Sequencing the Treatment of Metastatic Castration-Resistant Prostate Cancer

Cassandra Hacker, PharmD
PGY-2 Oncology Pharmacy Resident
Barnes-Jewish Hospital
St. Louis, MO

Katie Lentz, PharmD BCOP
PGY-2 Oncology Residency Program Director
Oncology Clinical Pharmacy Specialist
Barnes-Jewish Hospital
St. Louis, MO

Prostate cancer is the second most common cancer among males, with an estimated 191,130 new cases in 2020, and the second leading cause of cancer-related death in males in the United States.^1,2 Localized and regional disease confers a relatively optimistic prognosis, with 5-year overall survival of 100% versus 30% for patients with advanced disease.2 Treatment of advanced prostate cancer is driven by androgen deprivation therapy via surgical or medical castration with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist, with or without an antiandrogen or abiraterone.² The goal is to achieve castrate levels of testosterone <50 ng/dL to reduce hormonal stimulation of cancer growth. Eventually, many patients with metastatic disease develop castration resistance, known as metastatic castration-resistant prostate cancer (mCRPC), characterized by cancer progression despite the use of standard androgen deprivation therapy and maintainence of  castrate levels of testosterone.^2,3

The recommended treatments used in the mCRPC setting include taxanes (docetaxel and cabazitaxel), androgen-signaling-targeted inhibitors (ASTIs) (abiraterone and enzalutamide), sipuleucel-T, and radium-223 dichloride.⁴ Cabazitaxel is a next-generation taxane approved for mCRPC in patients previously treated with a docetaxel-based regimen.⁵ It has been shown to retain activity in patients who previously failed treatment with docetaxel or an ASTI.^5-7 Abiraterone inhibits CYP17A1, an essential enzyme involved in androgen synthesis, which is often upregulated in mCRPC and contributes to resistance.⁸ Enzalutamide inhibits the androgen receptor and is able to overcome upregulated androgen-receptor expression implicated in resistance and disease progression.⁹ Historically, minimal data were available to guide the sequence of therapies for mCRPC. This article summarizes recently published studies evaluating the sequencing of cabazitaxel, abiraterone, and enzalutamide for mCRPC.

Cabazitaxel Versus Abiraterone or Enzalutamide in mCRPC: The CARD Trial

De Wit and colleagues conducted a multicenter randomized open-label trial at 62 sites across Europe, investigating whether cabazitaxel is superior to abiraterone or enzalutamide in mCRPC patients previously treated with docetaxel and an ASTI.¹⁰ Included were mCRPC patients previously treated with at least three cycles of docetaxel with disease progression occurring during 12 months of therapy with abiraterone or enzalutamide before or after the docetaxel. Patients were randomized 1:1 to receive cabazitaxel or an ASTI not previously given, and the treatments continued until imaging-based confirmation of disease progression, unacceptable toxicity, initiation of subsequent therapy, or another request to discontinue. Cabazitaxel was administered as 25 mg/m2 intravenously (IV) over 1 hour every 3 weeks plus prednisone 10 mg orally daily according to the European drug label. Abiraterone was administered as 1000 mg orally daily plus prednisone 5 mg orally twice daily to patients who had previously received enzalutamide. Enzalutamide was given as 160 mg orally daily to patients who had previously received abiraterone. Crossover to the opposite treatment arm was allowed upon disease progression. Patients were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status 0–1 versus 2, time to disease progression ≤6 months versus >6–12 months, and timing of previous ASTI before docetaxel versus after docetaxel. The primary outcome evaluated was imaging-based progression-free survival (PFS).

Between November 2015 and November 2018, 255 subjects were included in this study, with 129 patients randomized to receive cabazitaxel and 126 randomized to receive either abiraterone (n = 58) or enzalutamide (n = 66). The median duration of treatment was longer in the cabazitaxel group (22 weeks vs. 12.5 weeks), and more patients discontinued therapy in the ASTI group overall (63.5% with cabazitaxel vs. 79.9% with an ASTI), mostly because of disease progression (43.7% vs. 71%, respectively). At median follow-up at 9.2 months, median PFS was 8 months versus 3.7 months in favor of cabazitaxel (hazard ratio [HR] = 0.54, p < .001). Median overall survival (OS) was significantly improved with cabazitaxel (13.6 months vs. 11 months; HR = 0.64, p = .008). Prostate-specific antigen (PSA), tumor, and pain response rates were all improved with cabazitaxel (PSA response, 35.7% vs. 13.5%, p < .001; tumor response, 37% vs. 12%, p = .004; pain response, 45% vs. 19.3%).

In a comparison of safety outcomes, the proportion of patients with adverse effects (AEs) of any grade and serious AEs were similar (38.9% vs. 38.7% serious AEs). AEs leading to discontinuation were more common with cabazitaxel (19.8% vs. 8.9%), but cabazitaxel patients required fewer dose reductions (21.4% vs. 37.9%). The most common grade ≥3 AEs reported for cabazitaxel versus ASTI respectively were infection (7.9% vs. 7.3%), musculoskeletal pain (1.6% vs. 5.6%), fatigue (4% vs. 2.4%), diarrhea (3.2% vs. 0), and peripheral neuropathy (3.2% vs. 0).

