Patient-Reported Outcomes: XTANDI (enzalutamide) in mCSPC (ARCHES Trial)

Effect of Enzalutamide plus Androgen Deprivation Therapy on Health-Related Quality of Life in Patients with Metastatic Hormone-Sensitive Prostate Cancer: An Analysis of the ARCHES Randomised, Placebo-Controlled, Phase 3 Study1

Stenzl A, Dunshee C, De Giorgi U, et al. Eur Urol 2020;78(4):603-14.

The information below is not included in the USPI for XTANDI. Because adjustments for multiple comparisons were not made in the analysis of the PRO data, the results shown here call for cautious interpretation. They may represent chance findings and should be understood as descriptive and exploratory.

PRO data were evaluated in patients with mCSPC taking XTANDI*1

Baseline demographics and PRO scores were well balanced between the groups. Overall, 63% of patients had high-volume disease and 82% had no prior docetaxel therapy for prostate cancer. Baseline PRO scores suggest that patients were generally asymptomatic with good health-related quality of life (HRQoL), low symptom burden, and minimal functional limitations. Pain was low at baseline; 48% of patients (similar in both groups) reported a worst pain score of 0 (“no pain”).1-3

Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire (version 4)

  • The FACT-P questionnaire measured 27 cancer-specific items across 4 domains (physical, social or familial, emotional, and functional well-being) and 12 prostate cancer–specific items in the prostate cancer subscale to evaluate function during the previous 7 days3

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Prostate 25 (EORTC QLQ-PR25)

  • EORTC QLQ-PR25 was created to evaluate quality of life (QoL) in prostate cancer patients4
  • EORTC QLQ-PR25 evaluated QoL based on 4 symptom scales measuring bowel, urinary, treatment-related, and sexual symptoms during the previous 7 days1,5

Pain progression was measured using the Brief Pain Inventory Short Form (BPI-SF) questionnaire

  • BPI-SF allowed patients to rate the severity of their pain and the degree to which their pain interferes with common dimensions of feeling and function using a recall period of 24 hours6

Study methods of ARCHES PRO1

PROs were assessed at baseline, at week 13, and every 12 weeks until disease progression. PRO analyses are reported up to week 73 to minimize the impact of missing data given that the median radiographic progression-free survival for placebo plus androgen deprivation therapy was 20 months. After treatment discontinuation, patients underwent long-term follow-up, including monitoring for survival, new antineoplastic therapies for prostate cancer, and symptomatic skeletal events. Patients were scanned every 12 weeks and PROs were measured (for those continuing with radiological assessments, if seen in clinic) until confirmed radiographic progression (independent central review) or predefined radiographic progression events (≥ 262) were reached. The primary endpoint in ARCHES was radiographic progression-free survival.

Prespecified secondary PRO endpoints included time to first confirmed clinically meaningful symptom worsening/HRQoL deterioration.

  • Time to first confirmed clinically meaningful deterioration was defined as time from randomization to first deterioration in PRO score ≥ 1 threshold unit that connotes clinically meaningful change to patients vs baseline that is confirmed at the next consecutive visit or followed by drop out, resulting in monotone missing data. Patients with no confirmed clinically meaningful deterioration before the end of follow-up, radiographic progression, or death (if not progressed before death) were censored at the last available PRO assessment (date of last non-missing value)

Limitations of ARCHES PRO1

  • Study limitations include patient selection using specific criteria, so the results might not be generalizable to other disease-stage prostate cancer populations
  • There was an absence of HRQoL data before androgen deprivation therapy initiation and limited data after treatment discontinuation. This limited the ability to document improved HRQoL with initial androgen deprivation therapy before XTANDI, and missing HRQoL data over time is a well-established drawback of studies incorporating PRO data as secondary or exploratory endpoints
  • This pattern of attrition makes data interpretation difficult and can lead to overestimation of HRQoL at later time points. To address this imbalance, the mixed model for repeated measures analysis of longitudinal data is limited to 73 weeks
  • The follow-up duration in ARCHES is short

PRO, patient-reported outcomes.

