Expert Discusses Evolving Role of Chemotherapy in Hormone-Sensitive Prostate Cancer

Tanya Dorff, MD

Several recent trials have supported the use of chemotherapy in the frontline setting for patients with hormone-sensitive metastatic prostate cancer.

For example, in the phase III CHAARTED trial, the median overall survival was 57.6 months with the addition of docetaxel to androgen-deprivation therapy (ADT) versus 44 months with ADT alone (HR, 0.61; 95% CI, 0.47-0.80; P <.001) in patients with metastatic, hormone-sensitive prostate cancer.

At the 2016 OncLive State of the Science Summit on GU Cancer, Tanya Dorff, MD, an assistant professor of Clinical Medicine, Keck School of Medicine, University of Southern California, discussed developments in the upfront treatment of hormone-sensitive metastatic prostate cancer.

OncLive: Can you provide an overview of your lecture at this State of the Science Summit?

What are the big takeaways from those trials?

In an interview with OncLive, Dorff highlighted the key points of her presentation, including the integration of chemotherapy into the frontline setting and the development of biomarkers to personalize treatment in this population.Dorff: I discussed the role of chemotherapy in hormone-sensitive prostate cancer. This is largely based on the very exciting CHAARTED trial results that were presented at the 2014 ASCO Annual Meeting by Dr. Chris Sweeney. However, there are 2 other large randomized studies that have shed some light on this. We looked at those 3 trials and then some practical tips as to how to select patients for whom this is the right approach.The big takeaway is that we always knew chemotherapy worked for prostate cancer, but we used it at the time of castration resistance—when hormone therapy was starting to fail. These trials show that using it early for a newly diagnosed patient with metastatic prostate cancer who is just starting out on hormone therapy actually creates an even bigger impact. However, there are some caveats. Chemotherapy has its toxicities and there may be certain groups of patients, particularly high-volume patients, for whom the benefit is much greater and worth any risk that comes with it.

What are some factors you consider to determine what therapy is best for patients?

The first study is CHAARTED, which was the intergroup trial of ADT alone or with 6 doses of docetaxel upfront. The second trial is the GETUG 14 study, which were similarly patients with metastatic prostate cancer receiving upfront hormone therapy alone or 9 cycles of docetaxel. The third study is STAMPEDE, which is a very large study—about 2000 patients and 4 arms&mdash; and was much more complicated. The standard of care was ADT with or without radiation therapy, and then 3 non-standard arms: one with zoledronic acid, one with docetaxel, and one with both. This is also a little bit of a different study because it wasn’t purely a metastatic population. There were some high-risk or locally advanced type patients in there.The high-volume versus low-volume disease is a good stratifier. It is pretty clear that someone with just a few pelvic lymph nodes and just 1 or 2 bone metastases doesn’t stand to gain as much from intensifying therapy early on. Then, you have to look at your patient’s age, frailty, and comorbidity because there is significant toxicity that can occur with docetaxel. You do get febrile neutropenia. There were some deaths on some of these trials in the chemotherapy arms.

For patients with hormone-sensitive prostate cancer, is there 1 approach that is best for most patients, or does it vary from individual to individual?

Typically, I talk to patients about the risks. I’ll assess their robustness. Most oncologists have a good eye for someone who is going to get through chemotherapy well versus not. There are also some formal tools that can be applied, especially in a geriatric population, which is a large part of our prostate cancer population. There are geriatric comprehensive assessments that might be able to help give a more objective or quantifiable reason why someone may or may not be a good candidate for chemotherapy. However, most of us are using a lot of our gut instinct on that.These studies that tested docetaxel upfront added to hormone therapy represent a selected population. We know that clinical trials don’t always reflect everyone who presents to an oncologist’s office. That being said, they did have broad inclusion criteria and the trials are broadly applicable. However, it doesn’t mean that every single patient needs docetaxel upfront.

There is a lot we are going to learn from ongoing clinical trials that are testing intensified ADT—so some of our next-generation AR-targeted therapies, including TAK-700 and ARN-509&mdash;as an upfront strategy. This is similar to the CHAARTED or STAMPEDE study; however, instead of chemotherapy, we are just intensifying the suppression of AR signaling. Those studies may show that there is more than 1 option, and we really need that because patients with prostate cancer are very different, and they need to be handled differently.

What are the comorbidities that you look at to consider which treatment is best?

There is room to personalize a treatment plan based on their disease characteristics, as well as their comorbidities. Then, hopefully, if some of these other trials are positive, we will have more than 1 choice and we can potentially personalize even more. In the ideal world, we would have a biomarker that would say this patient is taxane sensitive, this patient is AR-targeted—sensitive. That would be the ultimate way of personalizing, but even now there is not just 1 way to treat a patient with prostate cancer.Diabetes is a big one. It’s not that a diabetic can’t receive chemotherapy; however, a diabetic with peripheral neuropathy, in my experience, is far more likely to have significant worsening of their neuropathy on docetaxel. I also look at things like falls. An elderly person who’s falling is someone who worries me, when I’m talking about giving them chemotherapy.

Where will the field of personalized therapy and care for patients with prostate cancer be in the next several years?

I also look at the support system, which isn’t a comorbidity but it may be one of the most important predictive factors. You really want someone who has someone looking out for them for those days when they’re not going to feel like eating or might get dehydrated. Someone needs to be able to see that, pick up the phone, and call. That can be hard to assess, but it’s as important as looking down the list for cardiac disease, diabetes, and other factors. Weight loss, too, worries me. You want someone with an adequate nutritional status going into chemotherapy.We have made a lot of headway in terms of biomarkers. We are on the brink of potentially having a useful blood biomarker to predict whether we should use chemotherapy or hormone therapy. There have been some setbacks, but it is something that is foreseeable in our near future.

What would it mean to finally have a biomarker for prostate cancer?

We really have to support clinical trials. If we all just treat our patients on our own, we are never going to develop a biomarker that’s going to help us personalize therapy. If we support clinical trials, there’s built-in science looking at tissue and blood. Those are going to become the tools of the future. There is a lot of interest now in both genetic and genomic profiling. It’s not as relevant, I would say, in the hormone-sensitive metastatic prostate cancer setting, and probably some of the other speakers are addressing those biomarkers.I think there won’t be just “a” biomarker. AR-V7, the androgen-receptor splice variant, is probably the one that will come on the scene first as a clinically available and clinically relevant tool. However, there are many more tools that I envision being used at different points in the disease; some are tissue and some are blood based.

There is going to be hopeful ways to predict not only chemotherapy sensitivity or how likely patients are to have a good deep remission to ADT, but also—hopefully, in the future&mdash;an eye toward immunotherapy-sensitive patients. Then, there are all of these targeted therapies that are not AR targeted, things such as PARP inhibitors. Well, we already know that having a DNA-inherent repair deficiency predicts for benefit.

Therefore, a lot of work needs to be done on those biomarkers to have a readily available blood or tissue assay. PTEN loss is another biomarker that is under active development. Then, we have some biomarkers that we know exist but we don’t know yet how to target them. There will be a whole panoply of biomarkers that will be relevant, and that’s why people have been looking broadly. People have not focused only on 1 test, 1 protein, 1 pathway, or 1 result because that would never get to the heterogeneity of how we see prostate cancer behave.