Initial Management of Non-Castrate Advanced, Recurrent, or Metastatic Prostate Cancer Guideline Update

An interview with Dr. Katherine S. Virgo from Emory University in Atlanta, GA on "Initial Management of Non-Castrate Advanced, Recurrent or Metastatic Prostate Cancer: ASCO Guideline Update." This guideline updates recommendations for initial hormonal management of non-castrate advanced, recurrent, or metastatic prostate cancer. Read the full guideline at www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

PRESENTER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Katherine Virgo from Emory University, lead author and co-chair on initial management of non-castrate advanced, recurrent, or metastatic prostate cancer, ASCO guideline update. Thank you for being here, Dr. Virgo.

DR. KATHERINE VIRGO: Thank you, Brittany.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Virgo, do you have any relevant disclosures that are directly related to this guideline topic?

DR. KATHERINE VIRGO: No, I do not.

BRITTANY HARVEY: OK, thanks. Then let's delve into some of the guideline content. What prompted this update of the initial management of non-castrate advanced, recurrent, or metastatic prostate cancer guideline, and what is the scope of the update?

DR. KATHERINE VIRGO: Well, the update of the 2007 version of the guideline was largely prompted by the many Phase III randomized clinical trials that had been completed or were nearly complete in the non-castrate space. It was believed that the results of these trials might permit revisiting previous recommendations regarding intermittent versus continuous androgen deprivation therapy and early or immediate versus deferred androgen deprivation therapy.

As you might imagine, it took quite some time to gather and review 13 years of literature for each of the study questions from the original 2007 guideline. So in the interim, a sufficient number of randomized clinical trials reached completion to also inform recommendations regarding the use of newer therapies in combination with androgen deprivation therapy as initial therapy for men with metastatic disease, such as docetaxel, abiraterone, enzalutamide, and apalutamide, and thereby also update another existing ASCO guideline authored by Morris et al in 2018, which previously only provided guidance on the use of docetaxel and abiraterone for men with metastatic disease.

BRITTANY HARVEY: Great, yeah, definitely a large volume of literature to review there. So then you talked about the recommendations. So I'd like to go through some of those. For men with metastatic non-castrate prostate cancer, what are the recommended standard initial treatment options?

DR. KATHERINE VIRGO: So docetaxel, abiraterone, enzalutamide, and apalutamide, each when administered with androgen deprivation therapy, represent four separate standards of care for non-castrate metastatic prostate cancer. The use of any of these agents in any particular combination or in any particular series cannot yet be recommended. That said, we were able to make a recommendation for each agent individually. So I'll go through those recommendations now, first for docetaxel.

So for men with metastatic non-castrate prostate cancer with high-volume disease who are candidates for treatment with chemotherapy, the addition of docetaxel to androgen deprivation therapy should be offered. Here, high-volume disease is defined per the charted trial as four or more bone metastases, one or more of which is outside of the spine or pelvis, and/or the presence of any visceral disease.

Second, for abiraterone, for men with high-risk de novo metastatic non-castrate prostate cancer, the addition of abiraterone to androgen deprivation therapy should be offered per the latitude trial. For men who are considered low-risk, androgen deprivation therapy plus abiraterone may be offered for the STAMPEDE trial.

Third, for enzalutamide, androgen deprivation therapy plus enzalutamide should be offered to men with metastatic non-castrate prostate cancer, including those with de novo metastatic disease and those who have received prior therapies, such as radical prostatectomy or radiation therapy for localized disease. Enzalutamide plus ADT has demonstrated short-term survival benefits, such as PSA progression-free, clinical progression free, and overall survival when compared to androgen deprivation therapy alone for men with metastatic non-castrate prostate cancer per the ENZAMET trial.

And finally, fourth, androgen deprivation therapy plus apalutamide should be offered to men with metastatic non-castrate prostate cancer, including those with de novo metastatic disease or those who have received prior therapy, such as radical prostatectomy or radiation therapy for localized disease, per the TITAN trial. Thus in summary, to your initial question, all of the recommendations were phrased as "should be offered" except in the case of androgen deprivation therapy plus abiraterone for men with low-risk de novo metastatic non-castrate prostate cancer, for which the recommendation was phrased as "may be offered," as the evidence was not as strong as for the other recommendations.

BRITTANY HARVEY: Great, thank you for reviewing those standard initial treatment options for men with metastatic non-castrate prostate cancer. So then what does the guideline say regarding combination therapy for men with non-castrate locally advanced non metastatic prostate cancer?

