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Zachary Klaassen: Hello, and thank you for joining us for this UroToday discussion on the NCCN clinical practice guidelines in oncology, specifically focusing on prostate cancer, which was updated in February of 2021. Today, we will be discussing androgen deprivation therapy as listed in the NCCN guidelines. I'm Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia, and joining me is Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto.

So, this part of the NCCN guidelines specifically looking at ADT is broken down into essentially six subsections including ADT for clinically localized N0M0 disease, ADT for regional disease, palliative ADT, ADT for castration-naive disease, intermittent versus continuous ADT, and adverse events for traditional ADT.

Today, we'll be focusing on the top three, as you can see here, with subsequent discussions looking at the final three subtopics in this ADT section. Several points for introduction to general principles with regards to ADT. We all know that ADT is administered as primary systemic therapy for regional or advanced disease and also is administered as a neoadjuvant, concomitant, or adjuvant therapy in combination with radiotherapy and localized or locally advanced prostate cancer.

The guidelines note that in the community, ADT commonly is used as primary therapy for the early-stage low-risk disease especially in elderly patients. However, there are two studies that suggest that this may not be the ultimate way of treating these patients. Looking at a SEER-Medicare study amongst 66,717 patients of men older than or equal to 65 years of age with T1 or T2 tumors, there was no 15-year survival benefit for those receiving ADT versus observation alone. In another cohort study of 15,170 men diagnosed with clinically localized prostate cancer that did not undergo curative treatment, there was no benefit with adding primary ADT to these patients. So, in conclusion, placing patients with early prostate cancer on ADT should not be part of routine clinical practice.

Another point is an antiandrogen monotherapy, specifically bicalutamide, after completion of primary treatment when it was investigated as an adjuvant therapy in patients with localized or locally advanced prostate cancer. The results from these studies did not support the use of anti-androgen monotherapy. We should be striving for castrate levels of serum testosterone less than 50 nanograms per deciliter, which should be achieved with the use of ADT given that data from the PR-7 trial showed that low nadir serum testosterone was associated with improved cause-specific survival. And finally in this introductory section, monitoring testosterone levels 12 weeks after the first dose of LHRH therapy should be anticipated or used particularly if there is an increase in the PSA during this treatment time period.

So, now we will discuss ADT for clinically localized N0M0 disease.

In terms of ADT for clinically localized disease, ADT should not be used as monotherapy in clinically localized prostate cancer unless there is a contraindication to definitive local therapy. And so we may see this in patients who have a life expectancy of fewer than five years or patients with extensive comorbidities. And in these circumstances, ADT may be acceptable if the disease is high or very high risk.

In the clinically localized setting, LHRH agonists, or an LHRH antagonist, can be used. Especially in the neoadjuvant, concurrent, and or adjuvant to EBRT in patients with unfavorable intermediate, high, or very high-risk prostate cancer. Specifically, ADT used as neoadjuvant treatment before radical prostatectomy is strongly discouraged by the guidelines unless using the context of a clinical trial.

Looking more specifically at neoadjuvant, concurrent, and/or adjuvant ADT with External Beam Radiotherapy for intermediate-risk disease, there were three trials, the TROG 9601, DFCI 95096, and RTOG 9408 trials, that showed that the addition of short-term ADT to radiation improved both overall survival and cancer-specific survival. A fourth study, the RTOG 8610 trial only showed a cancer-specific survival benefit, but no OS benefit.

The EORTC 22991 trial, showed that six months of ADT significantly improved biochemical disease-free survival compared to radiation alone in patients with intermediate-risk prostate cancer, which comprised 70% of this study population.

Looking more in-depth at several trials here, this is the RTOG 9910 trial published in the Journal of Clinical Oncology in 2015. This was a phase three randomized trial targeting men with intermediate-risk prostate cancer, which was 1,579 men. And they looked specifically at comparing four months versus nine months of ADT. On the left, you can see disease survival. The Kaplan-Meier curve on the right is an overall survival Kaplan-Meier curve.  And essentially there was no difference in the curves when comparing four months versus nine months of ADT. So, this concluded that based on this comparison of length of ADT, there was no difference in disease-specific survival or overall survival.

The RTOG 9902 trial, was a randomized trial comparing long-term ADT and external beam radiotherapy plus or minus a chemotherapy regimen, paclitaxel, estramustine, and etoposide, looking at 397 patients with locally advanced or high-risk prostate cancer.

Over a median follow-up of 9.2 years, there was no difference in overall survival. You can see the Kaplan-Meier curve on the right with essentially overlapping blinds between these two treatment comparisons with a log-rank p-value of 0.81. Additionally, there was no difference in biochemical recurrence, no difference in metastases, and no difference in disease-free survival, but a substantial increase in toxicity for patients receiving chemotherapy with a 3.9% rate of treatment-related deaths for those receiving chemo to 0% treatment-related deaths for those not receiving chemo.

So, the panel recommendation for these intermediate-risk prostate cancer patients is that four to six months of androgen deprivation therapy, when external beam radiotherapy is given to patients as initial treatment of unfavorable intermediate-risk prostate cancer is reasonable. Certainly, if brachytherapy is added to the external beam radiotherapy regimen, then four to six months of ADT is an option.

Now we'll discuss neoadjuvant, concurrent, and/or adjuvant ADT with external beam radiotherapy for high-risk or very high-risk disease. The combination of ADT plus external beam radiotherapy has been consistently associated with improved disease-specific survival and overall survival compared to single-modality treatment across many randomized phase three studies. There is also increasing evidence that favors long-term over short-term neoadjuvant, concurrent, or adjuvant ADT for patients with high and very high-risk disease.

