MECHANISM OF DISEASE
LHRH THERAPY AND PROSTATE CANCER CELL ADAPTATION
In response to LHRH therapy, prostate cancer cells may adapt so that androgen receptor signaling continues to drive cell growth1-5
LHRH, luteinizing hormone-releasing hormone.
UNDERSTANDING mCSPC
In a projection based on SEER data15
It is estimated that from 2014 to 2020 the total incidence of men who newly present with mCSPC had increased 16% to over 13,00015
Based on a forward-looking model that used the Surveillance, Epidemiology and End Results (SEER) Program age-specific prostate cancer incidence rate data from 2008 to estimate prostate cancer incidence for each year from 2009 to 2020. To validate the model, the final results were compared with published estimates of prostate cancer incidence and prevalence in the United States for 2009 and 2020. The model estimates for the year 2020 are based on existing/current (2009) disease incidence, diagnosis, and treatment patterns, and reflect demographic changes in the US population over time (eg, the impact of the baby boomer population).16
Patients with mCSPC can be characterized with 1 of the 2 following diagnoses
| Recurrent metastatic disease16 | De novo metastatic disease16,17 |
|---|---|
|
|
PSA, prostate-specific antigen.
*Definitive therapy is defined as a radical prostatectomy or radiotherapy with curative intent.16
†Or prior bilateral orchiectomy.16
Patients with de novo mCSPC are estimated to have a lower relative survival rate than patients with clinically localized disease18
A SEER analysis* estimates a lower (32.3%) 5-year relative survival rate for patients with mCSPC vs those with clinically localized prostate cancer (100%)18
*A retrospective analysis* of the SEER database, a collection of cancer incidence and survival data from population-based cancer registries covering approximately 48% of the US population, was conducted between 2012 and 2018.18,19
Annual projected (2020-2025) incidence of newly diagnosed mCSPC20,21
*From a 2018 study, based on age-period–cohort models and population projections of incidence data for men aged 45-94 years who were diagnosed with metastatic prostate cancer at initial clinical presentation. Estimates were based on the population-based SEER Program registries (2004-2014).20
UNDERSTANDING CRPC
CRPC is defined as22:
Patient on LHRH
therapy*
+
Castrate levels of
testosterone (< 50 ng/dL)
+
Rising PSA, or progression of pre-existing or new radiographic disease, and/or clinical progression with symptoms
CRPC can be nonmetastatic (no radiographic evidence of metastasis) or metastatic (evidence of metastatic disease).
*Or after surgical castration.22
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%) castration-sensitive prostate cancer. Median follow-up was 5.1 years.23
*Or after surgical castration.23
†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*).23
In a retrospective analysis of patients with asymptomatic CRPC who were previously identified as nonmetastatic24
CT, computed tomography; mCRPC, metastatic castration-resistant prostate cancer; MRI, magnetic resonance imaging; nmCRPC, nonmetastatic castration-resistant prostate cancer.
*Or after surgical castration.24
“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.”
Retrospective analysis suggests an association between metastatic burden and clinical outcomes25
In a retrospective analysis of bone metastases among patients with mCRPC, those with fewer bone lesions at baseline experienced better overall survival and progression-free survival25
Meta-analysis evaluating the impact of site of metastases on overall survival in men with CRPC26
| MEDIAN OVERALL SURVIVAL BY SITE OF METASTASES IN mCRPC (N = 8736)26 | |
|---|---|
| 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) |
CI, confidence interval.
Early detection of advancing disease may help inform clinical decision-making27,28
Recommendations for the early identification of metastases from the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence (RADAR) Group27,28
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.
The RADAR VI Group convened to develop pathways and recommendations regarding how new targeted precision imaging (TPI) modalities could be used, given recent approvals of radiotracers.
