Coupling Novel Approaches With Chemo in Advanced Prostate Cancer

Daniel J. George, MD

Data from the phase III CARD trial suggest that sequencing cytotoxic chemotherapy with novel androgen receptor (AR)-directed therapy has a role in the metastatic castration-resistant prostate cancer (mCRPC) setting, explained Daniel J. George, MD.

“Prostate cancer is really in a dynamic state right now,” said George. “It's an exciting time for patients, caregivers, and physicians alike.”

Patients in the CARD trial had mCRPC and progressed on docetaxel and either abiraterone acetate (Zytiga) or enzalutamide (Xtandi), he explained. According to data presented at the 2019 ESMO Congress, patients in the study who received cabazitaxel (Jevtana) as third-line therapy experienced an 8-month median radiographic progression-free survival (rPFS) versus 3.7 months in those who received whichever AR inhibitor they had not progressed on (HR, 0.54; 95% CI, 0.40-0.73; P <.001). Moreover, overall survival (OS) was 13.6 months and 11.0 months in the cabazitaxel and AR inhibitor arms, respectively (HR, 0.64; 95% CI, 0.46-0.89; P = .008).

In an interview with OncLive, George, a professor of medicine and surgery, and member of Duke Cancer Institute, discussed staples of treatment in metastatic prostate cancer as well as novel therapies and emerging strategies in the field.

OncLive: Could you discuss some of the agents that have entered the prostate cancer paradigm?

George: For the past 7 years, we have focused primarily on hormonal therapy, particularly androgen deprivation therapy, for patients with metastatic prostate cancer. Over the past few years, that landscape has changed, with data showing the clinical benefit associated with the upfront use of docetaxel, abiraterone acetate, and most recently, AR antagonists such as apalutamide (Erleada) and enzalutamide in metastatic hormone-sensitive prostate cancer. The repercussions of that are being felt downstream. Now, we're seeing patients entering into the castration-resistant setting who have been exposed to some of these drugs.

We're going to have an opportunity to treat earlier, with novel agents that are going to show promise in that post-AR and post-chemotherapy setting; with other cytotoxic approaches that are targeting the disease with radiopharmaceuticals, such as radium-223 dichloride (Xofigo), docetaxel, cabazitaxel; or other targeted approaches, such as prostate-specific membrane antigen (PSMA)—directed therapy. Room has opened for more clinical trials. Patients are going to live longer and have more time to go on those studies, which is exciting. We're going to have an opportunity to treat patients earlier in the disease with life-prolonging therapies. We're going to begin to see some of these [approaches used] in the curative setting. Moving our investigational agents from the late-stage setting all the way into the early-stage setting is probably the most exciting change that has happened in the field. It's a paradigm shift with regard to how we consider the management of our patients with advanced prostate cancer.

Could you elaborate on some of these promising agents?

Downstream of the AR, there's a lot of work to be done in understanding how to couple that strategy with other treatments; they wouldn't necessarily have to be sequential. Some really novel approaches are looking at other transcription factors, such as EZH2 and DNA-dependent protein kinase catalytic subunits that could really modulate resistance to AR in ways we haven't done before. We also saw some data on the use of PARP inhibition. Right now, that [approach] may just be examined in selected patients, but in the future, that may be explored in unselected patients.

Additionally, we are going to see some novel ways to target AR besides just the ligand [binding] domain. Lastly, immunotherapy strategies are going to [emerge in] this space. PSMA-targeted strategies are coming, and it's an exciting time to see not just one strategy, but several come into the field. These strategies are going to include radiopharmaceuticals as well as bispecific antibodies. It's an exciting time for novel mechanisms in this field.

The results of the CARD trial were presented at the 2019 ESMO Congress. Could you discuss the rationale for that study?

The CARD trial was a unique design in advanced prostate cancer, partly because it dealt with the question of sequencing. This is a study in which investigators looked at patients with mCRPC who had been previously treated with docetaxel and an AR-signaling targeted therapy, either abiraterone or enzalutamide. This is an area where we have had a paucity of data regarding what to do next. Several possible treatment options exist. Patients can receive chemotherapy with cabazitaxel, either abiraterone or enzalutamide, radium-223, or other palliative supportive care. A lot of variation exists in terms of treatment patterns out there due to a lack of data.

The CARD trial randomized 224 patients to receive cabazitaxel at 25 mg/m² versus 1000 mg of daily abiraterone or 160 mg of daily enzalutamide. The choice of which hormone therapy to give depended on what the patient had previously received, so whatever they had been given prior, they received the opposite [in this trial]. Patients were followed for rPFS and OS. Results showed a big difference in rPFS in favor of cabazitaxel. In some ways, that is not surprising because cabazitaxel was FDA approved specifically for use in the post-docetaxel setting. However, it is surprising in that [the agent] has never been tested after abiraterone and enzalutamide.

What were the results of the trial?

Results showed an 8-month median progression-free survival (PFS) versus just 3.7 months for the opposite AR-signaling targeted agent with a hazard ratio of 0.54, which is a pretty dramatic difference. Moreover, a statistically significant difference in OS was observed, again, in favor of cabazitaxel, with a median OS of 13.6 months versus 11 months with the AR-directed strategies. [These findings] suggest that this idea of using sequential AR-targeted strategies doesn't work in this patient population. The 3.7-month median time to progression is what we would expect for placebos in this setting. To some extent, we're not seeing any clinical benefit there. The 8-month improvement in radiographic PFS associated with cabazitaxel translates into a survival benefit, so we can't underutilize our chemotherapy in these patients if extending OS is our goal.

How have these results changed treatment sequencing?

With these data, when someone who has been treated with an AR-targeted agent and chemotherapy has progressed, I'm going to be more compelled to [use cabazitaxel] knowing it has a proven survival benefit. What is difficult is looking at other agents in class, such as radium-223, and understanding where that falls. We are going to want to see more data with other agents in this setting. As far as cabazitaxel goes, we now have a second study demonstrating a survival benefit with that sequence.

In my daily practice, I'm going to educate patients about this approach of using sequential chemotherapy. It's important for others to realize that if we give patients chemotherapy, it's not for the rest of their lives. We can sequence other therapies, and we can sequence back to chemotherapy. Even if patients didn't necessarily have a durable response to docetaxel, they can get a PFS benefit and an OS benefit with cabazitaxel. We have to help others understand early on that this is a long course; there are going to be multiple lines of therapy. As such, we shouldn’t be afraid to use chemotherapy in a setting where we can revisit it again with a second survival benefit.

de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer [published online September 30, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1911206.