Read the Full Video Transcript

Christopher Wallis: Hello, and thank you for joining us for this UroToday discussion of the NCCN Clinical Practice Guidelines in Oncology, with a specific focus on the prostate cancer guidelines published in February 2021. I'm Chris Wallis, an Assistant Professor in The Division of Urology at The University of Toronto. With me today is Zach Klaassen, an Assistant Professor in The Division of Urology at The Medical College of Georgia.

Today, we are discussing the chapter entitled, Chemotherapy, Immunotherapy and Targeted Therapy in Advanced Prostate Cancer. This is part one of this topic, and we will discuss it further in part two.

For patients with mCRPC with or without symptoms, there are now a variety of treatment options. And you can see here, the table from the NCCN guidelines, the stratification according to prior lines of therapy. We'll walk through each of these in turn.

Within this context, we can look at six treatment approaches, including chemotherapy, immunotherapy, and targeted therapies. And in this talk, we are going to focus on the top three here, on the chemotherapeutic approaches.

So the first of these is docetaxel. Docetaxel in mCRPC was first introduced to our practice on the basis of the TAX-327 trial. This is a three-arm study looking at two different dosing regimens of docetaxel, compared to mitoxantrone, with prednisone for all patients. And you can see here on the Kaplan-Meier curve in the [inaudible 00:01:34] Seminal New England journal publication, that we get improved overall survival for men receiving docetaxel every three weeks. And compared to mitoxantrone, the change in overall survival at the median, was about two and a half months.

Similar results were seen in the SWOG 9916 trial, which compared docetaxel and estramustine, to mitoxantrone and prednisone. And so on this basis, docetaxel became the first life-prolonging therapy approved in mCRPC.

The standard approach on the basis of TAX-327 is to dose every three weeks. However, an alternative approach is every two weeks dosing, and in the Phase II data, this approach decreases the rate of febrile neutropenia, and may actually improve overall survival. So this is also recommended within the context of the NCCN guidelines. And for patients who are receiving docetaxel in the mCRPC setting, outcomes are better if they are able to receive at least eight cycles of therapy. And docetaxel is now considered the main stage treatment for patients with symptomatic disease, but may also be considered in asymptomatic patients who have either rapid clinical progression or visceral metastases, which suggests the preferential benefit of a chemotherapeutic regime. As a result, docetaxel is a category one preferred treatment option, in both first-line settings, as well as a second line, following and during access inhibition.  Additionally, it is worth noting that the panel believes that docetaxel can be given as a second line rechallenge in mCRPC if it has already been given in mCSPC. And we will discuss the data for mCSPC coming up.

And so there are three relevant trials, of which two form the basis of the NCCN's recommendations supporting docetaxel.

And so the first we'll discuss here is the CHAARTED trial led by Dr. Sweeney. And so this was a randomized controlled trial, with just under 800 men with mCRPC, randomized to receive ADT plus docetaxel, or ADT alone. And you can see that in the primary analysis, overall survival was improved for men who received ADT plus docetaxel, with the median overall survival benefit of over one year, just about 14 months.

However, when we look at both the initial analysis, as well as follow up with the longer duration of observation, we see stratification according to disease burden. And so within CHAARTED, high volume disease is defined as four or more bone metastases, with at least one located outside the pelvis or spinal column, or visceral metastasis. And in high-volume disease, we see both initially, and with prolonged follow-up, that there is a survival benefit to docetaxel. However, in patients with low volume disease, the benefit is less clear. And with longer follow-up, the survival curves cross.

We can now move to STAMPEDE, which most will know is a multi-stage, multi-arm, randomized controlled trial in the UK, which assesses a variety of novel treatment approaches, in conjunction with ADT, for men with advanced disease. Notably, this study also enrolls patients with N1 and high-risk localized disease, in addition to metastatic castrate sensitive disease. And so in the study design assessing docetaxel, this is a four-arm study with the standard of care being ADT alone, and other arms comprising docetaxel, zoledronic acid, or the combination of them. The docetaxel comparison here shows an overall survival benefit to the use of docetaxel with a hazard ratio of 0.78, which is statistically significant.

The NCCN panel specifically highlights that, while the approval for docetaxel includes all volumes of disease, the benefit is less certain in men with low volume disease. And so you can see this from longer-term follow-up, CHAARTED on the left, from the GETUG-AFU 15 trial, which was negative overall, and postulated to be that way, on the basis of an overall lower volume of disease in included patients, as well as longer follow-up of the GETUG-AFU 15 trial, on the far right of the screen.

Docetaxel has also been assessed in high-risk localized disease. And here, we can see two trials, one from the GETUG group in France, and one from RTOG in the US, assessing the role of adding docetaxel to external beam radiotherapy and ADT. And so in the GETUG trial, the eight-year relapse-free survival was significantly improved. Whereas, in the RTOG trial, the four-year overall survival was improved. In spite of these data, the NCCN guideline panel does not recommend the addition of docetaxel with ADT in high-risk prostate cancer.

We are now going to transition to discussing cabazitaxel, and. at this point in time, I'll hand it over to Zach.

