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Metastatic castration-resistant prostate cancer (mCRPC) refers to prostate cancer that has spread outside the prostate and no longer responds to traditional androgen deprivation therapy (ADT). Patients have several different treatment options, including second-generation androgen-signaling-targeted inhibitors (ARTA) like abiraterone or enzalutamide, and chemotherapy drugs (docetaxel, cabazitaxel). However, for patients whose disease progresses after treatment with one ARTA and with docetaxel, questions remain: Should the patient switch to the other ARTA? Should a chemotherapy drug be used?

The results of the CARD trial, an ambitious study presented at the 2019 European Society of Medical Oncology (ESMO) Congress, shed light on what the next step should be. Cabazitaxel, an FDA-approved drug, was shown to be more efficacious with similar toxicity as third-line treatment in patients who had received one ARTA and were progressive on this drug within 12 months, and had also received docetaxel.

At ESMO, researcher Dr. Ronald de Wit, MD, PhD, of Erasmus Medical Center, presented the trial results. Dr. Silke Gillessen, MD, of the University of Manchester, The Christie NHS Foundation Trust, and Kantonsspital St. Gallen, provided additional context during her discussion of the CARD trial, a phase 3 randomized-controlled trial that examined patients with mCRPC who received a third line-treatment after one ARTA and docetaxel, independent of the sequence. The trial included 255 mCRPC patients whose disease had progressed after treatment with two previous regimens: patients must have received and progressed within 12 months on an ARTA (enzalutamide or abiraterone), and must have received at least 3 cycles of docetaxel; the chemotherapy could have been given in the castration-sensitive or the castration-resistant state. Patients were randomized into two groups: 1. receive cabazitaxel OR 2. receive the alternative ARTA (enzalutamide or abiraterone).

Results showed that patients who received cabazitaxel experienced significantly better outcomes, including radiographic progression-free survival (no worsening of disease on scans; median of 8.0 months with cabazitaxel vs 3.7 months with the ARTA) which was the primary endpoint, reduction in PSA levels by at least 50% (35.7% vs 13.5% of patients), tumor shrinkage (36.5% vs. 11.5% of patients), and reduced pain than those who received the alternative ARTA (45.0% vs. 19.3% of patients). Additionally, toxicity from cabazitaxel seemed not worse vs the other study drug, (adverse events of Grade 3 or higher, 56.3% vs 52.4% of patients).

What does this mean for patients and physicians? The question of what is the optimal next line of treatment for patients fit for chemotherapy who have received docetaxel plus one line of ARTA and were progressing under the first ARTA within 12 months is answered with this trial. Gillessen notes that we need to resist “chemophobia.” Cabazitaxel is a new standard of care for third-line treatment in patients who have progressive disease after docetaxel and progressed within one year or less of abiraterone or enzalutamide and who are fit enough to tolerate chemotherapy.

“Before this trial, we knew from other trials that the response rates and duration of response, if any, to the alternate ARTA were low. This trial has shown very elegantly in a representative patient population, and in a randomized, prospective design, that cabazitaxel is superior in this setting. While only 13% of patients in this trial had docetaxel in the castration-sensitive setting and only one patient had abiraterone in the castration-sensitive setting, we will see these treatments being given in the castration-sensitive setting more frequently,” said Dr. Gillessen.  “The question remains how to treat patients with a very good response to the first ARTA of longer than 12 months. One may also raise the question if 20mg/m2 of cabazitaxel would be sufficient (a lower dose than the 25mg/m2 dose given in the trial). So, in summary, the authors have for the first time demonstrated a survival benefit in a third-line setting in a randomized trial, and that is a big step in the right direction, but some questions remain still unanswered.”

About Jason Musni

PCF