Overall Survival of Men with Metachronous Metastatic Hormone-Sensitive Prostate Cancer Treated with Enzalutamide and Androgen Deprivation Therapy - Beyond the Abstract

Evidence has been presented in the last seven years that has transformed the management of metastatic hormone-sensitive prostate cancer (mHSPC). The principles of management for about seven decades had fundamentally been around testosterone suppression. We now have clear data for the benefit of docetaxel (CHAARTED, STAMPEDE), abiraterone (LATITUDE, STAMPEDE), apalutamide (TITAN), and enzalutamide (ARCHES, ENZAMET).

All these approaches have been shown to improve survival substantially, but they have also provided new clues to previously undefined biology. The most obvious point is the stark difference in benefit when these agents are used in the mHSPC setting compared to patients with castrate-resistant prostate cancer (CRPC). There is something fundamentally different about how these agents work in cancers that have not yet experienced the selection pressure of testosterone suppression. Additionally, the pattern of disease is now known to be very important: for example, the benefits of adding docetaxel to testosterone suppression are mainly seen in patients with high burden of disease and who have so-called “de novo” metastatic disease, ie have synchronous metastases at the time of their initial diagnosis.1 Patients who have previously had definitive treatment for their primary prostate cancer in the setting of no known metastases on conventional imaging (CT abdomen/pelvis and 99mTc bone scan), and who later develop metachronous metastatic disease (also as assessed by conventional imaging), have cancers that behave differently. Those patients often have lower burdens of disease, and treatment with testosterone suppression alone is associated with longer survival compared to those with de novo/synchronous metastatic prostate cancer at the time of diagnosis.

The reasons underlying this observation are not clear. It might at first be thought that it relates to patterns of clinical management: patients who have had prior definitive therapy might be watched more carefully, and have metastatic disease diagnosed earlier and at a lower volume than those whose unsuspected cancer has progressed until metastases become clinically evident. This idea does not hold up to scrutiny. For example, it does not align with the observation that patients with de novo low volume metastases by conventional imaging have a median overall survival of about 4.5 years, compared to about 8 years for those with metachronous relapsing mHSPC. Patients who develop mHSPC after prior definitive therapy are usually monitored and are hence more likely to be diagnosed by PSA relapse. They often commence testosterone suppression at that point even if conventional imaging is negative and, in that case, subsequent metastatic disease is in the setting of castration resistance. In contrast, widespread de facto PSA screening means that clinically silent prostate cancers are more likely to be found earlier than later, and be less likely to be metastatic by conventional imaging at time of first diagnosis. Timing of progression and response will likely shift due to lead time bias, particularly if novel imaging technologies such as 68Ga-PSMA PET or similar are used, but otherwise, these cancers would be expected to behave similarly if the underlying biology is the same. Other as-yet-unknown factors must be contributing to the observed biological differences.

These observations have led to considerable controversy about which agent might be optimal for use for mHSPC. The benefits of the addition of docetaxel to testosterone suppression are clear for patients with high burdens of metastatic disease, defined in various ways, but are inconsistent: the benefit of docetaxel treatment is lower for those with de novo/synchronous or low disease burden mHSPC, and there is little evidence of benefit for metachronous low volume mHSPC. Patients with metachronous high volume mHSPC derive benefits from docetaxel comparable to those with de novo high volume disease.2 In contrast, the agents targeting androgen receptor signaling more directly (abiraterone, apalutamide, enzalutamide) all clearly show benefit in low burden mHSPC.3-7 However, until recently there has been a gap in the evidence: can outcomes be improved specifically in the group of patients with metachronous low volume/low burden mHSPC?

Work from the TITAN8 and ENZAMET7 trials now gives insight into this question.9 An unplanned subgroup analysis of ENZAMET data from its first interim analysis found 312 men with no metastatic disease documented at the time of original diagnosis, and metachronous mHSPC at the time of entry to ENZAMET. Most (205/312, 66%) had low-volume disease. The addition of enzalutamide to testosterone suppression gave a hazard ratio for death of 0.56 (95% CI: 0.29–1.06) for all men with metachronous metastases, and 0.40 (95% CI: 0.16–0.97) for those with low-volume metastases. This was reflected in the 3-year landmark analyses, with 3-year overall survival of  83% (95% CI: 0.74–0.89) and 89% (95% CI: 0.80– 0.94) for those with metachronous disease, and 83% (95% CI: 0.71–0.90) and 92% (95% CI: 0.82–0.96) for those low-volume disease. Only a small proportion (31/205, 15%) of these patients received concurrent docetaxel. In contrast, for those with metachronous high-volume disease, most (64, 60%) received docetaxel, and the benefit of additional enzalutamide was not evident at this analysis for this group or for the group of all patients with high volume metachronous disease.

The TITAN trial was similar in concept, although the experimental drug was apalutamide, and concurrent docetaxel was not administered. Nevertheless, similar patterns were seen for those with metachronous disease with a low and high volume combined, and a pooled analysis of data from both TITAN and ENZAMET showed HR 0.46 (95% CI 0.30–0.70) for these patients.