*As a prespecified outcome.1

ARCHES PRO: FACT-P Total Score Measured Over Time From Baseline3

FACT-P total score measured over time from baseline to week 73

CI, confidence interval.

  • FACT-P scores were measured with a questionnaire about 27 cancer-specific items and 12 prostate cancer–specific items to assess functioning over time3

Limitation of FACT-P

  • Although used widely in prostate cancer studies, the FACT-P questionnaire may not accurately assess treatment results and differentiate between treatment side effects and disease-related symptoms1

ARCHES PRO: FACT-P Time to Confirmed Deterioration1

Time to confirmed deterioration: FACT-P

Assessments were made based on time to first confirmed deterioration.

PCS, prostate cancer subscale.

*Or after bilateral orchiectomy.1

Select Safety Information

Adverse Reactions (cont’d) 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.

ARCHES PRO: EORTC QLQ-PR25 Modified Urinary Symptom Score Measured Over Time From Baseline3

FACT-P total score measured over time from baseline to week 73
  • EORTC QLQ-PR25 scores were measured with a questionnaire about modified urinary symptoms over time3

Limitations of EORTC QLQ-PR25

  • Interpretation of EORTC QLQ-PR25 data in a scientific context can be difficult because there are only a few published studies available at this time4
  • Because no threshold values for clinically meaningful change have been established for EORTC QLQ-PR25, we derived thresholds using distribution- and anchor‑based analyses; derivation of correlation coefficients between anchors and EORTC QLQ-PR25 scores showed that the anchors are adequate1

ARCHES PRO: EORTC QLQ-PR25 Time to Confirmed Deterioration1

Time to confirmed deterioration: eortc-qlq-pr25

Assessments were made based on time to first confirmed deterioration.

*Or after bilateral orchiectomy.1

Select Safety Information

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.

ARCHES PRO: BPI-SF Time to Confirmed Deterioration1

Time to confirmed deterioration: BPI-SF
  • BPI-SF scores were measured with a 9-item questionnaire to evaluate pain, including severity of pain over time3

Limitation of BPI-SF

  • A limitation of BPI-SF is that the questionnaire does not provide patients the opportunity to differentiate between the forms of pain experienced7

Assessments were made based on time to first confirmed deterioration.

*Or after bilateral orchiectomy.1

†Pain severity is measured based on the patients’ rating of their current pain, average pain, least pain in the last 24 hours, and worst pain in the last 24 hours.7

‡The interference score assesses the degree to which pain interferes with daily activities, from 0 (no interference) to 10 (complete interference).7

Select Safety Information

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.

References: 1. Stenzl A, Dunshee C, De Giorgi U, et al. Effect of enzalutamide plus androgen deprivation therapy on health-related quality of life in patients with metastatic hormone-sensitive prostate cancer: an analysis of the ARCHES randomised, placebo-controlled, phase 3 study. Eur Urol 2020;78(4):603-14. 2. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 3. Supplement to: Stenzl A, Dunshee C, De Giorgi U, et al. Effect of enzalutamide plus androgen deprivation therapy on health-related quality of life in patients with metastatic hormone-sensitive prostate cancer: an analysis of the ARCHES randomised, placebo-controlled, phase 3 study. Eur Urol 2020;78(4):603-14. 4. Bach P, Döring T, Gesenberg A, Möhring C, Goepel M. Quality of life of patients after retropubic prostatectomy - pre- and postoperative scores of the EORTC QLQ-C30 and QLQ-PR25. Health Qual Life Outcomes (Epub) 11-02-2011. 5. Tombal B, Saad F, Penson D, et al. Patient-reported outcomes following enzalutamide or placebo in men with non-metastatic, castration-resistant prostate cancer (PROSPER): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2019;20(4):556-69. 6. Cleeland CS. The Brief Pain Inventory: User Guide (2009). https://www.mdanderson.org/documents/Departments-and-Divisions/Symptom-Research/BPI_UserGuide.pdf. Accessed 04-06-2022. 7. Gater A, Abetz-Webb L, Battersby C, et al. Pain in castration-resistant prostate cancer with bone metastases: a qualitative study. Health Qual Life Outcomes 2011;9:88.

