Expert Discusses Docetaxel's Continued Significance in Prostate Cancer

William Oh, MD

Although targeted therapies and immunotherapy are revolutionizing oncology, chemotherapy retains a key role in the treatment of advanced prostate cancer, with recent data showing profound benefits with docetaxel in newly diagnosed patients, according to William Oh, MD.

The recent positive findings seen with docetaxel come from 2 randomized trials: CHAARTED and STAMPEDE. In the larger STAMPEDE trial (2962 patients), adding docetaxel to standard hormonal therapy significantly improved survival among men with newly diagnosed, hormone-naïve advanced prostate cancer. The median overall survival (OS) was 81 months with docetaxel plus standard of care (hormonal therapy with or without radiotherapy) versus 71 months with standard of care alone (0.78; 95% CI, 0.66-0·93; P = .006). In the CHAARTED study (790 patients), the median OS was 57.6 months with the combination of docetaxel and androgen-deprivation therapy (ADT) versus 44 months with ADT alone (HR, 0.61; 95% CI, 0.47-0.80; P <.001).

According to Oh, these results are particularly interesting because docetaxel has already been available for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) for over a decade. He added that there were multiple negative trials involving combining another agent with docetaxel in mCRPC, which preceded the surprising discovery that the addition of the drug early on led to such benefits.

OncLive: Can you provide an overview of the role of docetaxel in metastatic prostate cancer?

In an interview with OncLive at the 2016 Chemotherapy Foundation Symposium, Oh, chief, Division of Hematology and Medical Oncology, professor of Medicine and Urology, Mount Sinai School of Medicine, discussed the continued significance of docetaxel in advanced prostate cancer.Oh: The role of docetaxel in hormone sensitive metastatic prostate cancer is probably one of the biggest new advances in the last 2 years, based on 2 large randomized trials: CHAARTED from the United States and STAMPEDE from the United Kingdom.

While everyone else in other cancers is looking at targeted therapies and immunotherapy, unfortunately, we’re still in the era of chemotherapy; however, the reason we’re in the era of chemotherapy is that docetaxel has a profound effect when used in newly diagnosed metastatic hormone sensitive prostate cancer.

Were you surprised by the results?

In both studies the survival benefit was quite dramatic, ranging from up to 20 months of benefit in terms of the added benefit of chemotherapy in the group receiving docetaxel early. It’s 6 cycles of docetaxel given without prednisone within 4 months or so of the initiation of ADT for metastatic prostate cancer.This was an interesting result because docetaxel, as everyone knows, has been approved for mCRPC for over a decade, and we have been using it in our practice and it has value in the setting for CRPC. Unfortunately, we were never able to enhance that effect in CRPC; in other words, there have been multiple negative clinical trials adding another drug to docetaxel in CRPC.

How has tolerability been with docetaxel in your patients?

This was a bit of a surprise when we found that docetaxel had so much added benefit when used early, and it makes some sense because obviously, we know that there are high-risk metastatic patients who have clones that are going to be resistant to primary hormonal therapy and by using early chemotherapy, we seem to be pushing off the cancer. We’re not curing any of these patients, but we are basically delaying progression enough that there is a significant survival benefit.Tolerability is very, very important because this is an older group of men. The traditional approach would be ADT alone, which men don’t like but they can tolerate and live sometimes for many years with this treatment. Adding about 4 and a half months of treatment with docetaxel chemotherapy is not a trivial matter.

Now that said, the toxicity in general was very reasonable, and I have been using this now for the past 2 and a half years in my own practice, and I found that it is difficult in some patients but it is mostly neutropenia, fatigue, some fluid retention. These are side effects that we have understood to be related to docetaxel for many years, so I have made adjustments.

Any challenges with docetaxel that are important to tackle in the next couple of years?

For older patients, I might start with a lower dose, I might use growth factor if they are particularly at risk for neutropenia, but I have not had a lot of trouble with giving this treatment. Neutropenia is something that I would focus on, unfortunately it remains an issue, although I wouldn’t use prophylactic growth factor, but there was also differential effect in the 2 studies I mentioned. There was about a 6% rate of neutropenia in the American study but it was about 12% in the UK study, so we don’t fully understand those differences, but we are going to continue to monitor this situation.I think the biggest question in the next few years is determining whether using these treatments earlier—the treatments that are approved for mCRPC—will have a more profound impact. That may or may not be true for some of the newer treatments that have been approved for mCRPC, such as abiraterone (Zytiga), enzalutamide (Xtandi), or radium-223 (Xofigo)—those that are being tested in the same population, and will be tested in randomized trials over the next few years.

What are the key takeaways on these docetaxel findings for community oncologists?

The real question is can we substitute those treatments for the benefit of chemotherapy with docetaxel, but we don’t know the answer yet. We’ll learn more about whether drugs like abiraterone or enzalutamide can be substituted for chemo, but for now, in general, it’s not an option, given the power and the magnitude of the benefit of early docetaxel.I think this is one of the most profound survival benefits that we have seen in metastatic prostate cancer and that I have seen, basically in my entire career. While I’m very excited about the new treatments in mCRPC, I would strongly urge oncologists to talk to their urological colleagues—who don’t regularly see these patients—to refer these patients for early chemo.

The other thing I would emphasize is many of these men are older, but they may be very fit, and while some doctors are concerned about giving chemotherapy, for me, there is no upper limit of age for who I would give chemotherapy to. Many of the patients I have been treating recently have been in their 80s, I’ve given chemo to men in their 90s—it all depends on their physiologic age, and you can always give this chemotherapy if you think their risk of dying of cancer is high enough to justify the relative survival benefit.

References

1. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177.
2. Sweeney CJ, Chen YH, Carducci M. et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746.