Jianqing Lin, MD
Wm. Kevin Kelly, DO
BASICS
DESCRIPTION
• Castration-resistant prostate cancer (CRPC) is defined as prostate cancer with disease progression despite effective androgen deprivation (serum total testosterone <50 ng/dL)
• CRPC patients are classified as having metastatic disease (bone or soft tissue visible on imaging) (mCRPC) or nonmetastatic disease (CRPC rising PSA without any radiographic evidence of metastasis)
• CRPC survival is improved significantly with more effective treatment options
• Synonym(s): The preferred term is castrate-resistant prostate cancer but sometimes called castrate refractory prostate cancer. Older terms such as hormone refractory or androgen-independent prostate cancer are not considered accurate
– Latest data shows that in CRPC prostate cells are still sensitive to low levels of androgens
EPIDEMIOLOGY
Incidence
• 233,000 cases of prostate cancer will be diagnosed in the United States in 2014
• There will be 29,480 deaths due to prostate cancer in 2014
• The vast majority of patients who die with prostate cancer will die from progressive metastatic CRPC
• Historically the median survival with mCRPC is <2 yr; newer agents, most introduced since 2010, have improved overall survival by several months
Prevalence
N/A
RISK FACTORS
• No definitive tool is available to determine the risk of developing CRPC
– Molecular biomarkers and genomic profiles are being explored for prognosis and treatment
• CRPC risk features for poor survival
– Low hemoglobin
– Elevated lactate dehydrogenase
– Elevated alkaline phosphatase
– Poor performance status
– Visceral metastasis particularly liver metastasis
– Narcotic use for pain
– Nomogram based on these clinical features can predict overall prognosis for CRPC (1)
Genetics
Common chromosomal translocations found in CRPC include the TMPRSS2-ERG fusions. Epigenetic abnormalities are common in CRPC
PATHOPHYSIOLOGY
Restored androgen receptor (AR) activity is a major driver of therapeutic failure and CRPC development. This may occur through intracrine (intracellular) androgen synthesis, AR deregulation; AR mutation and alternative splicing; and posttranslational modifications and cofactor alterations.
ASSOCIATED CONDITIONS
• Fatigue, muscle wasting, metabolic syndrome
• Bone pain/fracture
• Hematuria, urinary retention
• Edema
• Spinal cord compression
• Anemia
• Renal failure, usually due to hydronephrosis
• Cognitive dysfunction
GENERAL PREVENTION
N/A
DIAGNOSIS
HISTORY
• Prostate cancer history including Gleason score, disease stage at diagnosis, initial treatment for localized prostate cancer
• Time of 1st diagnosis of metastatic disease
• Past hormonal treatments including time when treatments were started
• PSA history
• Extent of disease at the time of diagnosis and also current extent of disease on the bone and CT/MRI scan
• Recent changes in bowel and urinary habits
• Potency
• New neurologic symptoms
• Past medical history including any specific cardiac, renal, or gastrointestinal disease
• Performance status
• Mental status evaluation
• Current medications and allergies
• Caregiver
• Family history of prostate cancer or other cancers
• Smoking, alcohol, and drug history
PHYSICAL EXAM
• Examine for adenopathy
• Gynecomastia
• GU and rectal exam
• Extremity edema and swelling
• Neurologic exam with focus on lower extremity weakness and sensation
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Complete blood count
• Renal, electrolyte, and liver function panel
• Testosterone: Confirm <50 ng/dL
• Prostate-specific antigen (PSA)
Imaging
• Determine presence of radiographic metastasis as a guide to treatment
• Bone scan, CT, or MRI of the abdomen and pelvis at baseline and then every 6–12 mo or based on clinical setting
• Bone density as needed
Diagnostic Procedures/Surgery
• Postvoid residue (PVR) to evaluate for urinary retention
