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CARD Trial Regimen After AR-Targeted or Chemotherapy
Metastatic Castration-Resistant Prostate Cancer: Real-World Implications of the CARD Study
Results from the CARD study confirmed that cabazitaxel treatment should represent the standard of care for men with metastatic castration-resistant prostate cancer (mCRPC) whose disease has progressed within 12 months despite docetaxel treatment. Treatment with cabazitaxel led to longer imaging-based progression-free survival (PFS) and overall survival (OS) than treatment with an androgen-signaling (AS)–targeted inhibitor among patients with mCRPC who had previously received docetaxel and the alternativeAS–targeted inhibitor (abiraterone or enzalutamide).1
Background and Epidemiology
Prostate cancer is the leading cause of new cancer cases among men in the United States.2 Estimates suggest that 191,930 new cases of prostate cancer will be diagnosed in the United States in 2020, and that roughly 33,000 men will die from the disease.2 Approximately 6% of all prostate cancers are metastatic in nature3; those patients with metastatic disease have a 5-year survival rate of only 31% compared with a 5-year relative survival rate of nearly 100% in patients whose disease is discovered at a local or regional stage.2
The majority of metastatic prostate cancer cases are considered castration resistant,4 meaning that the disease has spread to other parts of the body despite androgen deprivation therapy.5 Although many cases of metastatic disease are initially hormone-sensitive, progression to mCRPC is almost inevitable, occurring over an average of 13.1 months in this patient population.6 In a retrospective analysis of a large claims database, 65% of patients with hormone-sensitive metastases progressed to mCRPC over a follow-up period of 4 years (2013-2016).7
According to model-based predictions, the incidence of mCRPC will reach 42,970 cases in 2020, compared with an incidence of 36,100 cases in 2009.8 From 2011 to 2015, there was a decline of 7% per year in total prostate cancer incidence, which has been attributed to decreased screening after the US Preventive Services Task Force published recommendations against routine prostate-specific antigen (PSA) testing in 2008 and 2012.9 However, the effect of reduced screening on the incidence of advanced disease, such as mCRPC, is being studied closely. According to Negoita and colleagues, the overall decline in prostate cancer incidence masks an increase in distant-stage diagnoses across all ages and racial groups studied since 2010.10 Li and colleagues found that distant-stage prostate cancer incidence increased at an annual percentage change of 3.3% from 2010 to 2014,11 and in men 75 years or older, the incidence of metastasis at diagnosis began increasing after hitting a low point in 2011.12
The overall mortality rate for prostate cancer declined significantly from 1993 to 2016, dropping from 39.3% to 19.4%.3 This decline was primarily due to reductions in smoking and advances in early detection and treatment.9 However, the mortality rate stabilized at roughly 19% from 2013 to 20173; this leveling of rates coincides with a decline in PSA testing and an increase in distant-stage diagnoses.9 Mortality rates are highest among patients with metastatic disease. A model-based analysis estimated that the mortality rate for mCRPC was 55.3% in 2009.8 Although mortality rates for mCRPC may have decreased slightly since that time because of advances in treatment, a real-world retrospective data analysis of approximately 3700 men with mCRPC from 2008 to 2018 found 50% mortality over a 1.5-year (538-day) study period.13
Current Standard of Care
