiraterone, apalutamide or enzalutamide. And finally, LHRH antagonist + abiraterone, apalutamide or enzalutamide.

The NCCN Guidelines note that patients with averting metastasis in weight-bearing bones who are at risk of symptoms associated with a testosterone flare with an initial LHRH agonist alone should have seven days of prior antiandrogen therapy before receiving their LHRH agonist. However, the LHRH antagonists rapidly and directly inhibit the release of antigens, unlike the LHRH agonist that initially stimulates the LHRH receptors. So there is no flare scene when we give patients LHRH antagonists.

I will now pass it over to Chris who will take us through several of the key trials in the M1 castration-naive disease space.

Christopher Wallis: Thanks, Zach. So as we see from the slides presented so far, ADT forms the key backbone for the treatment of these patients, but we can now consider, based on data from the last few years, additions to the ADT backbone.  And in docetaxel's case, we have three trials to inform our view of this treatment approach, and we will walk through each of these in sequence. So the first here is GETUG-15. This is a French trial and the first one of these three which was published. As you can see in both the initial Kaplan-Meier curve on my left and then the update on the right, there was no significant improvement in overall survival for the addition of docetaxel to ADT in this study cohort.

The second trial to be published was CHAARTED. This study again used a similar design with patients randomized to ADT + docetaxel or ADT alone. Notably, patients initially were accrued only if they had high volume disease and subsequently low volume disease was allowed. And we will look at the stratification of the results according to this parameter on the next slide. But you can see on the right on this Kaplan-Meier curve, that there is a significant improvement in median overall survival with an absolute difference of nearly 14 months and a relative difference of nearly 40%.

We then see here on the top, the initial publication of CHAARTED and below updated long-term survival. And so you see that in the overall cohort of patients accrued, the benefit of the additional docetaxel was maintained with ongoing follow-up. We then look at stratification according to disease volume. And so these are the criteria that define high volume disease that is more than four or more bone metastases, but at least one outside the pelvis and vertebral column or visceral metastases. And when we use this stratification, we can see in patients with high volume disease, that there is a significant benefit to the addition of docetaxel, both initially and with long-term follow-up. However, in patients with low volume disease, there was an initial suggestion of benefits, however, this was not statistically significant. However, with longer follow-up, this became relatively clear that there was not a benefit to the addition of docetaxel. And so when we look at the subgroup analysis, the long-term follow-up will try to suggest that while there is a benefit in the overall study population, this is driven by that observed in those with high volume disease.

A third and a tiebreaker of the three trials looking at docetaxel here is one of the first publications from STAMPEDE which was a multi-stage, multi-arm, RCT in the UK. And notably while both the other trials assessed only patients with metastatic disease, STAMPEDE enrolled patients with metastatic disease, N1 disease, and high-risk localized disease. And the publication assessing docetaxel is a 4-arm study, including a standard of care, the standard of care + docetaxel, standard care + zoledronic acid, and standard of care + both docetaxel and zoledronic acid. Examining the effect of docetaxel, we see the Kaplan- Meier curve here on the right with a statistically significant hazard ratio favoring those who received docetaxel.

We now move on to abiraterone. This was assessed in a number of trials, which we will discuss, but subsequently approved in February 2018 by the FDA with the standard dosing of 1000 milligrams per day with prednisone, and an alternative of 250 milligrams per day is administered following a low-fat breakfast after an overnight fast. In this lower dose formulation, they reduced financial toxicity and improved compliance. The two trials on which the approval of abiraterone is based are LATITUDE and STAMPEDE. And first discussing LATITUDE, we see that there are 1,200 men who were randomized, and the Kaplan- Meier curve here on the right demonstrates the overall survival with a statistically significant benefit to abiraterone with a hazard ratio of 0.62, and final overall survival with a longer follow-up of 0.66.

LATITUDE did demonstrate that there was the anticipated toxicity associated with abiraterone and when we look at any adverse events, we see that there are similarities between the abiraterone and placebo groups, but grade 3 and grade 4 adverse events are somewhat more common in the abiraterone group, driven by rates of hypertension, hyperkalemia, and liver function abnormalities.

STAMPEDE similarly assessed the role of abiraterone in this patient population. And then like LATITUDE did, it allowed men with high-risk nonmetastatic disease or node-positive disease. However, despite these differences in the study population, the apparent benefit of abiraterone was similar with a statistically significant hazard ratio of 0.63. Notably, the authors demonstrate in a subgroup analysis that the survival benefit of abiraterone was greater among younger men than those older than age 70. Similarly, STAMPEDE demonstrated that the toxicity of abiraterone in this study population was comparable to prior publications in the castration resistance space.

So in terms of abiraterone, the panel recommends this as a category 1 treatment option for men with newly diagnosed N1 castration-naive prostate cancer. And for men undergoing curative-intent treatment of N1 disease, abiraterone may be added to external beam radiotherapy along with two to three years of conventional ADT or can be given with ADT alone for castration-naive disease without radiation. In the nonmetastatic space, there is insufficient survival, failure-free survival, and follow-up data available to recommend its use.

Then I move to another androgen axis targeting agent, apalutamide. This was assessed in this disease indication in the TITAN trial, which randomized just over a thousand men to apalutamide + ADT vs ADT alone. Both primary endpoints of radiographic progression-free survival and overall survival saw statistically significant benefits for the addition of apalutamide. And as a result, this was FDA approved in September 2019, and as provided in the NCCN Guidelines as a category 1 treatment option in this disease indication.

There are a couple of studies that assess the role of enzalutamide in castration-naive disease. The first we will discuss is ENZAMET with over a median follow-up of 34 months, we see a statistically significant benefit of the addition of enzalutamide with a hazard ratio of 0.67.  Notably, secondary endpoints, including PSA progression-free survival and clinical progression-free survival were also improved with the addition of enzalutamide. In ARCHES, a second randomized control trial assessing the role of enzalutamide in this disease space, unlike the others, the primary endpoint here was radiographic progression-free survival. Although we do see a statistically significant benefit to the addition of enzalutamide and the basis of both the ARCHES data, as well as the ENZAMAT data, enzalutamide is now a category 1 option in the NCCN Guidelines for treatment of patients with M1 castration-naive prostate cancer.

So you can see here a schematic of the treatment options assessing systemic therapies in castration-naive disease. For patients with non-metastatic disease, observation may be preferred though ADT is an option. For those with metastasis, ADT is the backbone, although a number of additions can be considered including apalutamide, abiraterone, docetaxel, or enzalutamide. Additionally, for those with low volume disease on the basis of data from STAMPEDE, external beam radiotherapy can be added. And ADT monotherapy remains a treatment option, although not the preferred choice.

At this time, I'd like to thank you for your time and attention and for joining us for this discussion of the role of ADT in castration-naive disease as highlighted in the NCCN Guidelines. Thank you again for joining us.