After about 70 years with no significant progress, the landscape for men with de novo metastatic prostate cancer has changed dramatically in the past 4 years, with statistically significant and highly clinically meaningful survival improvement reported from multiple phase III trials when abiraterone (Yonsa, Zytiga), prednisone, or docetaxel is used upfront. To reflect these major milestones, ASCO has recently released a clinical practice guideline on optimizing anticancer therapy for these men,¹ and abiraterone has recently been approved in this indication in many countries.

First- and Second-Generation Questions

Examples of issues that need to be addressed in this setting include the following questions:

• Which drug—abiraterone or docetaxel—should be used? Obviously, this is a matter of and will fuel further intense debate.
• Should we use these agents in all patients with M1 disease or restrict them to clinically defined subgroups (eg, those with extensive bone metastases and/or visceral metastases)?
• Do the data also apply to men who subsequently develop metastases after failure of local therapy? Indeed, these men were rare in the clinical trials, and data are lacking.
• What about long-term efficacy data in the abiraterone trials?
• If I am using one of these drugs upfront, will my next treatment work when the patient eventually develops castration-resistant prostate cancer?
• What about short-term (mostly with docetaxel) and long-term (mostly with abiraterone) side effects?
• Can our societies afford the cost of abiraterone in this indication? Will it soon become generic?

Of course, intense research is ongoing to address many of these issues, and some were addressed at the 2018 ASCO Annual Meeting. However, even if upfront abiraterone and docetaxel represent clear major advances for men with M1 prostate cancer, they are likely not curative in this setting. Therefore, we should concentrate on the next generation of questions below if we want to reach another efficacy milestone:

Will the impact of abiraterone (or other androgen receptor [AR] axis inhibitors) and that of docetaxel (or another taxane) be greater if used as adjuvant treatments together with local treatments and androgen-deprivation therapy in men with high-risk localized prostate cancer? This is obviously a key question, although patience will be needed to address it, given the required time to clinically relevant endpoints; of note, docetaxel phase III trials in this setting are currently maturing, and we expect answers by 2020.

In men with M1 disease, should we use a triplet with androgen-deprivation therapy–abiraterone–docetaxel? The PEACE-1 phase III trial is expected to complete its planned accrual this year, and other trials with a similar design testing next-generation AR inhibitors (enzalutamide [Xtandi], darolutamide, apalutamide [Erleada]) should also soon provide information.

After about 70 years with no significant progress, the landscape for men with de novo metastatic prostate cancer has changed dramatically in the past 4 years….

— Karim Fizazi, MD, PhD

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Should we (finally) start personalizing systemic treatment based not only on clinical characteristics but also on molecular biomarkers? Prostate cancer remains an exception in modern oncology, with no biomarker except prostate-specific antigen used routinely for decision making. Things may change in the not-too-far future (always safer to be vague!) with several excellent potential candidates such as DNA repair–defect gene abnormalities, PTEN loss, ERG-TMPRSS2 fusion genes, DNA mismatch–repair genes, etc.

Should we treat the local primary cancer in a man with M1 disease? Is the answer the same in a man with lymph node metastases or oligo-bone metastases alone vs one with highly disseminated disease? Phase III trials randomly testing the role of local radiotherapy or radical prostatectomy are currently maturing, and at least three of them are expected to report outcomes in the coming 3 years. 

Will other systemic drugs such as poly (ADP-ribose) polymerase inhibitors or immunotherapy improve outcomes in the M1 setting? Well, let’s do the trials. But let’s also design them carefully.

While we keep celebrating the recent important victory of abiraterone and docetaxel in men with metastatic prostate cancer (celebrating good news is mandatory when you’re an oncologist), let’s concentrate on these important questions and some others, and let’s do it in the most efficient and global way possible. ■

DISCLOSURE: Dr. Fizazi reported no conflicts of interest.

Dr. Fizazi is Professor of Oncology, University of Paris, Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France.

REFERENCE

1. Morris MJ, Rumble RB, Basch E, et al: Optimizing anticancer therapy in metastatic non-castrate prostate cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 36:1521-1539, 2018.