NCCN Guidelines on Prostate Cancer: A Focus on Castration-Resistant Prostate Cancer - Christopher Wallis and Zachary Klaassen
August 31, 2021
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
Zachary Klaassen: Hello, and thank you for joining us today for this UroToday discussion of the NCCN Guidelines on Prostate Cancer, which were updated in February of 2021. Today, we'll be discussing the castration-resistant prostate cancer aspect of this guideline. My name is Zach Klaassen, I'm an assistant professor in the Division of Urology at the Medical College of Georgia, and with me is Chris Wallis, an assistant professor in the Division of Urology at the University of Toronto.
So we'll start by looking at the progression to and management of CRPC. We know that most men treated with ADT will eventually progress to castration-resistance over time, with castration-resistant prostate cancer being defined as progressive disease either clinically, radiologically, or biochemically, despite castrate levels of testosterone, defined as less than 50 nanograms per deciliter.
So for men that progress on ADT, there's several things we must take into consideration, including: confirming castrate levels of testosterone; as well as considering intermittent imaging to monitor for metastases, which is typically individualized by oncological risk, age, overall health, and PSA velocity; it's also important that in this disease state, we continue androgen deprivation therapy. For men that are then based as metastatic CRPC, follow up additional work is also recommended, including a metastatic lesion biopsy for genetic testing, specifically MSI and MMR testing, in addition to germline tumor testing for HRR genes.
So there are several treatment considerations at this point in time. For patients with non-metastatic CRPC, if the PSA doubling time is greater than 10 months, the NCCN Guidelines recommend continued ADT plus observation. If the PSA doubling time is less than 10 months, it's important to consider secondary hormonal therapies, which we'll discuss in the future slides. For patients that are then deemed mCRPC, there's consideration of additional therapies, including secondary hormone treatment, chemotherapy, immunotherapy, radiopharmaceuticals, and targeted therapy. Repeating therapy is generally not recommended by the guidelines, apart from a docetaxel rechallenge in certain patients. For all patients, the decision to treat depends on evidence of efficacy and tolerability, as well as considering ongoing imaging, PSA testing, and clinical evaluations. I'll turn it over now to Chris who will walk us through the secondary hormone therapy for CRPC.
Christopher Wallis: Thanks, Zach. As Zach has highlighted, there are a variety of treatment options for patients who progress to CRPC, and in this summary, we're going to focus on secondary hormonal therapies, but future talks will also examine the role of chemotherapy, immunotherapy, and other treatment approaches.
In the context of a secondary hormonal therapies, it's important to remember that even following the development of castration-resistance, the androgen receptor axis remains important in the treatment of advanced prostate cancer. You can see among these FDA approvals for mCRPC, that a number still target the androgen axis.
So first in the NCCN Guidelines is to talk about the role of abiraterone. This is an androgen biosynthesis inhibitor, and you see a schematic of its mechanism on the right side of the screen. Abiraterone was initially approved in April 2011 in the post-docetaxel mCRPC space, the subsequent approvals thereafter, and it is co-administered with low-dose corticosteroids to manage toxicity. The trial leading to its initial approval and justifying its role in the post-chemotherapy setting, is COU-AA-301. In this study, nearly 1200 patients who had failed prior chemotherapy regimes, including docetaxel, we're randomized in a two-to-one fashion to receive either abiraterone with prednisone or placebo with prednisone. As you can see on the right side of the screen, there was a significant improvement in overall survival, with a median difference in overall survival of about 4 months, and a hazard ratio of 0.74, which was significant. Other secondary end points, including PSA response, time to PSA progression, and radiographic progression-free survival were also improved.
Following the COU-AA-301, we have COU-AA-302, which looks at the role of abiraterone in the chemotherapy-naive space. So these patients were accrued and randomized in a one-to-one fashion to receive either abiraterone and prednisone or prednisone with placebo. Here, the co-primary end points were radiographic progression-free survival and overall survival, and again, as you can see on the right side of the screen, overall survival was improved for patients who received abiraterone, with the final report showing an improvement in median OS of approximately 4.5 months and hazard ratio of 0.81, which was, again, statistically significant. Similar to COU-AA-301, secondary end points, as well as the co-primary endpoint, of radiographic progression-free survival were improved for patients who received abiraterone.
