Understanding CRPC

CRPC is defined as1:

Patient on LHRH
therapy*

+

Castrate levels of
testostrone (< 50 ng/dL)

+

Rising PSA
 

CRPC can be nonmetastatic (no radiographic evidence of metastasis) or metastatic (evidence of metastatic disease).

LHRH, luteinizing hormone-releasing hormone; PSA, prostate-specific antigen.

*Or after surgical castration.1

One study estimated that patients treated with LHRH therapy* stop responding within 1-3 years2

The median time to progression on LHRH therapy* (also known as androgen deprivation therapy) was assessed in a retrospective analysis of 553 patients initiating LHRH therapy* (+/- anti-androgen) with metastatic (49%) or nonmetastatic (51%) disease. Median follow-up was 5.1 years.2

Median prostate cancer progression time on LHRH

*Or after surgical castration.1

†Defined as the duration of time from LHRH therapy* initiation to the date of progression (2 rises in PSA above a nadir value while receiving LHRH therapy*).2

Patients who progress on LHRH therapy* may have asymptomatic mCRPC3

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

32% of men with asymptomatic mCRPC

  • 2577 patients were enrolled in a large phase 3 trial of patients with nmCRPC. Within 4 weeks of randomization, patients were screened by CT/MRI and bone scan. 818 patients (32%) failed screening due to evidence of metastases3

CT, computed tomography; mCRPC, metastatic castration-resistant prostate cancer; MRI, magnetic resonance imaging; nmCRPC, nonmetastatic castration-resistant prostate cancer.

*Or after surgical castration.1

The unexpectedly high rate of metastatic disease in this trial suggests that a high proportion of men thought to have nmCRPC may have had asymptomatic metastasis.

—Yu EY et al. (2012)3

Retrospective analysis suggests an association between metastatic burden and clinical outcomes

In a retrospective analysis of bone metastases among patients with nmCRPC, those with fewer bone lesions at baseline experienced better overall survival and progression-free survival4

One to four bone lesions; Five or greater bone lesions
  • 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 mCRPC4

Meta-analysis evaluating the impact of site of metastases on overall survival in men with CRPC5

  • This meta-analysis of nine phase 3 studies included 8736 men with CRPC who received docetaxel chemotherapy and was used to evaluate the impact of site of metastases on overall survival5
Median overall survival by site of metastases in mCRPC (N = 8736)5
Lymph node (LN) only 31.6 months (95% CI, 27.9–35.5)
Bone (with or without LN) 21.3 months (95% CI, 20.8–21.9)
Lung (with or without bone and LN) 19.4 months (95% CI, 17.8–20.7)
Liver (with or without bone, LN, and lung) 13.5 months (95% CI, 12.7–14.4)
  • 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 metastases5

CI, confidence interval.

Early detection of advancing disease may help inform clinical decision-making6

Recommendations for the early identification of metastases from the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence (RADAR) Group6

The RADAR I Group initially convened to provide recommendations for the early identification of prostate cancer metastases using traditional imaging modalities.

The RADAR III Group convened to evaluate the use of next-generation imaging (NGI) modalities and review the rationale behind choosing certain scans, frequency of scanning, interpreting results, and subsequent clinical usefulness.

RADAR III acknowledges the limitations of making recommendations when level 1 evidence-based data are not yet available.

CRPC scanning recommendations: RADAR6

Without detectable metastases
Without detectable metastases

RADAR I

Conventional scan recommendations

Scan patients when PSA is ≥ 2 ng/mL; if negative, rescan when PSA is 5 ng/mL and every doubling of PSA level thereafter

• Based on PSA testing every 3 months

RADAR III

NGI recommendations

Only consider NGI in the setting of PSADT < 6 months, when mCRPC therapies would be appropriate

With detectable metastases
With detectable metastases

RADAR III

NGI recommendations

Utilize conventional scans, and consider NGI only if conventional scans are negative and the clinician still suspects disease progression

NGI based on at least one of the following: 1. with every doubling of PSA since the previous image, 2. every 6-9 months in the absence of a PSA rise, 3. with a change in symptomatology, or 4. with a change in performance status

PSADT, prostate-specific antigen doubling time.