According to guidelines from the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and Cancer Care Ontario, patients with mCRPC should continue to receive androgen deprivation therapy with a luteinizing hormone-releasing hormone agonist or antagonist regardless of additional therapies,14 with the goal of maintaining castrate levels of serum testosterone below 50 ng/dL.15 Patients without visceral metastases have multiple options for add-on treatment. For asymptomatic patients, immune therapy with sipuleucel-T is a reasonable first option, as is therapy with an AS–targeted inhibitor (enzalutamide or abiraterone with prednisone). Another option is abiraterone with methylprednisolone.15 Chemotherapy with docetaxel plus concurrent steroid is the mainstay of treatment for patients with symptomatic metastases. Although not commonly used in patients without symptoms, it may be considered in those patients who rapidly progress.15 Radium 223 is considered a first-line option for patients with symptomatic bone metastases without visceral extension. Additional options for these patients include clinical trial participation and other secondary hormone therapy (eg, first-generation antiandrogen, antiandrogen withdrawal, ketoconazole with or without concurrent hydrocortisone, corticosteroid, diethylstilbestrol, or other estrogens).15
For patients with mCRPC and visceral metastases (defined as those occurring in the lung, liver, adrenal gland, peritoneum, or brain), docetaxel and a concurrent steroid (prednisone) is the preferred first-line treatment.15 Enzalutamide is another initial option, whereas abiraterone should be reserved for patients who are not candidates for docetaxel. Mitoxantrone is an option for patients who cannot tolerate docetaxel15; although it has not improved survival in this clinical scenario, it has shown quality-of-life (QOL) benefit.14 Alternatively, patients can participate in a clinical trial, choose secondary hormone therapy (as described previously), or opt for supportive therapy. Radium 223 by itself is specifically not recommended in this scenario.15
Patients who suffer disease progression with enzalutamide or abiraterone can either choose chemotherapy with docetaxel or switch to the alternative AS–targeted inhibitor (abiraterone if previously on enzalutamide; enzalutamide if previously on abiraterone). Additional options include sipuleucel-T and radium 223 in appropriate patients, and pembrolizumab in patients with microsatellite instability-high or mismatch repair-deficient tumors.15
If the disease progresses despite docetaxel treatment, chemotherapy with cabazitaxel is a standard-of-care option.15 Abiraterone with prednisone or enzalutamide are additional next-line options, provided they were not used prior to docetaxel treatment.15 Previous treatment with an AS–targeted inhibitor has been shown to confer at least partial cross-resistance with docetaxel therapy, potentially because docetaxel exerts some of its antitumor activity by disrupting the same androgen-receptor–signaling pathway.16 Additional treatment options for patients whose disease progresses despite docetaxel therapy would be based on disease presentation, extent of metastases, life expectancy, and prior therapies received.15
Cabazitaxel and the CARD Study
Cabazitaxel improves survival in patients with mCRPC whose disease progresses on docetaxel treatment. It was the first drug to receive FDA approval for this clinical scenario and is currently considered a standard of care for patients whose disease progresses despite chemotherapy with docetaxel.17 Although cabazitaxel and docetaxel are both taxanes, cabazitaxel does not appear to share the same cross-resistance concerns with prior AS–targeted inhibitor therapy.17 Prior treatment with either enzalutamide or abiraterone did not negatively influence PSA response or OS in men with mCRPC who were subsequently treated with cabazitaxel.18 Additional in vivo data showed cross-resistance between enzalutamide and docetaxel, but not between enzalutamide and cabazitaxel.19 This is likely due to cabazitaxel exerting greater antitumor activity via androgen receptor–independent mechanisms,19 as well as its faster uptake into cancer cells and longer intracellular retention times compared with docetaxel.20
AS–targeted inhibitors and docetaxel are both considered standard first-line treatments for patients with mCRPC,14 and are frequently used in earlier stages of the disease. Patients who are candidates for additional chemotherapy likely will have received both therapies.1 The CARD study investigated whether chemotherapy with cabazitaxel would be superior to treatment with an AS–targeted inhibitor in patients with mCRPC who had disease progression despite prior treatment with both docetaxel and the alternative AS–targeted inhibitor (enzalutamide or abiraterone).1
