Identifying castration-resistant prostate cancer (CRPC)
The development of castration-resistant cancer: progression on LHRH therapy1-3
LHRH, luteinizing hormone-releasing hormone.
*Despite castrate testosterone levels (≤ 50 ng/dL).1
†Or prior bilateral orchiectomy.1
Median time to progression on LHRH (months)§4
‡LHRH therapy refers to luteinizing hormone-releasing hormone ± antiandrogen. While LHRH therapy is received by nearly 90% of men in the United States undergoing androgen deprivation,5 patients who underwent surgical castration (bilateral orchiectomy) were also included in this analysis.4
§From a retrospective analysis of 553 patients initiating androgen deprivation therapy (LHRH ± antiandrogen or after bilateral orchiectomy) with metastatic (49%) and nonmetastatic (51%) disease. Median follow-up was 5.1 years. Progression was defined as 2 PSA rises above nadir while receiving androgen deprivation therapy.4
In a retrospective analysis of patients with asymptomatic CRPC who were previously identified as nonmetastatic
2577 patients were enrolled in a large phase 3 trial of patients with nonmetastatic CRPC. Within 4 weeks of randomization, patients were screened by CT/MRI and bone scan. 818 patients (32%) failed screening due to evidence of metastases6
CT, computed tomography; MRI, magnetic resonance imaging.
The unexpectedly high rate of metastatic disease in this trial suggests that a high proportion of men thought to have nonmetastatic CRPC may have had asymptomatic metastasis.
In an analysis of bone metastases among patients with metastatic CRPC, those with fewer bone lesions at baseline experienced better overall survival (OS) and progression-free survival (PFS)7
- From a retrospective analysis of 561 patients with confirmed bone metastases from a randomized phase 3 trial. Bone metastases at trial entry were confirmed by bone scintigraphy supplemented by CT and/or MRI (where metastases were equivocal). The trial ended early due to a lack of efficacy, which allowed the authors to combine both cohorts and correlate the number of bone metastases present at baseline with the natural history of metastatic CRPC7
- A meta-analysis of nine phase 3 studies of 8736 men evaluating the impact of site of metastases on overall survival in metastatic CRPC who received docetaxel chemotherapy8
Median overall survival by site of metastases in mCRPC
- Limitations of this retrospective analysis include the inability to account for all known prognostic factors across trials. In addition, neither imaging nor imaging reports were centrally reviewed, which prevented an assessment of the impact of metastatic burden and number of metastases. Nevertheless, due to the sample size and number of patient deaths, this analysis is likely to have high validity8
Recommendations for the early identification of metastases from the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence (RADAR) Group9
The recommendations are generalized suggestions based on clinical experience. Clinical data are sparse, causing need for verification from appropriate clinical trials.
- Due to the lack of consensus in currently available imaging guidelines on eligibility criteria, type of imaging modality, or frequency of scanning for detecting metastatic disease, the multidisciplinary RADAR Group was convened to identify optimal strategies for early identification of metastases in patients with prostate cancer9
Important Safety Information and Indication
XTANDI (enzalutamide) is indicated for the treatment of patients with castration-resistant prostate cancer (CRPC).
Important Safety Information
Warnings and Precautions
Seizure occurred in 0.4% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. Patients in the study had one or more of the following pre-disposing factors: use of medications that may lower the seizure threshold; history of traumatic brain or head injury, cerebrovascular accident or transient ischemic attack, Alzheimer's disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.
Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.
Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions.
Ischemic Heart Disease In the placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.7% vs 1.2%). Grade 3-4 ischemic events occurred in 1.2% of patients on XTANDI versus 0.5% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease.
Falls and Fractures In the placebo-controlled clinical studies, falls occurred in 10% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 8% of patients treated with XTANDI and in 3% of patients treated with placebo. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.
Embryo-Fetal Toxicity Safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI. XTANDI should not be handled by females who are or may become pregnant.
The most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI patients from the randomized placebo-controlled trials were asthenia/fatigue, decreased appetite, hot flush, arthralgia, dizziness/vertigo, hypertension, headache and weight decreased. In the bicalutamide-controlled study, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.
In the placebo-controlled study of metastatic CRPC (mCRPC) patients taking XTANDI who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In the placebo-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. In the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher adverse reactions were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an adverse event as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients. In the bicalutamide-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.
Lab Abnormalities: In the two placebo-controlled trials in patients with mCRPC, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). In the placebo-controlled trial in patients with nmCRPC, Grade 1-4 neutropenia occurred in 8% of patients receiving XTANDI (0.5% Grade 3-4) and in 5% of patients receiving placebo (0.2% Grade 3-4).
Hypertension: In the two placebo-controlled trials in patients with mCRPC, hypertension was reported in 11% of XTANDI patients and 4% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm. In the placebo-controlled trial in patients with nmCRPC, hypertension was reported in 12% of patients receiving XTANDI and 5% of patients receiving placebo.
Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.
Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.
Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.
XTANDI (enzalutamide) is indicated for the treatment of patients with castration-resistant prostate cancer (CRPC).
Please see Full Prescribing Information for additional safety information.
The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.References: 1. Zhang T, Armstrong AJ. Evolution of clinical states and the castration resistant paradigm. In: Saad F, Eisenberger MA, eds. Management of Castration Resistant Prostate Cancer. 1st ed. New York, NY: Springer, 2014:9-30. 2. Thompson I, Carroll P, Coley C, et al. Prostate-specific antigen (PSA) best practice policy. Oncology (Williston Park) 2000;14(2):267-86. 3. Eisenberger MA, Saad F. Introduction—castrate resistant prostate cancer: a rapidly expanding clinical state and a model for new therapeutic opportunities. In: Saad F, Eisenberger MA, eds. Management of Castration Resistant Prostate Cancer. 1st ed. New York, NY: Springer, 2014:3-8. 4. Ross RW, Xie W, Regan MM, et al. Efficacy of androgen deprivation therapy (ADT) in patients with advanced prostate cancer. Cancer 2008;112(6):1247-53. 5. Sun M, Choueiri TK, Hamnvik OPR, et al. Comparison of gonadotropin-releasing hormone agonists and orchiectomy: effects of androgen-deprivation therapy. JAMA Oncol 2016;2(4):500-7. 6. Yu EY, Miller K, Nelson J, et al. Detection of previously unidentified metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic, castration resistant prostate cancer. J Urol 2012;188(1):103-9. 7. Tait C, Moore D, Hodgson C, et al. Quantification of skeletal metastases in castrate-resistant prostate cancer predicts progression-free and overall survival. BJU Int 2014;114(6b):E70-3. 8. Halabi S, Kelly WK, Ma H, et al. Meta-analysis evaluating the impact of site of metastasis on overall survival in men with castration-resistant prostate cancer. J Clin Oncol 2016;34(14):1652-9. 9. Crawford ED, Stone NN, Yu EY, et al; and the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence (RADAR) Group. Challenges and recommendations for early identification of metastatic disease in prostate cancer. Urology 2014;83(3):664-9.