CRPC scanning recommendations: RADAR27,28
| 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 |
RADAR VI TPI recommendations Appropriate use criteria • TPI is recommended for men with PSA progression while on ADT for BCR if metastasis directed therapy is a potential option. Otherwise, conventional imaging can be performed to verify nonmetastatic status • Patients whose disease is detectable only by TPI and not by conventional imaging should generally be treated as nmCRPC because this approach is the most consistent with available level 1 evidence • Role of TPI while on therapy for nmCRPC: - For patients on systemic therapy for nmCRPC who had TPI as baseline imaging for their nmCRPC: • Imaging should be repeated at least annually and at the time of PSA recurrence. No PSA cutoff for repeat imaging, as yet, because PSMA TPI can be positive even at low PSA levels - For patients treated with local therapy for nmCRPC who had TPI as baseline imaging for their nmCRPC: • TPI may be repeated within 4-6 months to document the response to therapy and assess for new metastases and then repeated annually as above |
| 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 |
RADAR VI Conventional imaging recommendations For detection of mCRPC In patients with nmCRPC based on PSADT (PSADT < 10 months): see nmCRPC recommendation Patients with mCSPC based on symptoms, PSA (rise), and at set frequency (6-12 months): • Scan at least once per year at physician discretion • Scans based on symptoms, PSA rise (PSA > 2 or PSADT < 6 months) During treatment For disease monitoring, to assess response and progressive disease • Baseline scans suggested at new treatment start and up to every 12 weeks on treatment based on clinical discretion and symptoms Flare phenomenon Flare is not uncommon and can be observed on both bone scan and CT imaging The first on-treatment scan is particulary subject to healing flare Such scans should be interpreted in the context of clinical symptoms and PSA Consider TPI only if CI is negative and clinician still suspects disease progression TPI recommendations For disease detection For initial staging, TPI is recommended for staging of mCRPC if it is likely to affect clinical decisions For treatment eligibility Based on the phase 3 VISION17 and TheraP23 trials: • PSMA-PET imaging can be used for treatment selection for PSMA-targeted therapies • 18FDG imaging/fluciclovine can be obtained in patients with treatment-refractory mCRPC to inform subsequent treatment strategies For treatment monitoring At present, response criteria are lacking for TPI. TPI should not be used alone to make decisions regarding treatment discontinuation in the context of mCRPC |
|
18FDG, 18fluorodeoxyglucose; ADT, androgen deprivation therapy; BCR, biochemical recurrence; PET, positron emission tomography; PSADT, prostate-specific antigen doubling time; PSMA, prostate-specific membrane antigen.
References: 1. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004;10(1):33-9. 2. Holzbeierlein J, Lal P, LaTulippe E, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol 2004;164(1):217-27. 3. Attard G, Swennenhuis JF, Olmos D, et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res 2009;69(7):2912-8. 4. Taplin ME, Bubley GJ, Shuster TD, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 1995;332(21):1393-8. 5. Linja MJ, Savinainen KJ, Saramäki OR, Tammela TLJ, Vessella RL, Visakorpi T. Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res 2001;61(9):3550-5. 6. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009;324(5928):787-90. 7. Bubendorf L, Kononen J, Koivisto P, et al. Survey of gene amplifications during prostate cancer progression by high-throughput fluorescence in situ hybridization on tissue microarrays. Cancer Res 1999;59(4):803-6. Erratum in: Cancer Res 1999;59(6):1388. 8. Koivisto P, Kononen J, Palmberg C, et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res 1997;57(2):314-9. 9. Richards J, Lim AC, Hay CW, et al. Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res 2012;72(9):2176-82. 10. Zhao XY, Malloy PJ, Krishnan AV, et al. Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat Med 2000;6(6):703-6. Erratum in: Nat Med 2000;6(8):939. 11. Veldscholte J, Ris-Stalpers C, Kuiper GG, et al. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun 1990;173(2):534-40. 