Patients eligible for the CARD study had achieved sufficient androgen deprivation (defined as castrate levels of serum testosterone < 0.5 ng/mL). They also had disease progression despite previous treatment with both docetaxel (≥ 3 cycles) and 12 months of either abiraterone or enzalutamide (given prior to or after docetaxel treatment). Progression at enrollment was classified as: (1) PSA progression only, (2) imaging-based progression only (defined as tumor growth or the presence of at least 2 new bone lesions); or(3) pain progression.1
Eligible patients were randomly assigned 1:1 to receive either cabazitaxel (25 mg/m2 of body surface area intravenously every 3 weeks) plus 10 mg of prednisone daily and prophylactic granulocyte colony-stimulating factor, or the alternative oral AS–targeted inhibitor (either 160 mg of enzalutamide daily or 1000 mg of abiraterone daily plus 5 mg of prednisone twice daily). Treatment was open label and was terminated if patients experienced imaging-based disease progression or unacceptable adverse effects (AEs), started different treatment, or requested the discontinuation of study drug.1
The primary end point for the study was imaging-based PFS, defined as time from randomization to tumor growth, occurrence of new bone lesions, or death. Secondary end points included OS; PFS; PSA, tumor, and pain responses; first occurrence of a symptomatic skeletal event; and safety.1
A total of 255 patients comprised the intention-to-treat population and were randomly assigned to treatment with either cabazitaxel (n = 129)or the alternative AS–targeted inhibitor (n = 126). Of these patients, 250 received treatment: 126 with cabazitaxel, 58 with abiraterone, and 66 with enzalutamide. The median age of treated patients was 70 years, and 31% of patients were aged at least 75 years. Patients receiving cabazitaxel had a longer median duration of treatment (22 weeks vs 12.5 weeks in the comparator arm). Among patients who discontinued treatment, those who received abiraterone or enzalutamide were more likely to stop treatment because of disease progression (71.0% vs 43.7% of discontinuations with cabazitaxel). Conversely, those who received cabazitaxel were more likely to stop treatment because of an AE (19.8% vs 8.9% of discontinuations with abiraterone or enzalutamide).1
After a median follow-up of 9.2 months, results for the primary end point significantly favored cabazitaxel treatment. Imaging-based disease progression or death from any cause occurred in 95 patients (73.6%) in the cabazitaxel arm and in 101 patients (80.2%) who received 1 of the 2 AS–targeted inhibitors (HR, 0.54; 95% CI, 0.40-0.73; P < .001). The median time of imaging-based PFS was 8 months with cabazitaxel and 3.7 months with abiraterone or enzalutamide. Results for the primary outcome were consistent across different ages of patients (< 70 or ≥ 70 years), type of progression noted during the trial, as well as those with different timing of AS–targeted inhibitor (before or after docetaxel) and those with visceral metastases at randomization.1
A post hoc analysis showed that cabazitaxel was superior to therapy with an AS–targeted inhibitor regardless of whether patients received abiraterone or enzalutamide in the comparator arm (imaging-based progression or death with cabazitaxel vs enzalutamide: HR, 0.57; 95% CI, 0.36-0.90; and cabazitaxel vs abiraterone: HR, 0.44; 95% CI, 0.29-0.67). In addition, post hoc multivariate Cox regression analyses employed several models (each including 3 stratification factors [eg, PSA level, age, testosterone level, and presence of visceral metastases]) to confirm the robustness of the primary outcome results from the intention-to-treat analysis.1
The key secondary end point of OS also significantly favored cabazitaxel treatment. Death from any cause occurred in 54.3% of patients in the cabazitaxel group and 65.9% of patients who received an AS–targeted inhibitor (HR, 0.64; 95% CI, 0.46-0.89; P = .008). The median OS was 13.6 months with cabazitaxel compared with11 months in the comparator arm. Other secondary end points including PFS; PSA, tumor, or pain responses; and occurrence of a symptomatic skeletal event also favored cabazitaxel.1