What does this mean for practice? Although these analyses were unplanned, they are consistent with previous observations and give more confidence that patients with metachronous low-volume mHSPC should be offered treatment additional to testosterone suppression, with the strongest evidence for benefit lying with either apalutamide or enzalutamide. It is possible this could also be true for abiraterone, another strategy to target AR more potently with evidence of benefit regardless of volume of disease, but these patients were either not included or accounted for <10% of participants in the respective studies.3,4 Translational work and longer follow-up from these trials might shed light on the underlying mechanisms for these observed biological differences and might offer clues as to more reliable ways of selecting which patients should receive which treatment in addition to testosterone suppression. This will result in optimal use of these medications and can only improve patient outcomes. Details of the collaborative clinical and biological harmonization projects in localized and metastatic hormone-sensitive prostate cancer can be found at icecap.movember.com.

None of this information will benefit our patients if the evidence is not taken up into practice. Recent work from Australia showed a clear and rapid uptake of the use of docetaxel in mHSPC after the CHAARTED data were presented in 2014,10 although almost 80% of men aged 70 or more did not receive it. It is now clear that men aged 70 or older who are able to receive docetaxel in this setting have benefits similar to those aged younger than 70.11 Data presented at ASCO 202112,13 show that less than one-third of patients with mHSPC received treatment additional to testosterone suppression by 2018, with substantial disparities across racial classifications.

Perhaps there is a view that patients with better prognoses, such as those with metachronous low volume mHSPC, do not require systemic treatment intensification. We now know that such a view is not supported by the available evidence. It is incumbent upon all of us to understand the data and to have conversations with our patients to ensure they are offered the best and most appropriate treatments.

Conflict of interest statement:

IDD has been a member of the following advisory boards within the last two years: Astellas, AstraZeneca, Bayer, Eisai, Ipsen, Janssen, Merck/MSD, Pfizer, Roche. All honoraria are paid directly to ANZUP Cancer Trials Group. IDD is unremunerated director and chair of ANZUP Cancer Trials Group. IDD is global co-chair with CJ Sweeney of the ANZUP ENZAMET trial.

Written by: Ian D. Davis MB BS (Hons) PhD FRACP FAChPM, Professor of Medicine, Monash University and Eastern Health, Head, Eastern Health Clinical School, Monash University Faculty of Medicine, Nursing and Health Sciences, Medical oncologist, Eastern Health, Chair, ANZUP Cancer Trials Group


  1. Gravis G, Boher J-M, Chen Y-H, et al: Burden of Metastatic Castrate Naive Prostate Cancer Patients, to Identify Men More Likely to Benefit from Early Docetaxel: Further Analyses of CHAARTED and GETUG-AFU15 Studies. Eur Urol 73:847-855, 2018
  2. Kyriakopoulos CE, Chen YH, Carducci MA, et al: Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial. J Clin Oncol 36:1080-1087, 2018
  3. Fizazi K, Tran N, Fein L, et al: Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 377:352-360, 2017
  4. James ND, de Bono JS, Spears MR, et al: Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med 377:338-351, 2017
  5. Chi KN, Agarwal N, Bjartell A, et al: Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 381:13-24, 2019
  6. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al: ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol 32:2974-2986, 2019
  7. Davis ID, Martin AJ, Stockler MR, et al: Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med 381:121-131, 2019
  8. Chi KN, Chowdhury S, Bjartell A, et al: Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol 2021, April 29 (online ahead of print).
  9. Sweeney CJ, Martin AJ, Stockler MR, et al: Overall Survival of Men with Metachronous Metastatic Hormone-sensitive Prostate Cancer Treated with Enzalutamide and Androgen Deprivation Therapy. Eur Urol 2021 May 21;S0302-2838(21)00354-7. doi: 10.1016/j.eururo.2021.05.016. Online ahead of print.
  10. Azad AA, Tran B, Davis ID, et al: Predictors of real-world utilisation of docetaxel combined with androgen deprivation therapy in metastatic hormone-sensitive prostate cancer. Int Med J 2021, Accepted Author Manuscript, online 12 March 2021.  https://doi.org/10.1111/imj.15288
  11. Lage DE, Michaelson MD, Lee RJ, et al: Outcomes of older men receiving docetaxel for metastatic hormone-sensitive prostate cancer. Prostate Cancer Prostatic Dis, 2021 May 5, https://doi.org/10.1038/s41391-021-00389-2
  12. Freedland SJ, Agarwal N, Ramaswamy K, et al: Real-world utilization of advanced therapies and racial disparity among patients with metastatic castration-sensitive prostate cancer (mCSPC): A Medicare database analysis. J Clin Oncol 39 (suppl 15; abstr 5073), 2021
  13. George DJ, Agarwal N, Rider JR, et al: Real-world treatment patterns among patients diagnosed with metastatic castration-sensitive prostate cancer (mCSPC) in community oncology settings. J Clin Oncol 39 (suppl 15; abstr 5074), 2021

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