However, these improvements don't come for free, and so there are both common and severe toxicities associated with abiraterone. The table here highlights data from COU-AA-302, but notably, common adverse events include: fatigue; back and joint discomfort; peripheral edema; diarrhea; GI symptoms, including nausea and constipation; hypokalemia; hypophosphatemia; and atrial fibrillation. The common adverse events, which lead to treatment discontinuation were transaminase elevations, as well as cardiac disorders, and this is due in part due to the mechanism of action.
So there are some formulation and dosing considerations. In 2018, a fine-particle formulation was approved by the FDA, and this is bioequivalent at 500 milligrams to conventional abiraterone at 1000 milligrams. So the FDA panel states that this fine-particle formulation can be used in place. Additional work in a phase II study has shown that 250 milligrams of abiraterone in the conventional formulation taken with a low-fat breakfast was non-inferior to 1000 milligrams after an overnight fast. Use of this decreased dose regime may decrease financial toxicity and improve patient compliance.
So concluding this section on abiraterone, this remains a category 1 preferred treatment option for patients in first-line mCRPC, in second-line treatment following docetaxel, in the subsequent lines of therapy for patients who do not have visceral metastasis. It should be co-administered with steroid to avoid mineralocorticoid excess, and as a result, requires monitoring of liver function tests, potassium, phosphate, as well as blood pressure.
The next agent we're going to discuss is enzalutamide, and this is indicated in both non-metastatic and metastatic CRPC. Enzalutamide is the next generation anti-androgen, with a variety of treatment effects, including: inhibition of binding of the androgen receptor and testosterone, which it performs with higher affinity than bicalutamide; as well as blocking activational change, inhibiting translocation and DNA transcription. So this agent was initially approved in August 2012 in the post-chemo setting, on the basis of data that we're going to discuss next.
The AFFIRM trial, much like COU-AA-301, enrolled approximately 1200 patients with progressive mCRPC who had failed chemotherapy, including docetaxel. In two-to-one randomization, patients received either enzalutamide or placebo and were followed for the primary endpoint of overall survival. As you can see on the right side of the screen, overall survival was significantly improved for patients who received enzalutamide, with an improvement in median overall survival of approximately 5 months, and a hazard ratio of 0.63, which was significant. Other secondary end points, including PSA response, time to PSA progression, radiographic progression-free survival, and time to first skeletal-related event, were also improved.
In parallel to the COU-AA-302 trial, PREVAIL looked at the role of enzalutamide in patients who had not yet received docetaxel for mCRPC. Approximately 1700 men were randomized in a one-to-one fashion and followed for the co-primary end points of radiographic progression-free survival and overall survival. Highlighted in the figure on the right, overall survival was improved by approximately 4 months, with a hazard ratio of 0.71, which was, again, significant.
Two trials compared enzalutamide to bicalutamide. TERRAIN enrolled men who were treatment-naive, with metastatic CRPC, and randomized them in a one-to-one fashion to enzalutamide or bicalutamide. Median progression-free survival was approximately 10 months longer for patients who received enzalutamide, and the hazard ratio is strongly significant. Similarly, STRIVE enrolled treatment-naive men, but these could have either non-metastatic or metastatic CRPC. Similarly, median progression-free survival was improved here by nearly 14 months, and the hazard ratio was even stronger in terms of the effect of enzalutamide. The panel authors conclude that enzalutamide extends progression-free survival to a greater extent than bicalutamide, however, bicalutamide could still be considered based on both specific toxicities of the two approaches, as well as treatment-related costs.