• Cystoscopy and other tests as needed
Pathologic Findings
N/A
DIFFERENTIAL DIAGNOSIS
• Bone pain may also be due to degenerative joint disease, osteoarthritis, Paget disease, or secondary malignancy
• Weight loss due to depression, other malignancies, or failure to thrive
• Anemia related to iron and vitamin deficiency, second malignancy (ie, multiple myeloma), or prior therapies
TREATMENT
GENERAL MEASURES
• Initial strategies for nonmetastatic CRPC are unclear as no randomized clinical trial has shown survival advantage in the setting of no radiographically measurable metastatic disease
• Continuing medical castration recommended
• Verify castrate levels of testosterone. If not <50 ng/dL, consider alternative LHRH agonist/antagonist administration or orchiectomy if not castrate
• Define the treatment objectives for patients: Palliative vs. prolonging survival
• Disease progression based on a rapidly rising PSA, objective changes on bone scan or CT/MRI scan or symptoms from the metastatic CRPC
• Sequencing of newer agents in the setting of disease progression remains under study
• AUA, ASCO, NCCN, and other groups have issued guidelines for the management of CRPC
MEDICATION
First Line
• There are multiple treatment options based on disease acuity and prior treatment history such as before or after docetaxel-based chemotherapy; clinical trials always need to be considered.
• Often secondary or tertiary hormonal manipulation is the initial therapy in asymptomatic mCRPC. These include
– Antiandrogen withdrawal (ie, stopping bicalutamide, etc.)
Paradoxical decrease in PSA after stopping
– 2nd-line hormonal therapy with nonsteroidal antiandrogen: bicalutamide, flutamide, nilutamide
Rarely results in a durable response
• Immunotherapy with sipuleucel-T: Autologous immunotherapy for minimally symptomatic or asymptomatic mCRPC; improved survival (2)
• Androgen biosynthesis inhibitors:
– Ketoconazole/hydrocortisone (not FDA approved for CRPC); a high-dose ketoconazole with steroid supplementation
– Abiraterone acetate/prednisone
1,000 mg (four 250 mg tabs) with 5-mg prednisone BID
Specific CYP17 inhibitor; approved both pre- and postchemotherapy
Improved overall survival (3,4)
• Pure AR antagonist:
– Enzalutamide (160 mg PO daily)
– Blocks AR translocation to nucleus; approved for both pre and post docetaxel chemotherapy in mCRPC (5,6)
• First-line chemotherapy: Docetaxel 75 mg/m2 IV every 3 wks w/prednisone (5 mg PO twice daily) (7)
• Radium 223 (Alpharadin)
– mCRPC with symptomatic bone metastases (not for visceral disease as only site)
– 6 injections at 4-wk intervals
– Delays time to disease progression and improves survival; low rate of adverse events (8)
Second Line
• Consider abiraterone or enzalutamide with mCRPC progression if either was not used previously
• Chemotherapy: Cabazitaxel (20–25 mg/m2 IV every 3 wk) with 10-mg prednisone daily (9)
– Approved postdocetaxel
• Mitoxantrone; chemotherapy FDA approved for palliation; limited utility
• Consider clinical trials
SURGERY/OTHER PROCEDURES
• Urinary diversion (stents or percutaneous nephrostomy) in cases of hydronephrosis and renal insufficiency
• Bladder outlet procedures such as TURP for obstruction
• Decompressive laminectomy for spinal cord compromise
ADDITIONAL TREATMENT
Radiation Therapy
• Samarium-153 or Strontium-89
– For palliation painful bony mets; no survival benefit; cause bone marrow suppression
• Palliative radiotherapy
– Focal painful bone lesion
– Epidural disease associated with neurologic symptoms or pain, or spinal cord compression
• Radium 223 (alpharadin) see “First Line" above
Additional Therapies
• Daily calcium (≥1,200 mg daily)/vitamin D (800–1,000 IU daily)
• Bisphosphonate (zoledronic acid) or denosumab for bone health for mCRPC to reduce skelet al-related events (fractures, etc.)
