Blink and You’ll Miss Something - Incorporating the Advances in Treatment of Metastatic Hormone Sensitive Prostate Cancer (mHSPC) into Clinical Practice
In fact, when initial trials proposed not only exposing men with mHSPC to chemotherapy but randomizing them to this treatment, there were some who said the studies would never accrue, let alone demonstrate a benefit. After persevering, and expanding the inclusion criteria to include low volume metastatic patients in addition to high volume patients, CHAARTED reached its accrual goals and demonstrated a survival benefit associated with chemohormonal therapy in mHSPC. Data from STAMPEDE supported these findings shortly thereafter, and the race to improve upon them has been on ever since. This channel on UroToday is dedicated to describing advances and controversies in the treatment of mHSPC, including the downstream effects of treating mCRPC in this new landscape. In addition to bringing coverage of new data presented at meetings and described in papers, we will interview authors of studies trying to improve treatment outcomes, and experts in the field trying to help us put new findings into practice. Given all that has happened in this disease space, and the studies that are poised to report out, there will be a lot to cover.
As things stand today, there are three main aspects of treatment on my mind for mHSPC.
1. Should we treat the primary in metastatic disease, and if yes, which local therapy is best?
2. Will the combination of chemo-hormonal therapy with androgen receptor (AR) targeted therapies result in superior outcomes than choosing one over the other? (And how does this intersect with the treatment of the primary tumor?)
3. Are there genomic features that will be more precise than high/low volume, or high/low risk that we can use to more accurately direct therapy and get the right treatment to the right patient?
At ESMO this year, STAMPEDE addressed the first question, though questions still remain. More than 2000 patients enrolled to answer the primary question: does radiation of the primary tumor improve survival in the mHSPC patient population? The answer was a resounding no. However the authors performed a subgroup analysis, planned prior to analyzing the data but after drafting the protocol, that assessed whether the effectiveness of treatment of the primary differed between high and low volume disease. In this analysis, there was a significant improvement in overall survival associated with treating the primary in men with low volume mHSPC, but not for men with high volume mHSPC. Just over 800 patients were included in the low volume population, and 1100 in the high volume group. The low volume analysis met statistical significance, and from my perspective, indicates that radiation of the primary tumor for men with low volume metastatic prostate cancer appears to improve survival and should be discussed as such with men who meet these criteria. Whether the radiation fields should be different from that included in the study (the fields are different in the US), and whether more effective systemic therapy may augment or otherwise change this effect, are unknown. It is also unknown whether surgery would have a similar effect.
We expect that some of these questions will be answered little by little over the next few years with some of the studies that are currently enrolling. PEACE 1 (ADT + docetaxel +/- abiraterone +/- radiation to the primary tumor) will contribute to the field’s understanding of whether we should radiate the primary, though it may be underpowered to demonstrate the benefit of radiating the primary in high vs low volume disease. This study will also help define the optimal systemic therapy to use in combination with radiation. We also expect to learn from the SWOG study in which men receive best systemic therapy for 6 months before randomizing men without progression to the treatment of the primary (surgery or radiation) vs no treatment of the primary. Questions about which systemic therapy should be used, which radiation schedule is ideal, and whether surgery will have a similar effect on outcomes as radiation persist.
Whether chemohormonal therapy plus an AR directed combination approach will be superior to either one on its own is also unknown at this point. ARCHES included 18% of patients in each treatment arm (ADT + enzalutamide vs ADT + placebo) who received docetaxel, which at least demonstrates the feasibility of a combination approach. However, it is unlikely to be sufficiently powered to answer the question of whether the combination is better than enzalutamide alone, and the data remains immature for overall survival. ENZAMET is a second international phase three trial that randomized men to treatment with ADT + enzalutamide vs ADT + a non-steroidal anti-androgen, and patients enrolled could receive treatment with chemotherapy. If a larger proportion of patients received combined chemohormonal and AR-directed therapy, a subgroup analysis from this study may shed more light on the benefit or lack thereof for combination therapy.
Finally, we all wonder whether we will soon have more precise molecular characterization available to guide treatment choice for patients with mHSPC. The criteria for high volume disease have inherent challenges, including the fact that men with 20 sites of metastatic disease all within the axial skeleton would still be categorized as low volume, and men with four small rib metastases are classified as high volume. What’s more, we don’t yet have data from STAMPEDE categorizing patients receiving chemohormonal therapy by high and low volume criteria, a long-awaited re-analysis that may shed light on whether the benefit of chemohormonal therapy is truly in higher volume patients only or not.
Many questions remain in the treatment of mHSPC. Each advance adds knowledge, but also areas of uncertainty. As the field continues the search for a cure, advances in mHSPC will certainly be a part of that journey. The definition of mHSPC includes a variety of men, from those with oligometastatic disease, to low volume, to high risk, to men with so much high volume metastatic disease that they have super scans and visceral disease. The disease in these patients is driven by different biology that is as of yet minimally characterized. If you blink, you will miss the rapid accumulation of advances as they roll in. Blink twice, and you’ll miss the many questions that each forward step brings, too. Join us as we try to make sense of it all, and put the noise into practical clinical guidance that helps patients live longer and better, and clinicians more effectively help them do so.
Written by: Alicia Morgans, MD, MPH, Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois
Published Date: April 9th, 2019
Related Content:
Watch: Treatment Decision Making for the Metastatic Hormone-Sensitive Prostate Cancer Patient Population - Alicia Morgans