12. Libertini SJ, Tepper CG, Rodriguez V, Asmuth DM, Kung HJ, Mudryj M. Evidence for calpain-mediated androgen receptor cleavage as a mechanism for androgen independence. Cancer Res 2007;67(19):9001-5. 13. Hu R, Dunn TA, Wei S, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res 2009;69(1):16-22. 14. Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res 2008;68(13):5469-77. 15. Supplement to: Scher HI, Solo K, Valant J, Todd MB, Mehra M. Prevalence of prostate cancer clinical states and mortality in the United States: estimates using a dynamic progression model. PLoS One 2015;10(10):e0139440. 16. Scher HI, Solo K, Valant J, Todd MB, Mehra M. Prevalence of prostate cancer clinical states and mortality in the United States: estimates using a dynamic progression model. PLoS One 2015;10(10):e0139440. 17. Finianos A, Gupta K, Clark B, Simmens SJ, Aragon-Ching JB. Characterization of differences between prostate cancer patients presenting with de novo versus primary progressive metastatic disease. Clin Genitourin Cancer 2018;16(1):85-9. 18. National Cancer Institute. Prostate: SEER 5-year relative survival rates, 2012-2018. https://seer.cancer.gov/statistics-network/explorer/application.html?site=66&data_type=4&graph_type=5
&compareBy=stage&chk_stage_101=101&chk_stage_104=104&chk_stage_105=105&chk_stage_106=106
&chk_stage_107=107&series=9&hdn_sex=2&race=1&age_range=1&advopt_precision=1&advopt_show_ci=on
&hdn_view=1. Accessed 03-17-2023. 19. National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) (07-2021). https://seer.cancer.gov/about/factsheets/SEER_Overview.pdf. Accessed 09-19-2022. 20. Kelly SP, Anderson WF, Rosenberg PS, Cook MB. Past, current, and future incidence rates and burden of metastatic prostate cancer in the United States. Eur Urol Focus 2018;4(1):121-7. 21. Supplement to: Kelly SP, Anderson WF, Rosenberg PS, Cook MB. Past, current, and future incidence rates and burden of metastatic prostate cancer in the United States. Eur Urol Focus 2018;4(1):121-7. 22. Lowrance W, Dreicer R, Jarrard DF, et al. Updates to advanced prostate cancer: AUA/SUO guideline (2023). J Urol 2023;209(6):1082-90. 23. 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. 24. 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. 25. 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. 26. 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. 27. 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. 28. Crawford ED, Albala DM, Harris RG, et al. A clinician’s guide to targeted precision imaging in patients with prostate cancer (RADAR VI). JU Open Plus (Epub) 12-29-2022.
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 coadministration with strong CYP2C8 inhibitors. If coadministration cannot be avoided, reduce the dosage of XTANDI.
Avoid coadministration with strong CYP3A4 inducers. If coadministration cannot be avoided, increase the dosage of XTANDI.
Effect of XTANDI on Other Drugs Avoid coadministration with certain CYP3A4, CYP2C9, and CYP2C19 substrates for which minimal decrease in concentration may lead to therapeutic failure of the substrate. If coadministration cannot be avoided, increase the dosage of these substrates in accordance with their Prescribing Information. In cases where active metabolites are formed, there may be increased exposure to the active metabolites.
Indications
XTANDI (enzalutamide) is indicated for the treatment of patients with:
Please see 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 coadministration with strong CYP2C8 inhibitors. If coadministration cannot be avoided, reduce the dosage of XTANDI.
Avoid coadministration with strong CYP3A4 inducers. If coadministration cannot be avoided, increase the dosage of XTANDI.
Effect of XTANDI on Other Drugs Avoid coadministration with certain CYP3A4, CYP2C9, and CYP2C19 substrates for which minimal decrease in concentration may lead to therapeutic failure of the substrate. If coadministration cannot be avoided, increase the dosage of these substrates in accordance with their Prescribing Information. In cases where active metabolites are formed, there may be increased exposure to the active metabolites.
Indications
XTANDI (enzalutamide) is indicated for the treatment of patients with:
Please see Full Prescribing Information.
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