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Challenges in mCRPC Landscape Surround Sequencing, Biomarkers, and PARP Inhibition

Chelsea LoCascio
Published: Wednesday, Nov 22, 2017

On the other hand, for someone who has fragile diabetes or has a history of a bad reaction to prednisone, that might be someone for whom I would prefer to start with enzalutamide even though that prednisone level is fairly low. It's not supposed to be super physiologic; you do see some of the prednisone side effects. That’s a conversation that definitely some patients have strong opinions about when you bring that into the discussion.

If apalutamide gets approved, how could that agent fit into the mCRPC paradigm?

Well, it will depend a bit on how apalutamide’s approval comes through and in what context. Assuming it comes through for biochemical recurrence—for example, the SPARTAN trial— then the whole paradigm is just going to shift earlier and earlier. We’ve gone from using these life-extending drugs in the castration-resistant setting to now upfront for metastatic castration-sensitive setting. Moving it into the M0 setting is a continuation of that.

It will be interesting to see the side effect profile and what the magnitude of benefit might be. Not every patient can be an optimal candidate or choose to start on therapy that early. We also won’t have a sense, from the early data, of what the long-term consequences might be from early and intense androgen-deprivation therapy with the novel agents. Of course, we are all excited to welcome a new tool but, just like with the other drugs, as there have been new data and new ways to use these tools, there are also still going to be some new questions.

Are there any next steps that we're looking to take with radium-223?

Radium-223 is interesting because we don't actually know so much about what it does in the marrow. We know it’s an alpha-emitting, calcium-mimetic [agent] similar to strontium-89 and samarium-153 of the past. We know it acts in bone-only [metastatic disease] and that is where prostate cancer affects most of our patients. We use it as a life-extending therapy just like we would use abiraterone acetate, enzalutamide, or docetaxel. It is a nice alternative for some patients who aren't really a good candidate for docetaxel or who are resistant to that treatment because the side effect profile might be a little bit more acceptable. But, we have a lot to learn.

We are going to be looking at the bone marrow. What is happening is that there is immune activation that might give us some clues as to whether there is synergy with immunotherapy. There are also clinical studies asking whether the combination of radium-223 together with abiraterone acetate or enzalutamide may be advantageous compared with abiraterone acetate or enzalutamide alone–so a combination versus single sequential therapy, which is the current paradigm. Hopefully, from those studies, we will learn a little bit more about how to use the agent best.

Looking to the future, what potential do you think immunotherapy and PARP inhibitors are going to have in the field?

It looks like immunotherapy and PARP inhibitors will definitely benefit a subgroup of patients with prostate cancer. That is really the key—identifying who those patients are. We saw with ipilimumab (Yervoy) that there were definitely responses with mCRPC. Then, the phase III trial was negative because it was an unselected population. The pembrolizumab story seems to show that it's effective in patients who are progressing on enzalutamide, in which you have PD-L1 upregulation. That's a smarter course for development—to look at, hopefully, an enriched subgroup.

Similarly, if we tested the PARP inhibitors in an unselected population, they would undoubtedly fail. We know that the presence of a DNA-repair deficiency mutation is a strong biomarker predicting response. The questions with the PARP inhibitors will be, in that selected population, “Which agent? In what sequence? Early or later? Should it be combined with androgen-targeted therapy?” Those are some of the questions that are being asked in numerous ongoing clinical trials with PARP inhibitors.

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