The American Urological
Association (AUA) has issued a new guideline (http://www.auanet.org/education/guidelines/castration-resistant-prostate-cancer.cfm) for the management of castration-resistant
prostate cancer (CRPC) that provides a "rational basis" for treatment
decisions.
Those decisions are now
"complex" because a group of treatment options for metastatic disease
has emerged in a short period of time, according to a press release issued at
AUA 2013 Annual Scientific Meeting, held in San Diego, California.
The treatment options in
metastatic CRPC (mCRPC) include 4 new therapies that have been approved since
2010: sipuleucel-T (Provenge, Dendreon), cabazitaxel
(Jevtana, sanofi-aventis), abiraterone (Zytiga, Janssen), and enzalutamide (Xtandi, Astellas/Medivation). These therapies, along
with docetaxel (approved in 2004), have all been shown to improve overall
survival in metastatic disease.
"Prior to 2004,
once patients failed primary androgen deprivation, treatments were administered
solely for palliation," write the guideline authors, led by
Michael S. Cookson, MD, from Vanderbilt-Ingram Cancer Center in Nashville,
Tennessee.
The guidelines are much
needed, according to a clinician not involved with their writing. "There
is a lack of clarity as to the best method for treating castration-resistant
prostate cancer," said Willie Underwood III, MD, MPH, from the
Roswell Park Cancer Institute in Buffalo, New York.
The guidance is
especially important given the publicity that has accompanied the new
therapies, as well as their cost, he told Medscape Medical News in an interview. "When a drug comes out
with a lot of hype, every patient wants that drug."
A large part of the new
guideline is recommendations for 6 different types of patients. These
"index" patients represent the most common clinical scenarios in men
whose prostate cancer is not responsive to traditional androgen-deprivation
therapy.
The profiles of the
index patients comprise symptoms, performance status, the presence or absence
of metastases, and whether or not docetaxel has been administered.
The guideline authors
acknowledge that treatment is rapidly changing, and advise clinicians to use it
in conjunction with the "current literature" and an individual
patient's treatment goals.
The following are the
index patients and the associated recommendations.
Index Patient 1:
Asymptomatic Nonmetastatic CRPC
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Profile
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The typical patient has a rising
prostate-specific antigen (PSA) level and no radiologic evidence of
metastatic prostate cancer. He is also required to have castrate levels of
testosterone (less than 50 ng/mL).
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Treatment recommendations
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Observation with continued androgen
deprivation
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First-generation antiandrogens (flutamide,
bicalutamide, and nilutamide) or first-generation androgen-synthesis
inhibitors (ketoconazole plus steroid) to patients unwilling to accept
observation
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Discussion
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No treatment has been shown to improve overall
survival in these men. "Since all agents have potential side
effects...we must first do no harm," write the authors.
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Index Patient 2:
Asymptomatic or Minimally Symptomatic mCRPC Without Previous Docetaxel
Chemotherapy
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Profile
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These patients have "a rising PSA in the
setting of castrate levels of testosterone" and metastatic disease
documented on radiographic imaging.
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Treatment recommendations
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Abiraterone plus prednisone, docetaxel, or
sipuleucel-T
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First-generation antiandrogen therapy or
ketoconazole plus steroid or observation to patients who do not want or
cannot have one of the standard therapies
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Discussion
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The 3 standard therapies are approved by the
US Food and Drug Administration for this indication and improved overall
survival in randomized clinical trials. There are no direct comparison
studies to inform optimal sequencing. "As a general principle, it is
preferable to give the least toxic agent first," the authors note.
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Index Patient 3:
Symptomatic mCRPC With Good Performance Status and No Previous Chemotherapy
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Profile
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These patients have a rising PSA level in the
setting of castrate levels of testosterone. Their symptoms should be related
to prostate cancer alone (and not other conditions), and might include pain.
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Treatment recommendations
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Docetaxel
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Abiraterone plus prednisone
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Ketoconazole plus steroid, mitoxantrone, or
radionuclide therapy for patients who do not want or cannot have one of the
standard therapies
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Discussion
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Sipuleucel-T immunotherapy is not recommended
in symptomatic disease, the authors note.
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Index Patient 4:
Symptomatic mCRPC With Poor Performance Status and No Previous Docetaxel
Chemotherapy
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Profile
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Clinical trials have generally excluded
patients with a poor performance status (ECOG 3 or 4); as a result, data
guiding their management are extrapolated from randomized trials of healthier
patients.
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Treatment recommendations
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Abiraterone plus prednisone
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Ketoconazole plus steroid or radionuclide
therapy to patients who are unable or unwilling to receive abiraterone plus
prednisone
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Docetaxel or mitoxantrone chemotherapy in
select cases, specifically when performance status is directly related to the
cancer
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Patient 5: Symptomatic
mCRPC With Good Performance Status and Previous Docetaxel Chemotherapy
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Profile
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A focus of therapy should be to maintain the
excellent performance status without significant toxicity from additional
therapy.
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Treatment recommendations
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Abiraterone plus prednisone, cabazitaxel, or
enzalutamide
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If the patient received abiraterone plus
prednisone prior to docetaxel chemotherapy, offer cabazitaxel or enzalutamide
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Ketoconazole plus steroid if abiraterone plus
prednisone, cabazitaxel, or enzalutamide is unavailable
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Retreatment with docetaxel for patients who
were benefiting from but discontinued treatment with docetaxel because of
reversible adverse effects
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Discussion
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Abiraterone plus prednisone and enzalutamide
appear to provide clinical benefit equivalent to (if not superior to)
additional intravenous chemotherapy with an agent such as cabazitaxel. These
2 therapies have "significantly less acute toxicity and no apparent
cumulative toxicity" over prolonged periods, say the authors.
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Index Patient 6:
Symptomatic mCRPC With Poor Performance Status and Previous Docetaxel
Chemotherapy
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Profile
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"Treatment given in the last months of
life may delay access to end-of-life care, increase costs, and add
unnecessary symptom management. Patients with poor performance status
(ECOG 3 or 4) should not be offered further treatment," write the
authors.
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Treatment recommendations
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Palliative care
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For selected patients, offer treatment with
abiraterone plus prednisone, enzalutamide, ketoconazole plus steroid, or
radionuclide therapy
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Discussion
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There is insufficient evidence demonstrating a
treatment benefit in this patient population.
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Because the skeletal
system is the most common site for prostate cancer metastasis, the guideline
also makes recommendations regarding bone health.
Bone Health
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Treatment recommendations
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Offer preventative treatment (e.g.,
supplemental calcium, vitamin D) for fractures
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Choose either denosumab or zoledronic acid as
preventative treatment for skeletal-related events
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"Prostate cancer
deaths are typically the result of mCRPC, a painful disease," said Dr.
Cookson in a press statement. "In recent years, a number of new treatments
and therapeutic agents have entered the market that have been shown to minimize
adverse effects and pain and prolong survival in some patients, but the fact
remains that mCRPC is the terminal stage of prostate cancer."