This is the RTOG 9202 study. This was published in the journal of clinical oncology in 2008. This was a phase three randomized trial of T2c to T4 prostate cancer patients who received four months of ADT before and during external beam radiotherapy with subsequent randomization to no further treatment versus an additional two years of ADT.

At 10 years, there were long-term group superior outcomes except for overall survival, you can see the Kaplan-Meier curves on the bottom right. There was an improvement in disease-specific survival on the top left, for distant metastasis failure on the top right, and for biochemical failure with a wide gap in the curves on the Kaplan Meier curve on the bottom left. And as I mentioned in overall survival, no difference with the p-value of 0.35, and essentially overlapping lines on the Kaplan-Meier curve.

The trial also did a subgroup analysis of Gleason 8-10 prostate cancer patients and did find an overall survival advantage for long-term ADT at 10 years, with a 45% survival rate compared to 32% in those that did not receive long-term ADT. And in a follow-up study looking at 19.6 years of follow-up, all outcomes did eventually favor long-term ADT, including overall survival.

There are also several additional trials favoring long-term ADT that we will mention briefly. The EORTC 22961 trial showed superior survival when 2.5 years of ADT was added to external beam radiation therapy with six months of ADT. The DART01/05 GICOR trial showed superior five-year survival when 24 months of ADT was added to external beam radiotherapy given with four months of ADT. And finally, the secondary analysis of the RTOG 8531 trial, which mandated lifelong ADT for patients treated with locally advanced prostate cancer, found that those who adhered to the protocol had better survival outcomes versus those that discontinued ADT within that five-year window, with a five-year overall survival rate of 100% compared to 66.7% among those that stopped or discontinued ADT.

Looking briefly at neoadjuvant, concurrent, and/or adjuvant ADT with external beam radiotherapy for recurrent disease, the guidelines state that men who develop PSA recurrence after radical prostatectomy without evidence of metastases can receive pelvic external beam radiotherapy with neoadjuvant, concurrent, or adjuvant ADT.

I will now pass it off to Chris who will discuss ADT for regional disease.

Christopher Wallis: Thanks, Zach. That was a tour de force in ADT in localized disease. And now we will take it slightly more broadly. And so in the context of ADT for regional disease, we can consider a number of trials as well as guideline statements from the experts. And so the general principle is that for patients with node positive disease who have a life expectancy of at least five years, primary ADT is a treatment option. It's not the only option, but it's certainly a valid option.

And when considering this, we can look at standard ADT. So, that is option one, through a variety of mechanisms. Option two, which is ADT with abiraterone. And option three, which would be external beam radiation with two to three years of ADT. And as the second bullet point here notes, abiraterone can be added to either treatment option although it should not be used with a first-generation anti-androgen like bicalutamide.

And so this report of the EORTC 30846 study looks at the effect of early versus delayed androgen deprivation. So, 234 treatment-naive patients with node-positive disease were randomized to immediate versus delayed ADT and notably, these patients did not receive local treatment to the primary tumor.

With a mean follow-up of 13 years, we see similar survival outcomes with the median overall survival of 7.6 years for those who started ADT early on and 6.1 years for those who had delayed treatment with a non-significant hazard ratio of 1.2, and a confidence interval including one.

And so for patients who have regional disease when we are looking at external beam radiation, we have some mixed literature. It does bear note that the role of adjuvant ADT after radical prostatectomy relies on the pathologic findings. And so, this is looking at the Messing trial. This trial has its limitations but remains some of the highest quality data in the space. So, we have here 98 patients with clinically pathologically positive lymph nodes at the time of radical prostatectomy. These patients were then randomized to receive either immediate ADT or observation with ADT at the time of metastases or symptomatic recurrence.

And over a median follow-up of nearly 12 years, we have improvements in overall survival, prostate cancer-specific survival, and progression-free survival for those who received immediate ADT. However, the population accrued to this study does not really represent currently treated patients, given that these were clinically detected cancers.

However, when we look at the similar question in an observational fashion using SEER-Medicare, we see no difference in overall survival between patients who received adjuvant ADT and those who did not. So, the panel recommendation, as a result, is for patients who had lymph node metastases at the time of radical prostatectomy can be considered for immediate ADT on the basis of the Messing trial, either with or without external beam radiotherapy. However, observation remains an option for these patients as well.

Transitioning from regional disease to the role of ADT in palliative treatment. ADT can be given to men who have a shortened life expectancy that is less than five years across a variety of disease indications, including high-risk disease, very high-risk disease, regionally involved disease, or metastatic prostate cancer.

Additionally, palliative ADT can be given for patients who have disease progression during their observation, typically at the time of symptomatic recurrence or progression, or when changes in PSA suggest that symptomatic progression is imminent.

And in this setting, while LHRH agonists are the most commonly used, orchiectomy and LHRH antagonists are also acceptable options.

Thank you for joining us in this first part of the discussion of ADT recommendations from the NCCN guidelines. Coming up, we will have two further talks looking at the role of ADT in castration-naive disease, as well as the role of intermittent versus continuous ADT, as well as adverse events associated with traditional ADT.  We hope that each of these summaries of the NCCN guidelines will help you in your care of patients with prostate cancer and we thank you for your time and attention in joining us today.