Prostate Cancer Paradigm Progresses, But Unanswered Questions Remain

Randy F. Sweis, MD

Large phase III studies, such as the CHAARTED and STAMPEDE trials, have helped to significantly improved outcomes for men with prostate cancer, but unanswered questions remain, including what role immunotherapy could play in the treatment paradigm, said Randy F. Sweis, MD.

Long-term survival data from CHAARTED demonstrated prolonged overall survival (OS) benefit with docetaxel when added to androgen deprivation therapy (ADT) for patients with high-volume metastatic hormone-sensitive prostate cancer. At a median follow-up of 53.7 months, median OS was 57.6 months for the docetaxel/ADT arm versus 47.2 months for ADT alone.¹

The STAMPEDE trial showed that in patients with locally advanced disease, ADT plus abiraterone acetate (Zytiga) and prednisone was associated with higher rates of OS and failure-free survival than ADT alone.²

Sweis, an instructor of medicine at the University of Chicago, said ongoing trials are testing immunotherapy in patients with prostate cancer. For example, the CheckMate-9KD study will look at nivolumab (Opdivo) combined with either a PARP inhibitor, androgen receptor therapy, or docetaxel in patients with metastatic castration-resistant disease.

OncLive: How has the treatment landscape of prostate cancer evolved in recent years?

In an interview during the 2018 OncLive^® State of the Science Summit™, Sweis discussed recent progress and next steps in the prostate cancer paradigm.Sweis: Prostate cancer is an interesting disease because numerous therapies have been FDA approved over the last few years. One of the areas in which it is most quickly evolving is the sequencing and timing of therapies. This has been an area of somewhat confusion, but we have also been able to make a significant impact on outcomes. Patients can live longer and have more time being in control of their cancer.

We are using these therapies that were initially approved in the metastatic castration-resistant setting early on. A lot of these are secondary androgen-targeting agents, such as enzalutamide (Xtandi) and apalutamide (Erleada). Abiraterone acetate and chemotherapy regimens, such as docetaxel—and these drugs have been around for quite a while—are being utilized in this space effectively. We're using them earlier. We're treating patients a lot more aggressively than we were 5 years ago. The duration of control of the disease is being extended.

Are there any indications as to a patient population who might best respond to immunotherapy?

We are seeing this in large international studies such as CHAARTED or the STAMPEDE trial. That is where the most change is occurring. There are some efforts investigating things like immunotherapy in prostate cancer. That's been a challenging area, but there are a lot of people working on it and it has some potential in this field. We've seen a couple responders with immunotherapy; we just need a better understanding of the biology. This is an area where we can see some breakthrough in the next 5 years.We don't know quite yet, especially in prostate cancer. How to select patients for this type of treatment is tricky, and it's something we definitely need more data for. We will hopefully see that in the next few years. It's an area of ongoing investigation.

What are the remaining questions with regard to sequencing?

We have some trials at our institution looking at combining a PARP inhibitor with an anti—PD-1 agent. This is a novel approach. There are others looking at the combination of ipilimumab (Yervoy) and nivolumab, which we've seen have promise in other cancer types. We have some hope here, and we'll see how it plays out. We've seen some responses, as I said before. It's just a matter of figuring out the right combination.We have a lot of drugs now, especially those targeting the testosterone and androgen pathway. Several of them have shown success, and now there is a question of which one is optimal. Could these be combined with another therapy? Also, there is the chemotherapy question. Docetaxel given in the metastatic castrate-sensitive setting has been shown to improve survival. However, so has abiraterone. Some patients are receiving either one. This is going to be a big question. Which therapies should we be using upfront? We have to test them head to head.

The other question is of radium-223 dichloride (Xofigo). It's an infusion that targets bone metastases, and it's shown efficacy in castration-resistant patients. We have to see where this really fits in.

References

1. Kyriakopoulos C, Chen Y, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED Trial. J Clin Oncol. 2018;36(11):1080-1087. doi: 10.1200/JCO.2017.75.3657.
2. James N, de Bono J, Spears M, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377:338-351. doi: 10.1056/NEJMoa1702900.