Evolving Treatment Landscape in Metastatic Prostate Cancer


A prostate cancer expert discusses promising and emerging treatments for prostate cancer.

Bobby Liaw, MD: The treatment landscape for prostate cancer will, of course, continue to evolve, and there are many ongoing studies. We are just now starting to see a lot of data starting to be read out for triple therapy for metastatic castration-sensitive prostate cancer. By triple therapy, I mean combining ADT [androgen deprivation therapy] with docetaxel, as well as an AR pathway inhibitor. Recently presented at ESMO just a couple of months ago, the PEACE1 study found that by using 3 drugs in the upfront setting led to better outcomes than just 2 drugs with patients with de novo metastatic hormone-sensitive prostate cancer. And the 3 and the 2 in this particular case is the combination of ADT, docetaxel, and abiraterone versus ADT plus a docetaxel as a 2-drug regimen. The studies showed that when abiraterone was added to ADT and docetaxel, that there was a significant survival benefit with a hazard ratio of 0.75 as compared to just the ADT and docetaxel by itself. That's an additional 25% reduction in the risk of death. Now, similar to how we need to consider volume disease with the original CHAARTED data, I think that is also going to play a role in how we reevaluate the PEACE1 data. Because as of this moment for patients with high-burden metastatic prostate cancer, the triplet regimen definitely showed that there was like a significant improvement in disease in risk of disease progression as well as improvement in overall survival. But there will probably still need to be a little bit more follow-up before we can say quite the same about patients with lower burden of metastatic of disease.

On the tolerability side, which a lot of people had a lot of concerns about as triplet therapy was starting to be tested; yes, there were some [side effects], perhaps a little bit of additional side effects with triple combinations, but they were generally pretty mild with very few severe side effects. Another study that's championing triplet therapy, ARASENS, actually just 2 weeks ago just reported out — and this was just a media update — but it met its primary endpoint for overall survival. This was a phase 3 randomized double-blind study that was designed to evaluate darolutamide in combination with ADT and docetaxel versus ADT and docetaxel on its own. The actual data has not yet been made public at this time, but we're expecting to hear more probably at GU ASCO next year. That's my guess. But we're seeing already now 2 different regimens of triplet therapy starting to meet its mark in their primary endpoint of overall survival. This may end up changing our standard of care with patients with metastatic castration-sensitive prostate cancer. The jury's probably going to be a little out about high versus low volume disease until we get a little bit more of like the longer-term follow-up. And while it's important for us to continue to find ways to optimize drug selections, sequencing, and combination of the drugs that we currently already have there, there's still a lot of room for innovation. A lot of interesting ongoing investigations surrounding the use of immunotherapy for prostate cancer. While we've seen a lot of significant successes with immunotherapy and other disease types, we're still looking for ways to really enhance immunotherapy responses in prostate cancer. But there are ongoing studies in checkpoint inhibitors, such as Keynote-991, which is studying the combination of pembrolizumab with enzalutamide as well as ADT in men with metastatic hormone-sensitive prostate cancer. PROSTVAC has been an active investigation for a little bit of time now. It's an active immunotherapy vaccine that contains PSA as the tumor-targeting antigen, trying to generate a T-cell response against prostate cancer. It's currently being evaluated in combination with docetaxel in the castration-resistant prostate cancer setting. PSMA directed by specific T-cell engages. Those are also ongoing, a different implementation of immunotherapy. That's a little bit more target-specific.

In thinking about PSMA directed therapy, there's also PSMA radioligand therapy to consider. The VISION study results came out pretty recently, just like over this last year with very positive results, where anticipating approval of lutetium-177-psma-617, probably sometime in the new year. And on the back of that success, I'm anticipating that we're going to see a lot more studies testing PSMA radioligand therapy, both in the hormone-sensitive prostate cancer setting, as well as in the CRPC setting, but in patients who are chemotherapy naïve. Targeted therapy is another arena that we're likely to see much development. PARP inhibitors, they're not particularly new to the prostate cancer space. They've been approved for prostate cancer patients with homologous combination repair gene mutations for a little bit of time now, but there are ongoing studies looking at its combined use with AR pathway inhibitors in both the hormone-sensitive and castrate resistance prostate cancer setting. And of course, as we have better understanding of disease biology, as well as treatment resistance, mechanisms of resistance, that will continue to drive innovation as well. As an interesting example of this recently presented at AUA by Armstrong at all, is a novel small molecule inhibitor currently dubbed LX1 that targets - that has like a dual targeting system. It targets both AKR1C3 as well as AR variants, both of which play key roles in prostate cancer progression and drive resistance to current therapies. Currently, not yet in human studies, but certainly the more that we can build more targeted therapies for prostate cancer, I think it'll only add to our armamentarium.

Transcript edited for clarity.

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