Debate on Treating Oligometastatic Metastatic Hormone-sensitive Prostate Cancer: The Argument for New-generation Hormone Therapy and Radiation Therapy to the Prostate

Advances in the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) over the past few years has changed the longstanding notion that androgen deprivation therapy (ADT) alone be the standard of care until the appearance of castration resistance [, , , , , , ]. The results of several studies that started with docetaxel in combination with ADT demonstrated a significant overall survival advantage [, ]. Following this important finding, several studies have shown the benefit of the combined approach of ADT plus a new-generation hormone therapy (NHT) or androgen receptor pathway inhibitor [, , , , ]. Benefit was observed regardless of whether mHSPC was de novo or asynchronous, and especially important was the finding that the benefit was clearly seen in low-volume/low-risk mHSPC. In fact, this advantage may actually be even greater in patients with low-volume mHSPC since they may harbor fewer hormone-insensitive clones given the lower tumor volume. During the same era that confirmed the importance of systemic intensification, an important study arm of STAMPEDE revealed that radiation therapy to the prostate, in addition to ADT, in patients with low-volume or oligometastatic mHSPC (detected on conventional imaging), delayed the time to castration resistance and improved overall survival []. The fact that two distinct therapeutic strategies, namely systemic intensification and local control, lead to better survival could suggest that one needs to choose one or the other. When reviewing all the data available on how best to improve the outcome for patients with oligometastatic mHSPC, I conclude that the best evidence points to ADT + NHT. Given the consistently strong evidence in phase 3 trials with apalutamide, enzalutamide, and abiraterone, these NHTs have become my preferred choice and is what we recommend for all of our patients outside of clinical trials. Added to this is the lack of evidence that chemotherapy is better, or even as beneficial, in these patients. In addition to what we consider the best systemic standard of care, we discuss local radiation therapy. Given the lack of evidence that the outcome would be better with surgery and that the morbidity would definitely be greater, we do not propose surgery in these patients outside of clinical trials. I acknowledge that there has not yet been a definitive study that has shown that combining both local control and intensified systemic therapy is additive or synergistic. However, the biological rationale and the low morbidity and the cost of adding local radiation to patients with mHSPC have led us to propose this “triplet approach” of ADT + NHT + prostate radiation for almost all patients with de novo oligometastatic prostate cancer. In our experience, as well as that of others, the results of this approach have been excellent. Regarding metastases-directed therapy (MDT) in patients with mHSPC, there is still very little evidence that treating sites of metastases significantly improves survival. Therefore, management of metastatic sites should not be considered a standard of care and should be studied in randomized trials such as the one we have open in Canada. In my opinion it is especially important to avoid using MDT as a means of delaying the use of proven life-prolonging systemic therapy in patients with detectable metastases on conventional imaging. The debate continues as to what is appropriate systemic therapy in patients who have metastases detected only on prostate-specific membrane antigen positron emission tomography imaging, but that is a discussion for another time.

In summary, the takeaway key messages are as follows:

• 1.
  First do no harm; then
• 2.
  Use the best evidence to guide treatment decisions.
• 3.
  Patients with mHSPC clearly need ADT and additional systemic therapy. The options include NHT or a combination of NHT + docetaxel.
• 4.
  In patients with de novo oligometastatic mHSPC, our first choice is ADT + NHT + local control in the form of radiation therapy.

The final decision should be taken in a multidisciplinary fashion taking into consideration the extent of disease, life expectancy and frailty, timing (de novo or asynchronous), the risk/benefit tradeoff for the choices, and, importantly, patient preference.

Conflicts of interest: The author has received consultancy honoraria and institutional research funding from Amgen, Astellas, AstraZeneca, BMS, Bayer, Janssen, Myovant, Pfizer, and Sanofi.