The CARD and PROfound Trials for Metastatic CRPC

Daniel J. George, MD: I want to pivot to our last section because this is our largest section. This is probably the area where we’re seeing the biggest changes in the field now in 2020, and that is in metastatic castration-resistant prostate cancer. Just to set the stage, we’re all aware of the progress that’s been made over the last 15 years with taxanes like docetaxel; in just the last 10 years with a number of newer agents, like cabazitaxel, sipuleucel-T, and radium; and over the last 7 years or so in our androgen-targeted strategies like abiraterone and enzalutamide in this metastatic castration-resistant setting. There are now some new developments going on in the field, and we’re beginning to understand a bit more about sequencing of drugs and recognizing the impact of that. When we sequence from 1 drug to another and 1 of those agents doesn’t work, we’ve essentially delayed the time to the next therapeutic benefit.

As Chuck mentioned earlier, those delays can have significant impact on overall survival. We’ve learned that from some of these crossover studies, so I want to spend some time talking about that. We’re moving beyond the 1 or 2 classes of agents and into a field where we have multiple targeted agents. We’ve just gotten some newer targeted agents with PARP inhibitors, and we’re getting potentially new targeted radiopharmaceuticals in the future. These classes of drugs are going to continue to expand, and it’s going to be ever more important that we make the right decisions, in terms of order, sequence, or combinations in the future.

Let’s dive into some of the data that have come out in the last 12 months. The first couple of studies were presented primarily at ESMO , but they’re still relatively fresh on our minds, in terms of the clinical implications of the CARD and PROfound studies. Tanya, I wonder if you could walk us through these studies and give us your initial thoughts on the clinical implications of their results.

Tanya Dorff, MD: The CARD study was super practice changing for me, personally. This was a study in which men with metastatic castration-resistant prostate cancer who had already been through abiraterone or enzalutamide were randomly assigned to cabazitaxel or the opposite AR [androgen receptor]–targeted therapy—abiraterone or enzalutamide—which was essentially the physician’s choice. I should mention that these men had also received docetaxel. What the study showed is a significant prolongation in radiographic progression-free survival, which was the primary end point but also a trend toward overall survival—11 months for AR-targeted therapy versus 13.6 months for cabazitaxel.

What really struck me, and you alluded to this, is they had a significant improvement in pain. One thing that was unique is most of the patients getting onto the study had not progressed just by PSA . Something like 70% of them had progressed based on pain, so it was a symptomatic progression. That’s a bit unique when we’re thinking about how to apply these data in our practice. Given that so many had pain, 45% of the cabazitaxel patients had pain benefit or pain relief, compared with 19% on the abiraterone or enzalutamide. We’re trying to help our patients live longer, but I always emphasize that we’re trying to help them live better, and that can be counterintuitive when you’re thinking about chemotherapy.

A lot of patients think of chemotherapy as something that’s going to make them feel worse. It’s important to emphasize that when we’re picking, we’re picking not just to help people live longer but to deal with palliation and control symptoms and skeletal-related events. Again, not to beat a dead horse, but that’s what drives morbidity in this disease, and overwhelmingly as these men suffer from bone metastases. So I found it very compelling.

Then you have PROfound. This was also very exciting, to see a new class of agents, PARP inhibitors, go head-to-head against a second-line abiraterone or enzalutamide. Again, this was a very similar population that had progressed through 1 of those agents and the control arm was physician’s choice. All these patients had to have a DNA-repair mutation—primarily BRCA1 or BRCA2, but there were also ATM mutations. I think PALB2, CHEK2, and a number of other mutations were eligible.

To find a progression-free survival advantage and overall survival benefit with an active comparator is really exciting. There was more placebo control here, but what we would consider a fairly active alternative choice. This really establishes the role for PARP inhibitors and speaks to the need for genomic testing and genetic testing in these patients, both germline and somatic. We need payers to cover this because there is a real survival implication for patients if we discover these mutations.

Transcript Edited for Clarity