Expert Discusses State of Immunotherapy in Prostate Cancer

Susan F. Slovin, MD, PhD

Advancements in immunotherapy in the field of prostate cancer have been slow ever since the FDA approval of sipuleucel-T (Provenge) several years ago.

“It’s an exceptionally challenging area. After the success of sipuleucel-T, there have been combinatorial approaches using radiopharmaceuticals, such as radium-223, the checkpoint inhibitor ipilimumab (Yervoy), as well as some chemotherapy regimens,” says Susan F. Slovin, MD, PhD.

OncLive: Can you give an overview of your talk on immunotherapy in prostate cancer?

In an interview with OncLive at the 2017 Interdisciplinary Prostate Cancer Congress, Slovin, a medical oncologist at Memorial Sloan Kettering Cancer Center, offered her expert insight on the current state of immunotherapy in prostate cancer.Slovin: Prostate cancer was among the first solid tumors to have a positive experience with immunotherapy. Until that time, I don’t believe that any solid tumor malignancy—whether it was kidney cancer, prostate cancer, or lung cancer—had any sort of success with an immune approach. For the last 30 years, we’ve seen a variety of different platforms of immunotherapy, including vaccine and viral vectors, none of which showed any impact on prostate cancer.

What agents are being investigated in this space?

With the FDA approval of sipuleucel-T, this represented the first successful immunotherapy that showed a survival benefit for a solid tumor, which happened to be prostate cancer. All approaches that have been done subsequently are trying to look at other ways of using the body's immune system to fight the cancer.It's an exceptionally challenging area. After the success of sipuleucel-T, there have been combinatorial approaches using radiopharmaceuticals, such as radium-223, the checkpoint inhibitor ipilimumab, as well as some chemotherapy regimens.

More recently, the checkpoint inhibitors have been extremely interesting. There have been at least 3 phase I and II trials of the CTLA-4 inhibitor ipilimumab. The original phase I and II trial was done with and without radiation and gave a signal that perhaps there was some long-term durable responses, although not without autoimmune events, such as hypothyroidism and rashes. This is all thought to be an on-target effect of these antibodies.

Overall, where would you say immunotherapy is at this point in prostate cancer?

What’s happened is that 2 phase III trials—1 prechemotherapy and 1 post-chemotherapy—have not shown or confirmed an overall survival benefit. While there have been several long-term responses, neither trial confirmed ipilimumab to be a standard of care in patients with castrate-resistant metastatic disease who either have or have not received chemotherapy, particularly docetaxel. We have made tremendous strides looking at different immune-based platforms, which is 1 of the benefits that I'm seeing now. There is a suggestion now that the anti—PD-1 agent pembrolizumab (Keytruda) may be generating a signal in patients with much more end-stage disease, particularly those with visceral metastases. It's interesting, because in 1 of the early phase III trials, this metastasis was thought to be an adverse prognostic indicator to the fact that people would not do well. However, using anti–PD-1 surprisingly ended up resulting in some patients having significant declines in PSA and radiographic improvement.

Other approaches being evaluated include the PROSTVAC platform, which is a transgene of PSA in a fowlpox vector given with 3 immune stimulatory molecules. Then you have these new checkpoint inhibitors, as well as a variety of other molecules to which immunotherapies are being developed, including molecules we call VISTA, LAG-3, FoxP3.

What would you want the main takeaways to be from your talk?

There are a lot of new targets—it’s just that we're waiting, because it takes a while for the immunotherapies to kick in. They don’t work immediately, hence the delay in development.The takeaway message is that people go through the various treatments over a time as their disease transforms in a dynamic process. We should be collecting tissues, blood, plasma, and circulating tumor cells—all of this is going to be helpful in looking at our ability to correlate certain changes with the treatments that patients are getting.

Is there anything else you want to highlight?

One of the major concerns about immunotherapies is that patients have been able to have some signal that the immune system kicked in, either using enzyme-linked immunospot assays suggesting that T cells are being activated, or the development of antibodies suggesting that whatever molecule you're using to introduce into the body, the immune system is recognizing it. However, many of these readouts are not correlating with the change in the biology of the cancer. To know that something works, is going to be a benefit, and should be approved, will depend on whether or not an immune endpoint correlates to a change in the biology of the cancer. Simply generating an antibody does not equal a response. You must show that something has changed in that cancer. That is what we have not been able to observe with a lot of these platforms. I think the most important thing is we must continue this work. The one thing that troubles me is that everybody thinks an immunotherapy means checkpoint inhibitors, but it doesn't. Through the last 30 or 40 years, immune-based therapy has encompassed antibodies, chimeric antigen receptor T cells, novel constructs, DNA vaccines, and peptide vaccines. Checkpoint inhibitors have just recently arrived on the scene.

A problem is that everybody associates immunotherapy with those drugs, but it’s not just that alone. It's the whole platform of different approaches, passively or adaptively using the body's immune system, either from active mechanisms themselves or by giving a patient something that will work on the body's behalf. I am hoping it will be very fruitful over the next 5 years.