Kantoff Highlights Continued Role for Docetaxel in Metastatic Prostate Cancer

Philip W. Kantoff, MD

While immunotherapy continues to make headway in various malignancies, the chemotherapy docetaxel maintains a key role in the treatment of patients with metastatic prostate cancer.

Philip W. Kantoff, MD, lectured on cytotoxic chemotherapy for prostate cancer during the 2016 OncLive State of the Science Summit on Genitourinary Cancers. He also offered insight on the use of PARP inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC) who have DNA damage-repair abnormalities.

OncLive: Please provide an overview of your presentation.

In an interview, Kantoff, chairman of Medicine at Memorial Sloan Kettering Cancer Center and a 2014 Giants of Cancer Care winner for Genitourinary Cancer, discusses data supporting the use of docetaxel in metastatic prostate cancer and ongoing studies exploring PARP inhibitors in the field.Kantoff: Docetaxel was approved for use in advanced prostate cancer about 12 years ago as a result of 2 studies, which demonstrated that docetaxel improved overall survival (OS) by about 3 months. That has been the standard of care for advanced mCRPC since that time. There have been a number of studies that have tried to add other agents to docetaxel chemotherapy without any success. Therefore, large randomized studies adding different biological agents to it failed to demonstrate any benefit.

For second-line chemotherapy, cabazitaxel (Jevtana) was approved about 6 years ago. This was the result of a study called TROPIC, in which patients who had been treated previously with docetaxel and had progressed were randomized to receive mitoxantrone chemotherapy, which was a standard palliative agent for the treatment of advanced prostate cancer, or alternatively, 25 mg/m2 of cabazitaxel. In fact, 25 mg of cabazitaxel given every 3 weeks was found to be superior to mitoxantrone chemotherapy and improved survival by several months.

A recent study was performed asking the question, “Could cabazitaxel be used as first-line chemotherapy and what is the appropriate dose of it?” A 3-arm randomized study called FIRSTANA was performed comparing the standard dose of docetaxel at 75 mg/m2 to the standard dose of cabazitaxel 25 mg/m2 or alternatively 20 mg/m2 with cabazitaxel. As it turned out, all 3 arms were exactly the same with regards to PFS and OS. It does not appear that cabazitaxel at either 25 or 20 mg is superior to docetaxel. Docetaxel remains first-line chemotherapy for men with mCRPC.

What about docetaxel’s potential in the setting of metastatic hormone-sensitive prostate cancer?

It turned out 20 mg/m2 and 25 mg/m2 of cabazitaxel were equivalent with regard to outcomes and 20 mg/m2 was less toxic than 25 mg/m2. For the second-line setting, it is perfectly reasonable to use the 20 mg/m2 dose because it is less toxic.There have been 2 seminal studies that were published in the past couple of years. One is the CHAARTED study and the other is the STAMPEDE study. In these 2 studies, men with advanced hormone-sensitive prostate cancer were randomized to standard of care, which was androgen-deprivation therapy (ADT), or ADT plus 6 cycles of docetaxel. These 2 studies gave remarkable results in that the concomitant use of docetaxel with ADT led to a marked improvement in OS in both studies.

The controversy that now exists is, who are the appropriate patients who should be treated with the combination of ADT and docetaxel? It appears that, based on follow-up from the CHAARTED study, only men with high-volume disease as defined by 4 or more bone metastases and/or visceral metastases were the ones who benefitted from the combination.

Will docetaxel always have a strong role in this field?

You mentioned other combinations with docetaxel were negative. Are there any that you think could hold promise?

What unanswered questions do we still have with docetaxel that we need to address?

DNA damage-repair abnormalities were also highlighted in your lecture. What is important to mention here?

My conclusion from the studies would be that men with high-volume metastatic disease who are hormone sensitive should be treated with a combination of ADT and docetaxel. Men who present de novo with newly diagnosed metastatic disease, as opposed to presenting with early disease and then eventually developing metastatic disease, probably have a different, more aggressive, biology and should be treated with the combination of ADT and docetaxel as well.Docetaxel really had a modest role in men with mCRPC prolonging survival by 2 to 3 months in that setting. It has a much more profound effect in men with hormone-sensitive metastatic prostate cancer, and the improvement in survival is much longer than anything we have seen before, so it is becoming part of the current armamentarium. Whether chemotherapy remains in the armamentarium in 5, 10, 15, or 20 years from now remains to be determined; however, it remains an important part of what we do right now.The interesting thing is the combination of ADT-type agents along with docetaxel. Combining docetaxel not only with standard ADT, but combining it with the newer drugs such as enzalutamide (Xtandi) or abiraterone acetate (Zytiga) in hormone- sensitive disease might be a very interesting avenue to pursue. Studies such as that are ongoing right now. The interesting thing is, why should it be and why is it more effective in the context of hormone-sensitive disease versus mCRPC? We do not really understand that biologically yet. Those are the types of agents that should be pursued.One of the interesting biological questions is why is it more effective in men with hormone-sensitive disease, in high-volume metastatic disease, and in de novo disease? What is the biological basis for that? That leads us to wonder what the mechanism is and leads us to try to determine the biomarkers that determine the sensitivity to docetaxel in hormone-sensitive disease.In a study that was conducted over several years and published last year, a group of us determined that the genomic landscape of men with mCRPC and, among other things, found a very high frequency of DNA damage-repair abnormalities. About 25% of men had abnormalities in a variety of DNA damage-repair genes, the most abundance of which was BRCA2. There have been other studies that have confirmed these findings.

Interestingly, about 12% of the abnormalities that are seen in men with advanced or germline prostate cancer are inherited, which have implications about genetic screening and implications for the families of those who are affected. The other implications are that agents such as PARP inhibitors or platinum-based chemotherapy should be effective, and appear to be effective in these men, with DNA damage-repair abnormalities.

What are the next steps we need to take with PARP inhibitors?

This is a very important finding and will lead to new therapeutics for men with advanced prostate cancer. It will have interesting implications for men with early prostate cancer therapeutically, as well as from a screening perspective.There was 1 study that was performed by Drs Joaquin Mateo and Johann de Bono from England in which they took 50 men with mCRPC and treated them with the PARP inhibitor olaparib (Lynparza). They found that those individuals who had DNA damage-repair abnormalities were the patients who responded to the PARP inhibitors, with a predictive ability of about 92%.

Therefore, 92% of the patients who had DNA damage-repair abnormalities responded to these agents, and few of these patients did not respond to olaparib. What is required is a randomized study in order to confirm those findings, and I suspect that those findings will be confirmed.