Identifying progression to metastatic castration-resistant prostate cancer (mCRPC)

The development of advanced prostate cancer: From progression on LHRH to metastatic CRPC1,2

Prostate Cancer Progression Graph

*In an analysis of 767,550 men diagnosed with prostate cancer between 2004 and 2013 from the National Cancer Database, 3% had hormone-sensitive, metastatic disease at diagnosis.3

LHRH, luteinizing hormone-releasing hormone.

Castration-resistant disease is defined as disease progression despite castrate levels of testosterone ( 50 ng/dL)1

Defined according to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria as a rising PSA value or radiographic progression despite castrate levels of testosterone.4

From the American Urological Association (AUA) Guidelines for castration-resistant prostate cancer.1

Most men with advanced disease eventually stop responding to LHRH therapy§2

Median time to progression on LHRH (months)II5

23.7 Months, Median Prostate Cancer Progression Time on LHRH

§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,6 patients who underwent surgical castration (bilateral orchiectomy) were also included in this analysis.5

IIFrom 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.5

Patients who progress on LHRH may have asymptomatic, metastatic CRPC7

In a retrospective analysis of patients with asymptomatic CRPC who were previously identified as nonmetastatic

32 Percent of Men with Asymptomatic mCRPC
  • 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 metastases7

    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.
—Yu et al. (2012)
Retrospective analyses of studies suggest an association of metastatic burden to clinical outcomes

In an analysis of bone metastases among patients with metastatic CRPC, those with fewer bone lesions at baseline experienced better overall survival and progression-free survival8

  • 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 CRPC8
One to four bone lesions Five or greater bone lesions
Meta-analysis evaluating the impact of site of metastasis on overall survival in men with castration-resistant prostate cancer9
  • 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 chemotherapy
    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 validity9
CI, confidence interval.
Early detection of metastatic CRPC may help inform clinical decision-making

Recommendations for the early identification of metastases from the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence (RADAR) Group10

Imaging recommendations for patients with nonmetastatic CRPC based on PSA testing every 3 months10
Early detection mCRPC
Imaging recommendations for patients with nonmetastatic CRPC based on PSA testing every 3 months10

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 cancer10

Indication

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Important Safety Information

Contraindications
XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy.

Warnings and Precautions
Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors, seizures were reported in 2.2% of patients. See section 5.1 of the Prescribing Information for the list of predisposing factors. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. 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.

Adverse Reactions
The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI patients from the two placebo-controlled clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. In the bicalutamide-controlled study of chemotherapy-naïve patients, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, upper respiratory tract infection, diarrhea, and weight loss.

In the placebo-controlled study of 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 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 bicalutamide-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 38.8% of XTANDI patients and 37.6% of bicalutamide patients. Discontinuations due to adverse events were reported for 7.6% of XTANDI patients and 6.3% of bicalutamide patients.

Lab Abnormalities: In the two placebo-controlled trials, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).

Infections: In the study of patients taking XTANDI who previously received docetaxel, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In the study of chemotherapy-naïve patients, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

Drug Interactions
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.

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. Cookson MS, Roth BJ, Dahm P, et al. Castration-resistant prostate cancer: AUA guideline. American Urological Association Education and Research, Inc. 2015. Accessed 02-14-2018. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.2.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed [March 8, 2018]. To view the most recent and complete version of the guideline, go online to NCCN.org. 3. Weiner AB, Matulewicz RS, Eggener SE, Schaeffer EM. Increasing incidence of metastatic prostate cancer in the United States (2004-2013). Prostate Cancer Prostatic Dis 2016;19(4):395-7. 4. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26(7):1148-59. 5. Ross RW, Xie W, Regan MM, et al. Efficacy of androgen deprivation therapy (ADT) in patients with advanced prostate cancer: association between Gleason score, prostate-specific antigen level, and prior ADT exposure with duration of ADT effect. Cancer 2008;112(6):1247-53. 6. 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. 7. 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. 8. 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. 9. 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. 10. Crawford ED, Stone NN, Yu EY, et al. Challenges and recommendations for early identification of metastatic disease in prostate cancer. Urology 2014;83(3):664-9.
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Indication and Important Safety Information

Indication

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Important Safety Information

Contraindications
XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy.