Finding ways to improve the survival for men with advanced prostate cancer

Q&A with Dr. Amar Kishan
UCLA Health radiation oncologist Dr. Amar Kishan.

Treating aggressive prostate cancers with radiation and androgen deprivation therapy (hormonal therapy) is the standard of care for many men diagnosed with this advanced disease. However, there can also be some major side effects that can hinder a person’s quality of life.

That’s why UCLA researcher and radiation oncologist Dr. Amar Kishan, a member of the UCLA Jonsson Comprehensive Cancer Center, is trying to find ways to improve the optimal duration of androgen deprivation therapy when used with radiation. By using a patient’s Gleason score, he is hoping to help establish a more personalized treatment plan for each individual.

In a recent paper in JAMA Oncology, Kishan, an assistant professor in the departments of radiation oncology and urology, and other UCLA Jonsson Comprehensive Cancer Center researchers have found that men with cancers in Gleason grade group 5, which is the most aggressive cancers, are very sensitive to androgen deprivation therapy. This means that androgen deprivation therapy plays a critical role in treating the disease.

Here, Kishan, who is also a member of the Institute of Urologic Oncology at UCLA, discusses the significance of the findings and how it can help lead to developing better treatments for men with advanced prostate cancer.

First, some definitions. What is a Gleason score

When you look under the microscopic, prostate cancer cells can be organized in a variety of ways, and, loosely speaking, the degree of abnormality in this architectural pattern corresponds with the Gleason score. These scores are in turn related to prognosis. The scores in the modern day range from 6-10 (we do not give out scores between 1 and 5 anymore), with Gleason scores of 9 and 10 corresponding to more aggressive cancers. Due to confusion and changes to the scoring system over the years, it is now recommended to refer to so-called “Gleason grade groups” where Gleason score 6 cancers are “Gleason grade group 1” and Gleason score 9-10 cancers are “Gleason grade group 5.”

What is androgen deprivation therapy? Radiotherapy?

Androgen deprivation therapy is a medical intervention in which testosterone levels are suppressed in order to help in the treatment of prostate cancer. Prostate cancer cells are driven by testosterone and thus a long-established treatment for prostate cancer has been to deprive the cancer cells of testosterone. Radiotherapy is the use of radiation (generally, photon or “light”/”X-ray” radiation) to kill cancer cells by causing DNA damage. It’s well known that when treating more aggressive prostate cancers, adding androgen deprivation therapy to radiotherapy improves survival outcomes over using radiotherapy or androgen deprivation therapy alone. We now understand that this synergy may be due to the fact that androgen deprivation therapy may interfere with DNA repair in prostate cancer cells, and radiotherapy causes DNA damage in these cancer cells in order to kill them off.

What is the problem you are trying to solve in this study?

When you treat more aggressive prostate cancers with radiation, the addition of androgen deprivation therapy (or hormonal therapy) has been shown to improve survival in many trials. This had led to long duration androgen deprivation therapy becoming the standard of care when treating high-risk prostate cancer with radiotherapy. Because of the side effects associated with androgen deprivation therapy, a major research focus is finding out what the optimal duration of androgen deprivation therapy is. The very aggressive Gleason grade group 5 lesions are rare, and have not been represented well in any of the seminal trials. The goal of our study was to pool data across six of these major randomized trials in order to identify how the most aggressive prostate cancers (the Gleason grade group 5 cancers) respond. We compared these response patterns to response patterns of Gleason grade group 4 (or Gleason score 8) prostate cancer.

Why does this matter?

Prostate cancer has an excellent prognosis in general. The more aggressive Gleason grade group 5 cancers, which are thankfully rare, are the ones that we need to understand better because we need to improve our clinical outcomes for this patient population. Some have suggested that these cancers are so abnormal that they will not respond to conventional androgen deprivation therapy. However, there is mounting evidence that the role of androgen deprivation therapy is to increase the effectiveness of radiation, and we at UCLA have led a large study that demonstrated that radiation is actually very effective against these aggressive Gleason grade group 5 cancers. So we wanted to establish whether androgen deprivation therapy would also help, and how much it would help, when these aggressive cancers are treated with radiation.

What did you find? How is this significant?

We found that Gleason grade group 5 prostate cancers are actually very sensitive to androgen deprivation therapy. This group of prostate cancers behave more aggressively than Gleason grade group 4 cancers, but we were able to show that as the duration of androgen deprivation therapy increased, that difference actually went away. This means that, rather than these aggressive cancers being so aberrant that androgen deprivation therapy doesn’t work, androgen deprivation therapy is actually critical. Another important point is that, practically speaking, if these cancers are sensitive to androgen deprivation therapy and require a long duration, one could examine using newer androgen deprivation therapy agents, which could allow for both improved outcomes and a more palatable duration of androgen deprivation therapy for patients.

How does your research differ from, or offer a new perspective on, prior studies on the same topic?

Because Gleason grade group 5 cancers are rare, essentially all studies that report the benefit of androgen deprivation therapy have focused on pooling Gleason grade group 5 cancers with Gleason grade group 4 (or Gleason score 8) cancers. However, we know that Gleason grade group 5 cancers behave more aggressively, and this was the premise of specifically looking at these two Gleason grade groups separately. That it is why we pursued a meta-analysis approach, where we were able to pool patient data across multiple trials. Our prior research in this area had shown that extremely dose-escalated radiotherapy offers excellent outcomes in this patient population; the present study shows that androgen deprivation therapy is also critical.

What is the takeaway from this research for the field? For patients?

In my opinion the crucial takeaway is that longer durations of androgen deprivation therapy are critical when treating patients with Gleason grade group 5 prostate cancer with radiation. In terms of an important takeaway for future studies, advanced androgen deprivation therapy agents may allow excellent outcomes with shorter duration of treatment – but that is something that we will have to study.

Why did you decide to enter the field of radiation oncology? What keeps you inspired to do research?

I entered the field of radiation oncology because I am passionate about taking care of patients with cancer. One thing I love about this field is that we can provide help to patients with curable diseases, like what we studied here—a big reminder is that Gleason score 9-10/Gleason grade group 5 disease is definitely curable! However, we can also provide help to patients who have incurable disease but are suffering from pain or other symptoms, thereby improving their quality of life even if we are not curing them. I am motivated to do research because we always have room to improve our ability to treat patients, and I enjoy being a part of the effort to do so.