The incidence of a serious AE of any grade was similar across treatment groups (38.9% in the cabazitaxel group compared with 38.7% of patients who received an AS–targeted inhibitor), as was the incidence of grade 3 or higher AEs (56.3% vs 52.4%, respectively). Patients in the cabazitaxel group were more likely to discontinue treatment because of a serious AE than those who received an AS–targeted inhibitor (19.8% vs 8.9%, respectively), although AEs leading to death occurred less frequently with cabazitaxel (5.6% vs 11.3%, respectively). Among AEs grade 3 or higher, those reported more commonly with cabazitaxel were peripheral neuropathy (3.2% vs 0%), asthenia or fatigue (4% vs 2.4%), diarrhea (3.2% vs 0%), and febrile neutropenia (3.2% vs 0%); those reported less commonly were renal disorders (3.2% vs 8.1%), cardiac disorders (0.8% vs 4.8%), spinal cord or nerve root disorders (2.4% vs 4.0%), and musculoskeletal pain or discomfort (1.6% vs 5.6%).1
Quality-of-Life Impact
Results from the CARD study (NCT02485691) showed clear benefit for imaging-based PFS and OS with cabazitaxel treatment compared with the alternative AS–targeted inhibitor.21 Although objective survival measures are of paramount importance when assessing cancer therapies, measures that affect QOL may be of equal or greater importance to patients.22 Thus, Fizazi and colleagues sought to further investigate changes in pain and health-related quality of life (HRQOL) among patients enrolled in the CARD study.21
Results of the study, by Fizazi and colleagues, were presented in abstract form at the 2020 American Society of Clinical Oncology Virtual Scientific Program. In this study, pain response was defined as a decrease of greater than 30% from baseline in Brief Pain Inventory-Short Form intensity score, without the aid of increased analgesic use.21 Of the 255 patients randomized in the CARD study, 172 (67.5%) had moderate to severe pain at baseline. Pain response was evaluable for 111 (86%) of patients in the cabazitaxel group and for 109 (86.5%) of patients who received an AS–targeted inhibitor. Cabazitaxel treatment was associated with both improved pain response and delayed pain progression. The probability of not experiencing pain progression after 12 months was 66.2% with cabazitaxel and 45.3% with abiraterone or enzalutamide (HR, 0.55; 95% CI, 0.32-0.97; P = .0348).21 These results substantiated pain response data from the original CARD study, in which de Wit and colleagues found that 45.9%of patients in the cabazitaxel group achieved a favorable pain response compared with only 19.3% of those who received an AS–targeted inhibitor (P < .001).1,21
The Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire was used to assess HRQOL. To be considered evaluable, patients were required to have received at least 1 dose of study drug and to have both a baseline and at least 1 subsequent FACT-P score. A difference in score of 10 points (in either direction) from baseline was considered clinically meaningful. Of the 255 patients randomized in the CARD study, HRQOL was evaluable for 108 (83.7%)of patients in the cabazitaxel group and for114 (90.5%) of patients who received 1 of the 2 AS–targeted inhibitors. Treatment with cabazitaxel and 1 of the 2 AS–targeted inhibitors yielded similar trends in FACT-P scores (improvement in 25% and 22.8% of patients; deterioration in 22.2% vs 24.6%, respectively). The median time to FACT-P deterioration was 14.8 months in the cabazitaxel group and 8.9 months in the AS–targeted inhibitor group, trending in favor of cabazitaxel but not reaching clinical significance (HR, 0.72; 95% CI, 0.44-1.20; P = .2072).21
Conclusions
Despite advances in treatment, prostate cancer remains the second-leading cause of cancer-related deaths among men in the United States. Androgen-deprivation therapy remains the cornerstone of therapy for men with mCRPC.However, men with mCRPC require additional treatments to slow disease progression, and not all cases will be responsive to first-line therapy. The CARD study confirmed that cabazitaxel should represent the standard of care for patients with mCRPC whose disease has progressed despite docetaxel therapy. In addition to reducing imaging-based disease progression and improving OS compared with the alternative AS–targeted inhibitor, cabazitaxel was found to improve pain response, delay pain progression, and help men with mCRPC maintain their QOL.
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