References: 1. American Urological Association. Castration-resistant prostate cancer: AUA guideline (05-2018). https://www.auanet.org/guidelines/prostate-cancer-castration-resistant-guideline (2013, amended 2018). Accessed 03-31-2020. 2. 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. 3. 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. 4. 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. 5. 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. 6. Crawford ED, Koo PJ, Shore N, et al. A clinician's guide to next generation imaging in patients with advanced prostate cancer (RADAR III). J Urol 2019;201(4):682-92.

Important Safety Information

Warnings and Precautions

Seizure occurred in 0.5% of patients receiving XTANDI in seven randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and 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. 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) There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that 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 seven randomized 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 combined data of four randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.9% vs 1.3%). Grade 3-4 ischemic events occurred in 1.4% of patients on XTANDI versus 0.7% 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 occurred in patients receiving XTANDI. 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. In the combined data of four randomized, placebo-controlled clinical studies, falls occurred in 11% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 10% of patients treated with XTANDI and in 4% of patients treated with placebo.

Embryo-Fetal Toxicity The 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.

Adverse Reactions (ARs)

In the data from the four randomized placebo-controlled trials, the most common ARs ( 10%) that occurred more frequently ( 2% over placebo) in XTANDI-treated patients were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension. In the bicalutamide-controlled study, the most common ARs ( 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to adverse events (AEs) were reported for 16% of XTANDI-treated patients. In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to AEs were reported for 6% of XTANDI-treated patients. In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs 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.

In PROSPER, the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AE as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients.

In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher AEs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to AEs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

Lab Abnormalities: Lab abnormalities that occurred in 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, and hypercalcemia.

Hypertension: In the combined data from four randomized placebo-controlled clinical trials, hypertension was reported in 12% of XTANDI patients and 5% of placebo patients. 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.

Indications

XTANDI (enzalutamide) is indicated for the treatment of patients with:

  • castration-resistant prostate cancer (CRPC)
  • metastatic castration-sensitive prostate cancer (mCSPC)

Please see accompanying Full Prescribing Information.

Important Safety Information

Warnings and Precautions

Seizure occurred in 0.5% of patients receiving XTANDI in seven randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and 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. 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) There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that 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 seven randomized 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 combined data of four randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.9% vs 1.3%). Grade 3-4 ischemic events occurred in 1.4% of patients on XTANDI versus 0.7% 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 occurred in patients receiving XTANDI. 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. In the combined data of four randomized, placebo-controlled clinical studies, falls occurred in 11% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 10% of patients treated with XTANDI and in 4% of patients treated with placebo.

Embryo-Fetal Toxicity The 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.

Adverse Reactions (ARs)

In the data from the four randomized placebo-controlled trials, the most common ARs ( 10%) that occurred more frequently ( 2% over placebo) in XTANDI-treated patients were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension. In the bicalutamide-controlled study, the most common ARs ( 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to adverse events (AEs) were reported for 16% of XTANDI-treated patients. In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to AEs were reported for 6% of XTANDI-treated patients. In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs 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.

In PROSPER, the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AE as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients.

In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher AEs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to AEs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

Lab Abnormalities: Lab abnormalities that occurred in 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, and hypercalcemia.

Hypertension: In the combined data from four randomized placebo-controlled clinical trials, hypertension was reported in 12% of XTANDI patients and 5% of placebo patients. 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.

Indications

XTANDI (enzalutamide) is indicated for the treatment of patients with:

  • castration-resistant prostate cancer (CRPC)
  • metastatic castration-sensitive prostate cancer (mCSPC)

Please see accompanying Full Prescribing Information.