Treatment for castration-resistant prostate cancer (CRPC) has evolved rapidly in the past several years, and there are now six drugs approved for this indication, including five that became available between 2010 and 2013 (table 1).
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Having multiple therapeutic options makes choosing initial and sequential treatment challenging, and the complexity of this task is further compounded by the fact that the approved medications were studied in varying patient populations. Thus, the AUA developed its first guideline to assist practitioners with clinical decision-making for men with CRPC.
Released in May 2013 and already amended twice to reflect new information, the evidence-based guideline takes into account the diversity of “disease states” found among men with CRPC in its aim to provide a rational basis for treatment. In its current iteration, the CRPC guideline contains 20 statements relating to treatments for six index patients defined by the presence or absence of metastatic disease, presence and degree of symptoms, ECOG performance status, and prior treatment with docetaxel (Taxotere) (table 2) along with two statements on the use of preventive treatments for bone health.
Each guideline statement is rated as a standard, recommendation, option, clinical principle, or expert opinion depending on the strength and quality of the evidence and the panel’s assessment of the benefits and harms of treatment. The guideline statements are also concisely summarized in a flowchart that enables clinicians to match a man they are treating with an index patient.
Dr. CooksonMichael S. Cookson, MD, MMHC, served as chair for the CRPC panel. He told Urology Times, “The growing number of treatment options for CRPC has been great news for patients. At the same time, however, it created challenges for clinicians who face the need to remain current with new developments in the setting of a rapidly evolving field.” The old adage that states, “We are starving for knowledge and drowning in a sea of emerging information,” is appropriate here, according to Dr. Cookson, professor and Donald D. Albers Endowed Chair in Urology at the University of Oklahoma Health Sciences Center & The Stephenson Cancer Center, Oklahoma City.
“The CRPC guideline does not answer all of the possible sequencing scenarios. However, unlike guidelines from some other organizations that are compendium-like lists of medications, the AUA CRPC guideline allows physicians to identify treatments that are appropriate for individual patients across the spectrum of CRPC presentations. Importantly, it also describes caveats for using various medications, recognizing there are important nuances for treatment selection.”
J. Brantley Thrasher, MD, praised Dr. Cookson and the CRPC Guideline Panel members for creating such a pragmatic guideline and user-friendly treatment algorithm.
“The CRPC guideline provides urologists with a straightforward tool that helps them with patient counseling and therapeutic decisions,” said Dr. Thrasher, professor and William L. Valk Chair of Urology at the University of Kansas Medical Center, Kansas City.
“The guideline treatment statements are clearly written and graded so that clinicians can understand the underlying strength of the evidence, and the flowchart, which I access in the clinic off a smartphone or tablet, allows clinicians to easily determine where a particular man with CRPC fits in among the index patients.”
Guideline development: Defining index patients
In creating the CRPC guideline, the panel first described six index patients that would be representative of the spectrum of men with CRPC typically encountered in clinical practice. The definitions also took into account how the characteristics of the patient populations enrolled in the CRPC pivotal clinical trials. This also closely paralleled the FDA approvals for each of the therapeutic interventions.
“In the past, we compartmentalized patients with prostate cancer as to whether they were hormone naïve and sensitive to androgen deprivation, or had failed medical or surgical castration. However, when the CRPC panel drilled down into the group with castration-resistant disease, we recognized there were differences in presentation that would influence whether a certain medication may be appropriate or not depending on the population in which it was studied,” Dr. Cookson said.
In that regard, all of the CRPC treatment options were approved based on clinical trials enrolling patients with demonstrable metastatic disease on radiographic imaging. However, index patient 1—an asymptomatic man with non-metastatic CRPC as defined by a rising PSA—was included in the guideline considering such men represent the earliest clinical manifestation of CRPC and are commonly seen in clinical practice.
“The guideline points out that there are currently no drugs approved in this important space. This is an important point for clinicians to know and incorporate in their patient counseling,” Dr. Cookson said. “This is also an area of active clinical trial investigation.”
The index patient definitions also recognize that men with mCRPC vary in their symptomatology and that among the CRPC medications, sipuleucel-T (Provenge) was uniquely investigated in patients who were asymptomatic or minimally symptomatic.
ECOG performance status was an important criterion for defining the index patients because practitioners are likely to see patients with poor performance status, but such men were generally excluded from the CRPC clinical trials. The inclusion of history of docetaxel treatment took into account that the eligibility criteria for the original enzalutamide (XTANDI), abiraterone (ZYTIGA), and cabazitaxel (Jevtana) trials required men to have failed docetaxel and recognizes that enzalutamide and abiraterone were also subsequently studied and approved for use prior to docetaxel chemotherapy.
Once the index patients were developed, a systematic review and meta-analysis of the literature were undertaken by an independent methodology team. Their search identified more than 5,000 English-language articles published in the peer-reviewed literature between January 1996 and February 2013, of which 303 were deemed eligible for inclusion.
“Following the AUA framework, the methodology team for guideline development did a great job distilling out and analyzing the studies that addressed the CRPC panel’s pre-identified questions of interest. Sorting of the studies by level of evidence and the data summaries that were created allowed the members of the multidisciplinary CRPC panel to review the information in an unbiased fashion and apply it to develop evidence-based statements,” said Dr. Cookson.
Dr. ThrasherDr. Thrasher noted that urologists may feel increasingly comfortable taking on the care of men with metastatic CRPC thanks to the availability of medications offering both the ease of oral administration and a manageable side effect profile combined with direction from the CRPC guideline.
“These new medications for metastatic CRPC have changed the face of patient care and are nicely allowing urologists to expand their role,” he said.
Concurring, Dr. Cookson said, “There are a lot of different models of care for men with metastatic CRPC, and almost all of those include a physician champion, which can be a urologist. The urologist will forever be the primary caretaker for men with prostate cancer, and I believe it is important for urologists to continue as the quarterback for management of these patients, even when their disease progresses to a stage where the urologist becomes a collaborator in the multidisciplinary care team.”
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To facilitate this shift in practice and as an AUA educational initiative, members of the CRPC guideline panel have been presenting courses at the AUA annual and regional meetings that teach about clinical aspects of the mCRPC medications (eg, indications, dosing, side effects, and monitoring needs) as well as logistical and business considerations.
Staying up to date
When the CRPC guideline was first released, the panel recognized the need for periodic updating to reflect the growing body of literature in this area, and within less than 2 years, the guideline was subject to two major amendments. The first of those updates was released in April 2014. Taking into account 37 studies identified through a search of literature published from February 2013 to February 2014, it incorporated radium-223 (Xofigo) as an option for index patients 3, 4, and 5 with symptoms from bony metastases.
The second update was released in March 2015. It was based on a literature search covering February 2014 to February 2015 that identified 10 studies having relevant data pertaining to the use of enzalutamide in men who had not received docetaxel chemotherapy and extended follow-up from chemotherapy-naïve men treated with abiraterone plus prednisone.
“The guideline requires constant gardening because management of CRPC continues to be a field in flux, but updating depends on publication of evidence in the peer-reviewed literature. There are no updates currently underway, but there is ongoing monitoring of the literature,” Dr. Cookson said.
Looking ahead, he anticipated amendments that might reflect expanded indications for available agents or approval of new therapeutics. Dr. Cookson said that developments in treatment for non-metastatic CRPC will be particularly exciting.
“Men whose PSA is rising despite hormonal therapy are anxious because they know metastatic disease is ahead. The available agents approved for treating metastatic CRPC were first tested in men who were at the most advanced stages of disease. Results from subsequent studies indicate almost consistently, however, that these modalities have better efficacy when they are initiated earlier, in men with a lower tumor burden,” he said.
“Therefore, we expect to see good benefit in studies evaluating available drugs for men with non-metastatic CRPC. When new information becomes available as published data from completed studies or an interim analysis, it will be reflected in an amendment to the CRPC guideline,” Dr. Cookson added.
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