Expert on Castration-Sensitive Prostate Cancer Challenges, Treatment Options

Walter M. Stadler, MD

Walter M. Stadler, MD

Targeting the androgen receptor pathway in patients with castration-sensitive prostate cancer is a key component of treatment, explains Walter M. Stadler, MD.

“Castration-sensitive prostate cancer is typically the initial portion of advanced prostate cancer when we can no longer necessarily treat it with just local therapy,” said Stadler. “It is, in many ways, the original cancer for which we have targeted therapy. In this case, the target happens to be the androgen receptor and castration, or lowering of testosterone, is a highly effective therapy that works in the vast majority of patients and is—compared with other cancer therapies—quite well tolerated.”

Stadler, the Fred C. Buffett Professor of Medicine and Surgery, chief of the Section of Hematology/Oncology, and director of the Genitourinary Program at the University of Chicago Medicine, discussed treatment options for patients with metastatic castration-sensitive disease, explaining that patients with advanced disease could have a long history, leaving opportunity to receive multiple therapies but also room for comorbid disease.

Therefore, the addition of docetaxel to androgen ablation in these metastatic patients improves survival, as seen in the phase III STAMPEDE trial, in which docetaxel significantly improved overall survival (OS) in men with newly diagnosed, hormone-naïve advanced prostate cancer. Results showed that OS was 77 months and 67 months for those receiving docetaxel with androgen-deprivation therapy (ADT) versus ADT alone, respectively.

In an interview withTargeted Oncology, Stadler shared emerging therapies, the most overriding challenges in this subset of patients, and understanding the evolving role of chemotherapy in metastatic castration-sensitive prostate cancer.

TARGETED ONCOLOGY:What are the main differences between patients with castration-resistant prostate cancer and those with castration-sensitive prostate cancer?

Stadler:Typically, as patients develop more advanced prostate cancers that cannot be treated with local therapy, that disease is almost always still sensitive to lowering of the testosterone level. In other words, it is a disease that is driven by testosterone and that testosterone then contributes not only to the survival, but also to the growth of the cancer.

TARGETED ONCOLOGY:What would you say are some of the biggest unanswered questions in this space right now?

Stadler:There are a lot of unanswered questions in the space of castration-sensitive prostate cancer. Despite castration being a well-tolerated therapy it, nevertheless, has toxicities. These toxicities can be important, especially for the elderly men who often suffer from this cancer.

One of the major questions, in terms of castration-sensitive disease, is determining the best time to start. Does one start immediately when a patient has evidence of biochemical recurrence of the disease, or does one wait for some later arbitrary time point?

TARGETED ONCOLOGY:What are the most commonly associated adverse effects to this therapy?

Stadler:The most common toxicities of androgen ablation or castration are fatigue and tiredness, loss of muscle mass—which contributes to the fatigue and tiredness—loss of bone mass or osteopenia and osteoporosis, and then marked effects on libido or sexual desire.

TARGETED ONCOLOGY:What clinical trials are ongoing in this space?

Stadler:There are a number of them. In regards to minimizing toxicity, people are thinking about things such as exercise programs or, what some geriatricians call, prehabilitation in order to prevent some of these adverse effects.

However, perhaps some of the more interesting ongoing studies are looking at those patients who we know ahead of time that, although they are castration-sensitive, are likely to become resistant very quickly. The question in those patients really is, “Can some of the more potent androgen receptor—targeted therapies given right at the beginning help, in terms of longer-term benefit?”

TARGETED ONCOLOGY:When is it time to be more aggressive with therapy?

Stadler:Getting back to the higher-risk patients, the vast majority of patients with castration-sensitive disease will go on to develop castration-resistant disease. One of our questions is, “What is the sequence and the order in which we should use some of these newer androgen receptor—targeted therapies?” At what point should we be more aggressive with the addition of things such as chemotherapy? When do we add other newer therapies, including agents such as radium-223?Moreover, immunotherapy tends to be fairly active in several different cancers. However, the current immunotherapies that we have available tend not to be as active in prostate cancer. A major area of research aims to try to understand the reasons behind that.

TARGETED ONCOLOGY:What evidence do we have in understanding the resistance to immunotherapy agents?

Stadler:There are some investigators at our institution who have talked about certain tumors being inflamed. In other words, they attract an inflammatory infiltrate, while other tumors are non-inflamed. Prostate cancer happens to be noninflamed, and that may likely be based on some of the molecular abnormalities that we know exist in prostate cancer. That is one of the areas of active investigation.

TARGETED ONCOLOGY:What is the evolving role of chemotherapy in castration-sensitive prostate cancer?

Stadler:Chemotherapy is going to have a major role for quite some time. However, I tend to be a little bit cautious about chemotherapy because we have lumped that term—or lumped a lot of drugs into that term that may work through different mechanisms of action.

What is important to consider here is that prostate cancer happens to be sensitive to taxanes, and the most commonly used taxane is docetaxel. We know that introducing docetaxel early into the treatment paradigm of patients, even with castration-sensitive disease—which means a more extensive metastatic cancer—does provide a long-term survival benefit. It is important that we do not forget about this.

Sometimes, we have this concept that, because it is labeled as chemotherapy, we do not want to use it. Yet, in many ways, I am not sure that it is much more toxic than perhaps some of our other therapies that are out there. It is effective, so we do not necessarily want to leave it only as a last resort because it has this bad name.

TARGETED ONCOLOGY:What else should community oncologists understand about castration-sensitive disease?

Stadler: