Choosing First-Line Systemic Therapy for Newly Diagnosed Metastatic Hormone Sensitive Prostate Cancer

Published in Everyday Urology - Oncology Insights: Volume 4, Issue 4

Published Date: December 2019

Metastatic hormone-sensitive prostate cancer (mHSPC) has become increasingly prevalent in the United States. Between 2009 and 2020, experts have projected a nearly 17% increase in the number of newly diagnosed mHSPC cases and a more than 18% increase in cases of mHSPC occurring after failure of local (curative-intent) treatment.1 This increase is likely multifactorial, reflecting changes in prostate-specific antigen (PSA) screening practices, the increased use of more sensitive imaging modalities, and other factors.2, 3

At the same time, we have seen a dramatic change in the mHSPC treatment landscape, which is both exciting and challenging for those selecting first-line therapy. To further explore this, this article will discuss treatment of mHSPC in the context of discussions at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) that took place in Basel, Switzerland.

The discussion began with a review of what is now widespread agreement that testosterone suppression with androgen deprivation therapy (ADT) alone is no longer the standard of care for mHSPC. Instead, ADT should be combined with other treatments, such as docetaxel, abiraterone acetate (with concomitant steroid therapy), enzalutamide, or apalutamide. 4, 5 The only patients who should not get combination therapy are those with significant comorbidities and a very short life expectancy, such as advanced cardiac disease or dementia, or those who understand the benefit of combination therapy but decline. Even in the United States, combination therapy is not yet used for the majority of patients. This trend must change.

When selecting which agents should be combined with standard ADT, the panel discussed that there is a paucity of head-to-head trials or predictive biomarkers to guide treatment selection. Given this, clinicians should consider both disease-specific and patient-specific characteristics to make treatment choices. One of the most important considerations may actually be whether the patient has de novo versus recurrent disease after treatment of the primary tumor. This was discussed in the context of the STAMPEDE secondary analysis describing outcomes for patients with high and low volume disease per the CHAARTED trial. High volume disease was defined as the presence of visceral metastases and/or >4 four bone metastases, with ≥1 bone metastasis located outside the vertebral column or pelvis; low volume was all other patients.6 Although specifics were not released until the presentation of the STAMPEDE data at ESMO 2019, we now know that there was a benefit to treatment of men with mHSPC in the STAMPEDE re-analysis in both high and low volume disease.7 This is in contrast to the benefit of docetaxel being only in men with high volume disease in the CHAARTED trial.  Importantly, however, the panel reviewed that the case-mix of patients in the two trials was entirely different, with nearly all STAMPEDE patients presenting with de novo mHSPC, while most patients in CHAARTED in the low volume subgroup had recurrent disease after primary treatment. This previously under-discussed difference in population clinical characteristics will likely play an important role in future treatment recommendations and decisions.   

Disease volume by the CHAARTED criteria does still play a role in treatment decisions, but this is predominantly in the setting of decisions about treatment of the primary tumor rather than decisions about systemic therapy. This was discussed at length at APCCC 2019, as treatment practices for men with mHPSC in the US and internationally have been increasingly open to treating the primary even in the face of metastatic disease. Some of the most heated discussions revolved around whether we should treat the primary tumor in the setting of optimal combination systemic therapy. Data describing the benefit of radiation to the primary tumor in the setting of low volume mHSPC comes from the STAMPEDE trial, in which radiation of the primary tumor was associated with a statistically significant improvement in overall survival in men with low volume metastatic disease only (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.52 to 0.90). The benefit for men with low volume metastatic disease was in contrast to men with high volume mHSPC who did not appear to benefit from radiation to the primary tumor. Importantly only a small proportion of men in this trial received optimal combination systemic therapy (ADT + docetaxel), and it remains unknown whether radiation to the primary tumor adds substantial benefit in the setting of optimal combination systemic therapy for mHSPC.

The group also debated whether radical prostatectomy should be considered in the setting of mHSPC when data already suggests a benefit for treatment of low volume mHSPC with radiation. The consensus was that the benefit of this approach remains unknown, outside of reliving symptoms due to local control of disease in the pelvis. Ongoing clinical trials, including SWOG 1802 and several other studies, seek to answer this question.8 Opinions on the best approach to treating the primary in the setting of mHSPC remain mixed, but treatment with surgery appears most acceptable only in the setting of a clinical trial. 

In my practice, both disease volume and de novo/recurrent metastatic status come into play when making treatment decisions. I also consider whether an individual is a chemotherapy candidate, the financial toxicity of daily oral AR directed therapy, and comorbidities that may be affected by treatment, particularly cardiovascular disease, pre-existing neuropathy, brittle diabetes, a history of falls, and hepatic disease. Most importantly, I talk with men and their families about their preferences for differences between treatments as well as discuss what they need to accomplish in the short and long term as we move along their treatment path. We work together to choose a systemic treatment to combine with standard ADT, and then consider radiation to the primary tumor for all men with low volume mHSPC, unless they wish to pursue the possibility of surgery on SWOG 1802. Radiation is always given in our clinics with ADT at a minimum for mHSPC, but is often given concurrently (ADT + abiraterone) or in series (ADT + docetaxel) to provide optimal combination systemic therapy.  This approach of combining optimal combination systemic therapy in combination with radiation to the primary for low volume metastatic disease has not yet proven to be superior to optimal systemic therapy alone or treatment of the primary tumor with radiation alone (for men with low volume disease), but it is being assessed in PEACE-1, SWOG 1802 and elsewhere. It is clear in my practice, as it was during discussions at APCCC 2019, that these decisions are very personal, and no one approach to treatment fits all.

Although speakers at the APCCC 2019 repeatedly considered data from separate trials, it is imperative that we do not directly compare results from separate clinical trials to each other. Similarly, we must also be cautious in drawing inferences from the results of subgroup analyses, especially if these were not preplanned and prespecified in the trial protocol or before the data has been analyzed.9 Statisticians who attended APCCC 2019 reminded us that biomarker studies and techniques for network meta-analyses are evolving and may help address some of these gaps in the future. In the meantime, our patients are counting on us to recommend first-line treatment based on a thoughtful and holistic assessment of their disease characteristics, treatment history, comorbidities, performance status, and preferences. As the field advances, these decisions will only become more complex, but our patients and we will inevitably be better for it.

Written by: Alicia Morgans, MD, MPH is an Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.


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