We now look at the role of enzalutamide in non-metastatic disease. This year highlights study design, which this is a two-to-one randomization to enzalutamide or placebo for patients who have what we deem high-risk non-metastatic castration-resistant disease, and this is on the basis of a baseline PSA of at least two and a PSA doubling time of less than 10 months. So looking at the initial primary endpoint, metastasis-free survival is substantially improved in patients who received enzalutamide, with the strongest significant hazard ratio of 0.29. Subsequent ongoing followup has shown improvements in overall survival, here with a hazard ratio of 0.73.
Enzalutamide does have toxicity, and so common adverse events are fatigue, diarrhea, hot flashes, headache, and seizures. However, seizure risk, when we look at AFFIRM and PREVAIL, is between 0.1 and 0.6%. Notably, the NCCN Guideline panel highlights the FDA label quotes a rate of 0.9%.
In conclusion, enzalutamide is a category 1 preferred treatment option for patients with mCRPC both pre- and post-docetaxel, as well as for patients with non-metastatic CRPC for those who have a PSA doubling time less than 10 months. This point in time, I'm now going to hand it over to Zach to walk us through the remainder of the approval guidelines for CRPC.
Zachary Klaassen: Thanks, Chris. So we'll next talk about apalutamide and non-metastatic CRPC. This is the New England Journal paper from 2018. You can see the trial design in the top left here. Eligibility included: non-metastatic CRPC, PSA doubling time less than or equal to 10 months. These patients were randomized two-to-one to apalutamide versus placebo, with metastasis-free survival as the primary outcome. This is the curve from the original paper, showing a drastic improvement in metastasis-free survival for apalutamide versus placebo, with a hazard ratio of 0.28 and a 95% confidence interval of 0.23 to 0.35. There was an updated overall survival analysis published in 2021 in European Urology, showing an OS benefit for apalutamide, with a hazard ratio of 0.78 and a 95% confidence interval of 0.64 to 0.96. So in terms of concluding this section, apalutamide is also considered a category 1 preferred option in non-metastatic CRPC for men with PSA doubling time less than or equal to 10 months.
Moving on to darolutamide in the non-metastatic CRPC section. Darolutamide also with a similar trial design in the ARAMIS trial, looking at men with non-metastatic CRPC with a PSA doubling time less than or equal to 10 months. These patients were, again, randomized two-to-one to darolutamide versus placebo. In the initial analysis, we see a metastasis-free survival favoring darolutamide versus placebo, with a hazard ratio of 0.41 and a 95% confidence interval of 0.34 to 0.50. There's also been an OS update from the ARAMIS trial published in New England Journal in 2020, with an overall survival benefit for darolutamide versus placebo of 0.69 hazard ratio and a 95% confidence interval of 0.53 to 0.88. So to conclude this section, much like apalutamide, darolutamide is a category 1 preferred option in non-metastatic CRPC for men with PSA doubling time less than or equal to 10 months.
We'll now move on to briefly discuss other secondary hormone therapies, and the majority are actually probably historical in nature to a certain degree. In terms of secondary hormone therapies, we can also give first-generation anti-androgens, anti-androgen withdrawal, ketoconazole plus or minus hydrocortisone, or corticosteroids. There's also several estrogens that have been administered in the past, including: DES, which can produce castration, but is also associated with gynecomastia and cardiovascular toxicity; also transdermal estrogens have shown better quality of life than the LHRH agonist, with castration and PSA responses similar to LHRH agonists, but also with increasing incidents of gynecomastia.
So to summarize this section on CRPC, as mentioned at the outset of this talk, CRPC is a progressive disease either clinically, radiologically, or biochemically, despite castrate levels of testosterone. So when patients become CRPC without metastases, if the PSA doubling time is greater than 10, observation is preferred, and as we've discussed over the last few slides, if PSA doubling time is less than or equal to 10 months, we have several options, including apalutamide, darolutamide, or enzalutamide.
This is a summary table for patients with M1 CRPC, and we will, in subsequent discussions, go through these in great detail. We thank you for joining us today, for looking at this first CRPC in the non-metastatic setting discussion, based on the NCCN Guidelines for Prostate Cancer.