CARD Trial Data Show Efficacy for Metastatic Castration-Resistant Prostate Cancer

William K. Oh, MD

During a Targeted Oncology virtual Case-Based Roundtable event, William K. Oh, MD, chief medical science officer, Sema4 and clinical professor of Medicine, Icahn School of Medicine at Mount Sinai in New York, NY, reviewed the data from the CARD trial as he shared the case of a 75-year-old man with metastatic castration resistant prostate cancer (mCRPC) with a group of peers.

Targeted Oncology^TM: How do you decide which regimens to use for patients such as this?

OH: More chemotherapy is in fact associated with a survival benefit. This is one of the key issues about why you might select [a certain] treatment. Everyone is a caring oncologist and trying to do the right thing [for the patient’s] quality of life and length of life. I think that’s always a difficult decision. This patient had a lot of toxicities and had progression of cancer, so you’re trying to balance the risks of treatment with the survival benefits.

How was the CARD trial (NCT02485691) designed for patients in the mCRPC setting?

CARD [results were] presented at the 2019 European Society for Medical Oncology meeting and subsequently published in the New England Journal of Medicine.1 This [trial] was in a group of patients with mCRPC who had received both docetaxel and an androgen receptor [AR] targeted therapy, either enzalutamide or abiraterone [Zytiga]. Then they were randomized to receive cabazitaxel [Jevtana] versus the opposite AR targeted therapy. So if they had abiraterone, they got enzalutamide [and vice versa].

They had to progress quickly, like this patient, within 12 months. [Patients] received 25 mg/m² cabazitaxel, [although] that dose is not necessary anymore; 20 mg/m² is the approved dose, so this is higher…than you need. It’s just less toxic when you give 20 mg/m².

A significant number of these patients, over a third, were over the age of 75. Most of them had pain and all of them had either enzalutamide or abiraterone. The order didn’t matter; they could have received docetaxel before the AR targeted therapy or after.

What was the efficacy of this trial?

The primary end point [was radiographic progression-free survival (rPFS)] and the secondary end point of overall survival [OS] was significantly different. Even though it seems short, remember this is third-line therapy. Cabazitaxel had an 8-month rPFS versus 3.7 months with AR therapy. There was a hazard ratio of 0.54 with a highly significant P value [of .001].

If you looked at the rPFS subgroups, all of them favored cabazitaxel compared with a second AR targeted therapy: performance status high, [before or after] docetaxel, older or younger patients, and visceral or nonvisceral metastases. Every single group was to the left of 1.00, suggesting that there were no subgroups for whom chemotherapy was neutral. It was also deemed to be associated with the better rPFS.

What convinced the New England Journal of Medicine to publish this were the OS data. The median difference was small, 2.6 months [13.6 months with cabazitaxel vs 11.0 months with AR targeted therapy]. But the hazard ratio is quite significant, 0.64 with a P value of .008. This is thirdline therapy. We know some patients won’t benefit from more chemotherapy, but these were all patients who got chemotherapy and an AR targeted therapy. And this suggests that if the goal is to improve survival, you should be thinking about an additional round of chemotherapy—in this case, with cabazitaxel.

I find that cabazitaxel has less neuropathy. Another advantage of cabazitaxel is that the men don’t lose their hair as much. It seems to be generally a little bit better tolerated.

Please expand on some other study details, such as the PSA, tumor, and pain responses, as well as the safety profile for cabazitaxel.

If you look at PSA responses—we still unfortunately spend a little too much time focused on PSA—[it] was 35% with more chemotherapy versus 13% with enzalutamide or abiraterone in this third-line setting. It was the same thing with objective tumor response. And if you want to focus on quality of life, the pain response was also better with cabazitaxel. The time to [symptomatic skeletal] events favored cabazitaxel.

I think, as experienced oncologists, we have the ability to adjust the dosing of cabazitaxel. I start with 20 mg/m², but sometimes I’ll start with 15 mg/m² if I’m worried about the patient, let’s say his tolerability. I think it’s reasonable to do that, [then] try to get them up to 20 mg/m2, but you don’t have to use 25 mg/m².

The chemotherapy had [slightly] more adverse events [AEs], but about twice as many patients had AEs leading to treatment discontinuation. AEs leading to death were probably related to progression of cancer, not from the drug itself, because there were twice as many deaths in the enzalutamide or abiraterone arm.

Do you give patients growth factors after you give cabazitaxel?

I do. I don’t want my patients to come into the hospital. They didn’t routinely do it in the study, but I find that in these older patients who are now getting second-line chemotherapy, I usually use both.

_REFERENCE:

_{de Wit R, de Bono J, Sternberg CN, et al; CARD Investigators. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206}