The CARD trial concluded that mCRPC patients previously treated with docetaxel and an ASTI achieved significantly longer imaging-based PFS and OS with cabazitaxel versus the alternative ASTI, despite crossover between treatment arms. Statistically significant benefit or trend toward benefit with cabazitaxel was seen across all subgroups, including ECOG performance status 0–1 versus 2, timing of ASTI before or after docetaxel, disease severity, and type of previous progression.¹⁰ These results align with previous data revealing poor outcomes for patients immediately initiating an alternative ASTI after progression, likely because of similar resistance mechanisms between agents.¹¹ Regarding therapy sequencing, this trial suggests that cabazitaxel should be used before the alternative ASTI in subsequent treatment of mCRPC.¹⁰ Conclusions from this trial are limited by its open-label design, lack of blinding for central review of imaging, and geographic limitation to Europe using the approved European cabazitaxel dosage. In addition, the CARD study lacks a subgroup analysis evaluating efficacy specific to abiraterone followed by randomization to enzalutamide or cabazitaxel. It is unclear whether cabazitaxel would still be favored if this sequence was specified.

Sequencing of Enzalutamide and Abiraterone in mCRPC

Khalaf and colleagues conducted a randomized open-label trial at six centers in British Columbia, Canada, assessing the ideal sequencing of ASTIs in patients with newly diagnosed mCRPC (N = 202).12 Patients were randomized 1:1 to abiraterone 1000 mg orally daily plus prednisone 5 mg orally twice daily, followed by enzalutamide 160 mg orally daily after PSA progression (abiraterone-enzalutamide, n = 101), or the opposite sequence (enzalutamide-abiraterone, n = 101). Treatment continued until symptomatic or clinical disease progression, unacceptable toxicity, or patient withdrawal. Patients were allowed prior docetaxel treatment for castration-sensitive disease and had to maintain LHRH agonist treatment throughout the study if they had no history of orchiectomy. Patients were excluded if they had previously taken abiraterone, enzalutamide, or another experimental ASTI. Primary outcomes included time to second PSA progression (time from start of first-line treatment to confirmed PSA progression on second-line treatment, or death from prostate cancer before crossover, whichever occurred first) and proportion of patients with PSA response on second-line therapy.

Patients were enrolled from October 2014 to December 2016 and had a median 22.8 months follow-up for analysis of the intention-to-treat population. At data cutoff, 72% and 74% from the abiraterone-enzalutamide group and enzalutamide-abiraterone group, respectively, had crossed over to second-line therapy. For the primary outcomes, median time to second PSA progression was significantly longer in the abiraterone-enzalutamide group (19.3 months vs. 15.2 months; HR = 0.66, p = .036), and PSA response with second-line treatment was significantly higher with abiraterone-enzalutamide (36% vs. 4%; p < .0001). Median time to PSA progression on second-line treatment was also significantly longer with abiraterone-enzalutamide (3.5 months vs. 1.7 months; HR = 0.42, p < .0001). However, no significant difference was seen in median OS (28.8 months vs. 24.7 months; p = .23), nor in median time to first progression (11.2 months vs. 10.2 months; p = .78), although PSA response rate with first-line treatment was significantly higher with enzalutamide-abiraterone (68% vs. 82%; p = .023).

Regarding safety outcomes, serious AEs were more common with enzalutamide-abiraterone (15% vs. 20%), and more patients on enzalutamide required dose reductions (6% vs. 18% with first-line treatment and 19% vs. 5% with second-line treatment).

In summary, enzalutamide showed significantly improved activity as a second-line agent over abiraterone, with prolonged time to second progression and a higher PSA response rate. Each drug was equally effective in the first-line setting according to median time to first PSA progression, despite higher PSA response in the first-line setting with enzalutamide. This study suggests that the greatest clinical benefit comes from the sequencing of agents with abiraterone followed by enzalutamide. Improved time to second PSA progression in the abiraterone-enzalutamide group seems to have been driven by second-line activity of enzalutamide, which was improved compared with abiraterone. A possible mechanism behind the efficacy of enzalutamide in the second-line setting is its ability to overcome abiraterone resistance conferred by progesterone-activated, androgen receptor ligand–binding domain mutations L702H and T878A, found in approximately 15%–20% of mCRPC cases.^13,14

Conclusion

The CARD study suggests that cabazitaxel followed by an ASTI after relapse on docetaxel and the opposite ASTI is useful.¹⁰ Khalaf and colleagues compared sequences of ASTIs in the upfront setting of mCRPC treatment, with results showing improved outcomes using abiraterone followed by enzalutamide.12 Combining the results of these studies, new research questions emerge, such as whether cabazitaxel is more efficacious when used before or after abiraterone, and, similarly, whether abiraterone is more efficacious when used before or after docetaxel.

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