• High dose of steroids (dexamethasone 2–10 mg) useful in acute pain syndromes or neurologic compromise
• Adding nonsteroidal anti-inflammatory drugs or narcotics for pain
• Palliative care or pain specialist referral for refractory pain
Complementary & Alternative Therapies
May be helpful but randomized clinical trials needed to establish clinical benefit
ONGOING CARE
PROGNOSIS
Median survival of patients with CRPC range from 18 to 27 mo depending on the extent of disease
COMPLICATIONS
• Altered mental status
• Anemia
• Bone marrow failure
• Cord compression with loss of motor or sensory function
• Cranial nerve deficits from prostate cancer in the base of the skull
• Depression
• Disseminated intravascular coagulation (DIC)
• Fatigue
• Hematuria
• Muscle wasting/weakness
• Pain
• Pathologic fractures (vertebral, hip, and long bone)
• Rectal bleeding
• Renal failure (acute and chronic)
• Urinary retention
FOLLOW-UP
Patient Monitoring
Frequency of visits, exams, blood work, and radiographs will be dependent upon the patient’s acuity and prostate cancer symptoms
Patient Resources
• American Cancer Society http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-references
• National Cancer Institute (NCI) http://www.cancer.gov/cancertopics/treatment/prostate
REFERENCES
1. Halabi S, Small EJ, Kantoff PW, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol. 2003;21(7):1232–1237.
2. Kantoff PW, Higano CS, Shore ND, et al. ; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–422.
3. de Bono JS, Logothetis CJ, Molina A, et al. ; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995–2005.
4. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138–148.
8. Scher HI, Fizazi K, Saad F, et al. ; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–1197.
9. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424–433.
5. Tannock IF, de Wit R, Berry WR, et al. ; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502–1512.
6. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213–223.
7. de Bono JS, Oudard S, Ozguroglu M, et al. ; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet. 2010;376(9747):1147–1154.
ADDITIONAL READING
• Basch E, Loblaw DA, Oliver TK, et al. Systemic Therapy in Men with Metastatic Castration-Resistant Prostate Cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline; JCO, Online before print September 8, 2014, doi: 10.1200/JCO.2013.54.8404.
• Cookson MS, Roth BJ, Dahm P, et al. Castration-Resistant Prostate Cancer: AUA Guideline. J Urol. 2013;190(2):429–438.
• Gomella LG, Petrylak DP, Shayegan B. Current management of advanced and castration resistant prostate cancer. Can J Urol. 2014;21(2 suppl 1):1–6.
• Knudsen KE, Kelly WK. Outsmarting androgen receptor: Creative approaches for targeting aberrant androgen signaling in advanced prostate cancer. Expert Rev Endocrinol Metab. 2011;6(3):483–493.
• Smith MR, Egerdie B, Hernández Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361(8):745–755.
See Also (Topic, Algorithm, Media)
• Prostate Cancer, General
• Prostate Cancer, Metastatic (N+, M+)
• Prostate Cancer, Rising PSA Following Androgen Ablation (Castration-resistant Prostate Cancer) Algorithm 
CODES
ICD9
• 185 Malignant neoplasm of prostate
• 790.93 Elevated prostate specific antigen [PSA]
• V45.77 Acquired absence of organ, genital organs
ICD10
• C61 Malignant neoplasm of prostate
• R97.2 Elevated prostate specific antigen [PSA]
• Z90.79 Acquired absence of other genital organ(s)
CLINICAL/SURGICAL PEARLS
• Castration resistant prostate cancer must be classified as with (mCRPC) or without (CRPC) radiographic metastasis.
• Bone or visceral metastasis will evolve if not initially present.
• Androgen–androgen receptor axis remains the key survival factor and treatment target for CRPC.
• Androgen receptor targeted therapy, immunotherapy, chemotherapy, and bone-targeted therapy are all effective to improve survival.