DR. KATHERINE VIRGO: So here, androgen deprivation therapy plus abiraterone and prednisolone should be considered for men with non-castrate locally advanced non-metastatic prostate cancer, rather than castration monotherapy, due to the failure-free survival benefit for the STAMPEDE trial. We were unable to make a recommendation for men with high-risk non-metastatic prostate cancer progressing after radical prostatectomy or radiotherapy or both, as it's currently unclear whether enzalutamide in the 160-milligram dose plus leuprolide improved metastasis-free survival compared to enzalutamide monotherapy or placebo. The recruitment is complete for the ongoing Phase III EMBARK trial, which is designed to answer this question. The results are not available yet.

BRITTANY HARVEY: Great. Then how does the guideline address early or immediate androgen deprivation therapy versus deferred therapy for men with non-castrate locally advanced non-metastatic prostate cancer?

DR. KATHERINE VIRGO: So here, early or immediate androgen deprivation therapy may be offered to men who initially present with non-castrate locally advanced non-metastatic disease who have not undergone previous local treatment, and are either unwilling or unable to undergo radiotherapy, based on evidence in one meta-analysis of a modest but statistically significant benefit in terms of both overall survival and cancer-specific survival among the larger population of men with locally advanced non-metastatic disease. Unfortunately, we were unable to make a recommendation for men with PSA relapse after local treatment. Though existing studies suggest a potential overall survival benefit, additional research is needed, as such studies were underpowered.

BRITTANY HARVEY: And then finally, for men with biochemically recurrent non-metastatic disease, what are the recommendations for intermittent androgen deprivation therapy versus continuous androgen deprivation therapy?

DR. KATHERINE VIRGO: So intermittent therapy may be offered to men with high-risk, biochemically recurrent non-metastatic prostate cancer after radical prostatectomy and/or radiotherapy, based on evidence and meta-analyses of the non-inferiority of intermittent androgen deprivation therapy when compared to continuous androgen deprivation therapy, with respect to overall survival. This is further supported by evidence from four meta-analyses testing superiority. And here, high-risk biochemical recurrence after radical prostatectomy is defined as a PSA doubling time less than one year or a pathologic Gleason score of 8 to 10. High-risk biochemical recurrence after radiation therapy has a different definition, here defined as an interval to biochemical recurrence of less than 18 months or a clinical Gleason score of 8 to 10.

BRITTANY HARVEY: Thank you for reviewing all those recommendations and the evidence supporting them. It's very interesting to hear where you were able to make recommendations and where you weren't. So in your view, what is the importance of this guideline, and how will it change practice?

DR. KATHERINE VIRGO: As mentioned earlier, the previous version of the guideline was 13 years old. And practice, as you might imagine, has changed considerably in the interim. Though consensus documents have been issued by other organizations since that time, it was important, given ASCO's global audience, to provide up-to-date, evidence-based guidance for the organization's worldwide membership.

Practice patterns of most clinicians based at large university medical centers likely approximate the guidance provided in the ASCO guideline update, at least with respect to the treatment of men with de novo metastatic high-risk or high-volume disease. Some may be surprised by the current lack of evidence for the use of docetaxel among patients with de novo metastatic low-volume disease. The new guidelines should be particularly useful for community-based clinicians, who may not be as actively involved in clinical trial enrollment.

BRITTANY HARVEY: Definitely. And then finally, how will these guideline recommendations impact patients with prostate cancer?

DR. KATHERINE VIRGO: So patients will be impacted in three ways. First, the guidelines should be helpful to patients in understanding the various treatment options available to them, depending on the extent of their disease and any previous treatment they may have already received. The guidelines also highlight treatment options that should not be offered to patients who have certain characteristics and hopefully assist patients with adjusting their treatment expectations.

Second, the cost table in the guidelines should also be helpful to patients, as it provides some idea of how costs vary by the type of treatment received, while also indicating when a less costly generic equivalent is available. And finally, third, the guidelines suggest that patients be counseled about the potential side effects associated with androgen deprivation therapy, such as depression, dementia, stroke, myocardial infarction, deep venous thrombosis, hot flush, fatigue, and nausea. Side effects vary by type of androgen deprivation therapy, as well as by age and patient comorbidities. Knowing up-front that such side effects are possible can assist patients in having more informed conversations with their physician when treatment discussions are underway.

BRITTANY HARVEY: Great. Then it sounds like these guidelines have a real impact for both community oncologists and for patients. So I want to thank you for your leadership on the development of these evidence-based guidelines, and thank you for taking the time to speak with me today, Dr. Virgo.

DR. KATHERINE VIRGO: Thank you, Brittany.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.