Zachary Klaassen: Thanks, Chris. So assessing cabazitaxel starts with the TROPIC study, which was a study that randomized patients with mCRPC progressing on docetaxel, to their mitoxantrone plus prednisone, versus cabazitaxel plus prednisone. And these patients were stratified by ECOG performance status, as well as measurable versus non-measurable disease. The primary endpoint for this study was overall survival, and key secondary endpoints are progression-free survival, response rate, and safety.

You can see here on the right, on the top half of this panel, is the overall survival Kaplan-Meier curve, favoring cabazitaxel, with a hazard ratio of 0.70, and a 95% confidence interval of 0.59 to 0.83. And again, you can see a benefit for cabazitaxel with progression-free survival, with a hazard ratio of 0.74, and a 95% confidence interval of 0.64 to 0.68.

Of note from this trial, is that improved overall survival was weighed against higher toxicity in the cabazitaxel group. We found that there was toxic death in 4.9% of cabazitaxel, versus 1.9% in the mitoxantrone group. As well as a higher rate of febrile neutropenia, at 7.5% versus 1.3%. There were also higher rates of severe diarrhea, fatigue, nausea, vomiting, anemia, and thrombocytopenia, in the cabazitaxel group. Interestingly, in the post-hoc analysis, it was suggested that grade 3+ neutropenia was associated with improved progression-free survival and overall survival.

The second study with regard to cabazitaxel was the PROSELICA study. This was a trial of mCRPC patients progressing during and after treatment with a docetaxel-based regimen, among 1,200 patients that were randomized to cabazitaxel at 20 milligrams per meter squared, plus prednisone, versus cabazitaxel at 25 milligrams per meter squared plus prednisone. And this basically showed that a lower dose of cabazitaxel 20 was non-inferior to cabazitaxel 25, with a median overall survival of 13.4 versus 14.5 months. And importantly, this was associated with lower toxicity. Basically, this trial suggested that cabazitaxel 20, every three weeks, plus or minus growth factor, was standard of care. And cabazitaxel 25, every three weeks, can be considered in healthy men who would like to be more aggressive with their treatment.

The next cabazitaxel trial in the mCRPC state is the FIRSTANA trial, which looked at patients that were chemotherapy-naive to mCRPC. This trial assessed 1,510 patients for eligibility, ultimately randomly assigned 1,168 to cabazitaxel 20, cabazitaxel 25, or docetaxel 75. And so basically, looking at three chemotherapy arms, you can see here on the right, is the overall survival Kaplan-Meier curve. When looking at the hazard ratios, cabazitaxel 20 versus docetaxel, no difference, a hazard ratio of 1.01, with a 95% confidence interval of 0.85 to 1.20. And again, with the cabazitaxel 25, versus docetaxel, a hazard ratio of 0.97, and a 95% confidence interval of 0.82 to 1.16. So cabazitaxel, particularly the cabazitaxel 20 milligrams per meter squared, had a lower rate of peripheral sensory neuropathy. And the study suggests that this could be offered to those who are not candidates for docetaxel therapy.

The CARD trial was published in 2019 in the New England Journal of Medicine. And this looked at patients with mCRPC that were previously treated with greater than or equal to three cycles of docetaxel, and disease progression after less than or equal to 12 months on abiraterone or enzalutamide, looking at 255 patients that were randomized to cabazitaxel plus prednisone, as well. And then also randomized to enzalutamide or abiraterone plus prednisone.

Looking at the key endpoints in this study, on the left is imaging-based progression-free survival, which benefited cabazitaxel versus androgen receptor signaling targeted inhibitors, with a hazard ratio of 0.54, and a 95% confidence interval of 0.40 to 0.73. And overall survival also benefited cabazitaxel, with a hazard ratio of 0.64, and a 95% confidence interval of 0.46 to 0.89.

So the cabazitaxel summary for mCRPC was approved in patients with mCRPC who previously received docetaxel in June of 2010. The NCCN guideline panel recommends it as a category one recommendation, that cabazitaxel be used as second-line therapy in symptomatic mCRPC, after progression on docetaxel. And importantly, this should be given with steroids, and guidelines regarding prophylactic growth factors should also be followed.

Moving on to mitoxantrone, briefly. This was assessed in two trials in the mCRPC population. Unfortunately, it had no evidence of survival benefit. It has been associated with palliative responses and improved quality of life. And the guidelines recommend it can be used for palliation in symptomatic patients with mCRPC, who cannot tolerate other therapies.

So to summarize this first part of the discussion of the NCCN guidelines, looking at advanced treatment, especially for chemotherapy in metastatic prostate cancer, for docetaxel in the mCRPC setting, this is a category one preferred option in first-line and second-line patients. For metastatic castration-sensitive prostate cancer, it's a category one preferred option, though the benefit is less clear in low-volume patients.

As Chris mentioned, for high-risk localized disease, docetaxel is not currently recommended.

For cabazitaxel, in the mCRPC setting, it's a category one option for patients with symptomatic disease after docetaxel. And it may be offered as first-line for those who are docetaxel ineligible. As we discussed in the previous slides, the C20 dose is preferred, based on lower toxicity. Though the C25 dose may be considered for healthier men.

And finally, mitoxantrone in the mCRPC setting can be used for palliation, and those unable to tolerate other therapies.

Thank you very much, and we hope you enjoyed this UroToday Journal Club discussion of the NCCN prostate cancer guidelines.