What Options Are Emerging in Treatment-Resistant Prostate Cancer?

Katherine Banwell: 

Dr. Hahn, what are researchers learning about why some prostate cancers become resistant to treatment?

Dr. Andrew Hahn: 

That’s a good question. First, in prostate cancer, we’ve leaned on hormone therapy as an up-front treatment. This is androgen depravation therapy and other medicines to inhibit testosterone signaling.

It’s a really powerful up-front treatment. It helps men live longer. And it’s why median survival times for men living with metastatic prostate cancer are better than many other cancers. Yet we know that almost all prostate cancers will eventually become resistant and figure out ways to bypass that androgen receptor. You can deplete testosterone. And even when you deplete testosterone, these cancers will eventually figure out workarounds.

We’ve learned there are a number of different ways these cancers can do it. Sometimes it’s through loss of specific proteins that keep the cancer in control and not dividing too rapidly. That’s become a growing unmet need for us. Other times, it’s just mutations within the androgen receptor itself. Alternatively, you can have alterations where you basically bypass the androgen receptor to get into it.

Learning how these different resistance mechanisms evolve and how they work in parallel has informed new treatments and the sequencing of treatments too. Let me highlight one kind of totally new treatment that I’m really excited about that takes advantage of some of this knowledge. We know that the androgen receptor, AR, increases when patients’ cancer worsens on our hormone therapies.

So, this new therapy, it’s called an AR RIPTAC therapy, JNJ-6143, it comes in and it takes advantage of that, and it binds to the androgen receptor as basically a tool to get into the nucleus of the brain of the cancer cell. There it binds to a really essential protein called BRD4. It prevents it from doing its job. It just holds the two together, and the cancer cell dies. So, you can see that these advances in understanding how the cancer is resistant leads to new therapies that then maybe have a chance to really move the needle for men living with prostate cancer.

Katherine Banwell: 

Are there advances in treating treatment-resistant disease?

Dr. Andrew Hahn: 

Absolutely. This is where a lot of drug development is ongoing because it’s clearly our space of unmet need. When a patient’s cancer worsens on hormone therapy and becomes resistant to hormone therapy, unfortunately, our expectations, our hope of longevity will worsen at that timepoint. So, this is where drug development and clinicians and academic centers have put a lot of effort in.

And let me highlight, I’ll start with three broad drug classes. I’m going to go broad here with just drug classes because there’s so much happening in the space. First, I mentioned it in one of the other clips was these new therapies targeting the androgen receptor. I’ll highlight AR RIPTAC as a really exciting concept. There are new ones probably coming down the pipeline afterwards too.

But the JNJ-6143 is one of those that’s moving into later phase development. Then I’ll say in addition to targeting the androgen receptor, there’s a whole group of drugs called T-cell engagers. Historically, prostate cancer has not been very responsive to amino therapies that have been successful for other cancers. 

So, these T-cell engagers, what they’re aiming to do is they’re trying to grab a two-headed molecule as well. And they’re trying to grab a T cell on one end and bring it just in very close proximity or really close to the prostate cancer cell which it grabs with the other part. And it tries to jam the two together to make the immune system recognize the cancer and have your own immune system fight the cancer.

There are a lot of those currently in development that are very exciting. I’ll highlight drugs such as pasritamig, xaluritamig, and there’s another one from a company called Veer that was really exciting data as well.

And then finally, I’ll highlight antibody drug conjugates. We’ve known that prostate cancer can respond to chemotherapy for many decades now. And antibody drug conjugates are a step forward in designing targeted chemotherapies that hopefully have less toxicity and more effectiveness, so helping patients more. Lots happening there.