Upfront Chemotherapy in Prostate Cancer

Nicholas J. Vogelzang, MD

Neal D. Shore, MD, FACS

Two large clinical trials have both recently demonstrated that men with metastatic prostate cancer have a greater benefit from a combination of upfront androgen deprivation therapy (ADT) plus chemotherapy compared with ADT alone. Today we are speaking with Neal Shore, MD, FACS, medical director for the Carolina Urologic Research Center in South Carolina, and Nicholas J. Vogelzang, MD, who works at the Comprehensive Cancer Centers of Nevada, on how these trial results are changing clinical practice.

-Interviewed by Anna Azvolinsky 

Cancer Network: Let’s start with the CHAARTED study, which was presented in 2014 at the American Society of Clinical Oncology (ASCO) Annual Meeting. Dr. Vogelzang, since you took part in the CHAARTED trial, could you briefly describe the design and outcomes?

Dr. Vogelzang: That was a very important trial and had been underway for quite a while. It was organized by Dr. Christopher Sweeney from ECOG. It was initially designed to be a high-risk trial for patients with more than four bone metastases or visceral lesions, such as liver or lung. The trial was a difficult randomization, as you might imagine, to hormones alone or hormones with 6 cycles of chemotherapy. When other clinical trials closed, the CHAARTED trial was then opened to some patients who were willing to be randomized who had a lower volume of disease. The trial was reported at ASCO 2014 at the plenary session as strikingly positive, showing a 17- to 19-month improvement overall. Most of the benefit at the time of reporting had been confined to the high-risk individuals. There were not enough events in the low-risk individuals to warrant a conclusion.

That trial immediately changed my practice. The logic for the low-risk, high-risk is that SWOG and other groups have long broken the metastatic hormone-sensitive population into a good- and poor-risk population with some slight variations-the number of lesions, whether they are in the axial or distal skeleton. But, be that as it may, this has certainly changed my practice, and I have been now doing it for probably the last year. And it was somewhat controversial because the French study, called GETUG (GETUG-AFU 15), had reached an opposite conclusion, namely that although chemotherapy with docetaxel improved progression-free survival, it did not improve overall survival. The difference was that in the French study, the chemotherapy had been given for 9 cycles, but when men did not get chemotherapy, they almost inevitably got chemotherapy when they relapsed. In the US study, the CHAARTED study, only a minority of men received chemotherapy when they relapsed, only about 20% to 30%. So it could be that it’s better to give everybody chemotherapy, but if you don’t give chemotherapy, it’s critical that they receive chemotherapy after hormone therapy fails. That could be an arguable point.

And so I always have that discussion with my patients, about whether they want to have chemotherapy now or chemotherapy later and most of the men say they will take the chemotherapy now, ‘I am stronger, healthier, and I feel good right now, and I would rather get the most benefit out of it before I get sicker later.’ So that is my take on the CHAARTED study along with a commentary on the French study.

Cancer Network: The second study that also showed benefit from upfront chemotherapy was the UK-based STAMPEDE trial. Dr. Shore, could you briefly describe that design and outcome of this study?

Dr. Shore: Yes. Nick did a very wonderful summary of GETUG and CHAARTED, which were conflicting trials. As he accurately states, the French based GETUG trial did not show a benefit of giving a chemo/hormonal combination in patients who presented with metastatic androgen-sensitive disease for the most part, whereas the CHAARTED trial clearly demonstrated for the first time, a marked improvement in median overall survival for patients with high-volume disease. So here we were left with conflicting trials and many of us, and really everyone who treats these patients, were awaiting the results of a third trial to see which would be the deciding factor, potentially.

The STAMPEDE trial was essentially UK-based-there were a couple of sites in Switzerland, but it was largely done in the United Kingdom and Nick James was the principle investigator. This trial (as opposed to the CHAARTED trial which included a little less than 1,000 patients), had over 2,500 patients. The patient population was very similar in the two trials, patients with newly diagnosed or recently diagnosed androgen-sensitive metastatic disease. The vast majority had radiographic evidence of disease and there was a smaller subset that was just biochemical relapse but the vast majority had radiographic evidence of disease.  And what that study now showed, 1 year later than the CHAARTED study, in 2015, just a few weeks ago in Chicago, was that the median overall survival for the entirety of the population was 10 months, but when one looked at the patients who were higher risk and had radiographic evidence of disease, it appeared that the survival moved out to almost 22 months. And it was a really similar trial design, ADT vs ADT plus 6 cycles of docetaxel.

It’s very important to recognize that the STAMPEDE trial was much more of an elaborate trial, the design is called a multi-arm, multi-stage study in that there were many different arms including a control arm for androgen-sensitive metastatic patients, everyone received ADT and then there were other arms that had additional therapies, so ADT plus 6 cycles of docetaxel, ADT plus zoledronic acid, ADT and a COX-2 inhibitor, so a very well-thought-out, adaptive trial design. The bottom line, at ASCO 2015 was showing the data on the chemotherapy plus hormonal therapy arm, very similar to the CHAARTED trial which clearly corroborated the positive survival benefit that was seen in the CHAARTED study. So now we have two very nice, well-designed, prospective, phase III trials clearly showing a very clinically significant survival benefit for these androgen-sensitive patients as opposed to the classic trials demonstrating an approximate 3-month benefit in the castration-resistant prostate cancer (CRPC) population.

So much like Nick, I converted early on. I was a convert when I saw the CHAARTED data. Now, interestingly, we are still awaiting publications of the CHAARTED trial in a peer-reviewed journal as we are for the STAMPEDE trial. But, I have enough confidence in the data that I’ve seen and the presentations I’ve seen and some of the early reviews that I feel strongly, like Nick, that in my patients, who present with high-risk, high-volume disease as manifested by multiple bone lesions and/or visceral metastases, if they have the appropriate performance status, that I absolutely have a shared discussion with patients about receiving docetaxel upfront.

Cancer Network: Thank you so much to both of you for joining us today.

Dr. Vogelzang: Thank you very much.

Dr. Shore: A pleasure.