Important Safety Information

Warnings and Precautions

Seizure occurred in 0.6% of patients receiving XTANDI in eight 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 eight 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 five randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (3.5% vs 2%). Grade 3-4 ischemic events occurred in 1.8% of patients on XTANDI versus 1.1% 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 five randomized, placebo-controlled clinical studies, falls occurred in 12% of patients treated with XTANDI compared to 6% of patients treated with placebo. Fractures occurred in 13% of patients treated with XTANDI and in 6% 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 five randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, diarrhea, hypertension, hemorrhage, fall, fracture, and headache. 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 ARs 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 ARs 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 AR as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

In PROSPER, the placebo-controlled study of nonmetastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AR 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 ARs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to ARs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

In EMBARK, the placebo-controlled study of nonmetastatic CSPC (nmCSPC) with high-risk biochemical recurrence (BCR) patients, Grade 3 or higher adverse reactions during the total duration of treatment were reported in 46% of patients treated with XTANDI plus leuprolide, 50% of patients receiving XTANDI as a single agent, and 43% of patients receiving placebo plus leuprolide. Permanent treatment discontinuation due to adverse reactions during the total duration of treatment as the primary reason was reported in 21% of patients treated with XTANDI plus leuprolide, 18% of patients receiving XTANDI as a single agent, and 10% of patients receiving placebo plus leuprolide.

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 hemoglobin decrease, neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, hyperphosphatemia, and hypercalcemia.

Hypertension: In the combined data from five randomized placebo-controlled clinical trials, hypertension was reported in 14.2% of XTANDI patients and 7.4% 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:

  • nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR)
  • metastatic castration-sensitive prostate cancer (mCSPC)
  • castration-resistant prostate cancer (CRPC)

Please see Full Prescribing Information.

Important Safety Information

Warnings and Precautions

Seizure occurred in 0.6% of patients receiving XTANDI in eight 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 eight 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 five randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (3.5% vs 2%). Grade 3-4 ischemic events occurred in 1.8% of patients on XTANDI versus 1.1% 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 five randomized, placebo-controlled clinical studies, falls occurred in 12% of patients treated with XTANDI compared to 6% of patients treated with placebo. Fractures occurred in 13% of patients treated with XTANDI and in 6% 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 five randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, diarrhea, hypertension, hemorrhage, fall, fracture, and headache. 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 ARs 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 ARs 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 AR as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

In PROSPER, the placebo-controlled study of nonmetastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AR 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 ARs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to ARs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

In EMBARK, the placebo-controlled study of nonmetastatic CSPC (nmCSPC) with high-risk biochemical recurrence (BCR) patients, Grade 3 or higher adverse reactions during the total duration of treatment were reported in 46% of patients treated with XTANDI plus leuprolide, 50% of patients receiving XTANDI as a single agent, and 43% of patients receiving placebo plus leuprolide. Permanent treatment discontinuation due to adverse reactions during the total duration of treatment as the primary reason was reported in 21% of patients treated with XTANDI plus leuprolide, 18% of patients receiving XTANDI as a single agent, and 10% of patients receiving placebo plus leuprolide.

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 hemoglobin decrease, neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, hyperphosphatemia, and hypercalcemia.

Hypertension: In the combined data from five randomized placebo-controlled clinical trials, hypertension was reported in 14.2% of XTANDI patients and 7.4% 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:

  • nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR)
  • metastatic castration-sensitive prostate cancer (mCSPC)
  • castration-resistant prostate cancer (CRPC)

Please see Full Prescribing Information.