Timepoints on the Same Journey, or Two Different Journeys? - Thoughts on De Novo vs. Metastatic Prostate Cancer

"When does a radical prostatectomy save a life?" is a question that has been asked in the medical literature. Studies from Scandinavia1 reported long term outcomes of a randomized trial of immediate radical prostatectomy versus observation and deferred treatment. The study evaluated the outcome of overall survival (OS) and showed that OS curves remained superimposed until the timeframe of year 10-15, suggesting that the ‘saving a life’ prostatectomy was occurring around year 15.

These were provocative data and can be useful when discussing whether local therapy is needed for men who, due to comorbidities, may not have a life expectancy that extends much beyond that.

An addition to the conversation is a new publication from the CaPSURE™ database published by my colleague Hala Borno, MD.2 This study is part of her broader mission of identifying groups that suffer from treatment and outcome disparities in prostate cancer. The current analysis evaluates the outcome of individuals diagnosed with metastatic disease, demographic findings that might be associated with this, and what the natural history looks like. It is an interesting paper that raises some slightly vexing questions.

The data came from CaPSURE™, a network of 36 community-based urology databases throughout the country that has been in existence for almost 30 years. Borno started with a total database of over 15,000 men diagnosed with the disease, of whom 731 either had metastatic disease at the time of diagnosis or had "progressed to" metastatic disease following some form of local therapy such as radiation or radical prostatectomy. Strikingly, she showed that men who had "progressed to" metastatic disease experienced a significantly worse overall survival (2.3 years) compared to those with de novo metastatic disease (5.4 years). Overall survival was measured from the time of initial treatment for metastatic disease.

A key take-home point from this paper is that men with metastatic disease at the time of diagnosis appear to have a better prognosis than those who develop metastatic disease after undergoing local therapy. This is counter-intuitive and it leads to many questions:

  • Does "progression to" metastatic disease mean the disease has acquired biological changes /mutations during the time that the disease was undetected following local therapy? This is plausible in patients who progress to metastasis after radiation and hormonal therapy, of which there were many when one considers that prior systemic therapy (androgen deprivation therapy) may result in earlier castration resistance.
  • Is it selection bias? This analysis ‘chose’ only to look at those patients who had localized disease and went on to develop metastatic disease. In total, this is a relatively small number of the nearly 200,000 men diagnosed with prostate cancer every year. Because of that, selecting these patients for study, by definition, includes the most aggressive cases. Remember – if the prostate was removed and metastatic disease develops later, it means that undetectable metastases were there at the time of the prostatectomy!

The two most mature prospective studies evaluating the outcome of men with metastatic prostate cancer (CHAARTED and LATITUDE) are very helpful in this conversation.

In the CHAARTED study of early docetaxel in men with untreated metastatic disease, about 30% of the patients had received prior local therapy ( e.g. progressed to metastatic disease) and the overall survival was 44 months for the control arm and 57.6 months for the treatment arm.3 Christos E. Kyriakopoulos and colleagues from the University of Wisconsin did a deeper dive into the CHAARTED data and revealed that the worst outcome was observed in patients with de novo metastatic disease who did not receive docetaxel (OS 33 months) whereas the best OS is seen in the low volume patients (regardless of docetaxel use).In their analysis, the OS  ranked from worst to best goes like this:

     De novo high volume = 33 months

     Prior Rx high volume  = 52 months

     De novo low volume  = 60 months

     Prior Rx low volume  = not reached ( but >70 months)

Similarly, in the control arm of the LATITUDE study (androgen deprivation therapy [ADT] vs. ADT plus abiraterone), the median OS of patients with >10 bone mets was 14.7 months (29.6 with abiraterone) versus 22 months for those with ≤ 10 bone mets (not reached with abiraterone).5 In this study all patients had de novo metastatic disease with only a small minority who had received prior radiotherapy.

I have not done a statistical analysis to look at these outcomes, but it does seem to suggest fairly convincingly that the poor prognosis of metastatic disease, whether de novo or after primary therapy, is driven by the volume of disease.

So at the end of the day what I think Dr. Borno’s data reveals is a confirmation of something we already know: volume of disease matters. But we should not stop there. Why does the volume of disease matter? I have many patients in my practice who have had great responses to ADT plus abiraterone or ADT plus docetaxel who started out with high volume disease. What is most likely going on is a wide range of genomic factors in high volume disease based entirely on the fact that more cancer leads to more opportunity for mutation and clonal heterogeneity, and more opportunity for treatment mediated selection pressure to drive resistant clones forward, leading to the death of the patient.

Thus, one of our key efforts moving forward has to be moving beyond simply counting lesions on a bone scan (we could have done that in the 1970s as this is still the technology we are using) and into describing metastatic disease by tumor subtype. My prediction and the data will be emerging to show this, is that in the future we will be describing metastatic tumor using these or similar descriptors:

  • Pure adenocarcinoma without genomic complexity
  • Neuroendocrine containing disease (may be a small subset of tumor)
  • PAM50 scoring: basal subtype vs. luminal subtyping
  • Key genomic driver – TP53, Rb1, PTEN loss alone or in combination

More to come on this important topic, I hope!

Written by: Charles Ryan, MD, B.J. Kennedy Chair in Clinical Medical Oncology, Professor of Medicine and Director of the Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota


1. Bill-Axelson, Anna, Lars Holmberg, Hans Garmo, Kimmo Taari, Christer Busch, Stig Nordling, Michael Häggman et al. "Radical prostatectomy or watchful waiting in prostate cancer—29-year follow-up." New England Journal of Medicine 379, no. 24 (2018): 2319-2329.

2. Borno, Hala T., Janet E. Cowan, Shoujun Zhao, Jeanette M. Broering, Peter R. Carroll, and Charles J. Ryan. "Examining initial treatment and survival among men with metastatic prostate cancer: An analysis from the CaPSURE registry." In Urologic Oncology: Seminars and Original Investigations, vol. 38, no. 10, pp. 793-e1. Elsevier, 2020.

3. Sweeney, Christopher J., Yu-Hui Chen, Michael Carducci, Glenn Liu, David F. Jarrard, Mario Eisenberger, Yu-Ning Wong et al. "Chemohormonal therapy in metastatic hormone-sensitive prostate cancer." New England Journal of Medicine 373, no. 8 (2015): 737-746.

4. Kyriakopoulos, Christos E., Yu-Hui Chen, Michael A. Carducci, Glenn Liu, David F. Jarrard, Noah M. Hahn, Daniel H. Shevrin et al. "Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial." Journal of Clinical Oncology 36, no. 11 (2018): 1080.

5. De Bono, Johann, Mario Eisenberger, and Oliver Sartor. "Abiraterone in Metastatic Prostate Cancer." The New England journal of medicine 377, no. 17 (2017): 1694.