Abiraterone in castrate-sensitive prostate cancer

  • Date: 14 Nov 2017
  • Author: Manuel Maia, Sumanta Pal
  • Affiliation: Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
  • Link: Read the original article
  • Topic: Genitourinary cancers
maia-manuel
pal-sumanta

Metastatic prostate cancer remains a lethal disease.[1, 2] In the past several years, we have seen an influx of numerous novel therapeutic approaches for this disease with a significant impact in overall survival (OS).[3-8] The majority of these treatments have been applied in the castration-resistant setting, whereas castration-sensitive prostate cancer (CSPC) therapy has been kept relatively unchanged for many years after Charles Huggins first demonstrated the impact of androgen deprivation therapy (ADT) on prostate cancer treatment.[9] However, about two years ago, docetaxel, an older chemotherapy agent already approved for castration-resistant disease, was shown to prolong OS when added to ADT in the context of castration-sensitive disease, although at the cost of increased toxicity and the risk of febrile neutropenia.[10, 11]

 Two studies support the early use of docetaxel: (1) the American CHAARTED trial and (2) one of the cohorts from the large European STAMPEDE trial. [10, 11] While both trials showed a significant improvement in OS in the overall population, the benefit among low volume disease is still questionable and most oncologists reserve this approach for high volume disease only.[12]

This year at the American Society of Clinical Oncology Annual Meeting, two new studies shed light on the metastatic CSPC field again: the LATITUDE and another arm of the STAMPEDE trial, both published in the same issue of the New England Journal of Medicine simultaneously with the meeting. [13, 14]

These studies investigated the impact on efficacy of the addition of abiraterone to ADT earlier in the disease course. Fizazi et al [13] reported the results of the LATITUDE trial, a phase 3, placebo-controlled study, which randomised 1199 metastatic, high-risk patients to ADT plus placebo or ADT plus abiraterone and prednisone. High-risk was defined as at least two of the following three variables: visceral metastasis, 3 or more bone metastasis and/or Gleason score of 8 or higher. The study met its two co-primary endpoints, showing a significant prolongation of the median OS (not reached vs 34.7 months; HR 0.62, 95%CI 0.51-0.76; P<0.001) and radiographic progression-free survival (33 months vs 14.8 months; HR 0.47, 95%CI, 0.39-0.55, P<0.001) in the abiraterone group compared to placebo group. The study also met all of its secondary endpoints: time to next skeletal-related event, time to PSA progression, time to next therapy for prostate cancer, time to initiation of chemotherapy and time to pain progression. [13]

The second study, reported by James et al [14], was also a phase 3 trial. In contrast to the previous study, patients with non-metastatic disease (48%) were also allowed and metastatic disease with any number and/or location was permitted.  A total of 1917 patients were enrolled and randomized to ADT alone or ADT plus abiraterone and prednisone. The addition of abiraterone + prednisone to ADT decreased the risk of death by 37% in the overall population (HR 0.63; 95%CI 0.52-0.76; P<0.001). The 3-year OS was 83% for abiraterone group and 76% for the control. A pre-planned subgroup analysis showed, however, that the benefit was restricted to the metastatic population (metastatic, HR 0.61; 95% CI 0.49-0.75; non-metastatic, HR 0.75; 95% CI 0.48-1.18). The study also met its co-primary endpoint of failure-free survival: 3-year failure-free survival was 75% in the combination group and 45% in the ADT alone group (HR for treatment failure, 0.29; 95% CI, 0.25 to 0.34; P<0.001). [14]

While these two important trials showed impressive results among metastatic CSPC population and add a new standard of care, the benefits seen are somewhat similar to those reported 2 years ago with the incorporation of docetaxel to ADT in this setting. In fact, OS curves are overlapping and the magnitude of benefit is similar. 

These results now pose the question of whether docetaxel or abiraterone should be sequenced first in metastatic CSPC patients. Some considerations to bear in mind and that may facilitate treatment decisions are: costs (abiraterone is considerably more expensive than docetaxel and used for a significant longer duration), disease burden (benefit with docetaxel mainly seen among high disease burden), disease stage (metastatic vs non-metastatic), comorbidities and fitness to withstand toxicities.

References         

  1. Vollmer, R.T. The dynamics of death in prostate cancer. Am J Clin Pathol 137, 957-62 (2012).
  2. Bastian, P.J. et al. High-risk prostate cancer: From definition to contemporary management. European Urology 61, 1096-1106 (2012).
  3. Kantoff, P.W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. The New England journal of medicine 363, 411-22 (2010).
  4. Berthold, D.R. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival in the TAX 327 study. Journal of Clinical Oncology 26, 242-245 (2008).
  5. Parker, C. et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369, 213-223 (2013).
  6. De Bono, J.S. et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. The Lancet 376, 1147-1154 (2010).
  7. Ryan, C.J. et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 16, 152-60 (2015).
  8. Beer, T.M. et al. PREVAIL Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. The New England journal of medicine, 1-10 (2014).
  9. Huggins C, S.R., Hodges CV. Studies on prostatic cancer: 2. The effects of castration on advanced carcinoma of the prostate gland. . Arch Surg 43:209. (1941).
  10. Sweeney, C.J. et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. New England Journal of Medicine, 150805140037008-150805140037008 (2015).
  11. James, N.D. et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. The Lancet 6736, 1-15 (2015).
  12. Lee, R., & Smith, M. (2017). Initial systemic therapy for castration sensitive prostate cancer. In Ross ME (Ed.), UpToDate. Waltham, MA. (Accessed on June 26, 2017).
  13. Fizazi, K. et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med (2017).
  14. James, N.D. et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med (2017). 

Discussion questions

  1. What is the best combination for ADT in the castrate-sensitive setting?
  2. Should abiraterone be used both in high-risk and non-high-risk patients?
  3. Should abiraterone be used in the non-metastatic population as well?

 

Manuel Maia and Sumanta Pal declare no actual, potential, real or apparent interest. The authors declare to have no involvement that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated.

Abiraterone in castrate-sensitive prostate cancer
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I completely agree with you, it takes a lot of time, resources to do such a trial.
Are there any trials ongoing which are evaluating the potential of combining abiraterone and enzalutamide given the different and possibly synergistic mechanism of action of both?
Dr Gumdal Vishesh

Dr Gumdal Vishesh, I completely agree with you in that a phase 3 comparison would be ideal. Indeed, the point you raised summarizes one of the greatest challenges that we face when running clinical trials: the field has often changed quite substantially by the time some studies are presented/published, as it takes several years before results from phase 3 studies mature. However, I am afraid that a formal comparison of these two agents in a phase 3 is unlikely to happen, since it would take many patients and many years to answer a non-inferiority trial, not to mention the cost to run a phase 3 study. Nevertheless, since STAMPEDE enrolled patients in both arms (docetaxel and abiraterone) in a prospective manner, I think it gives us a quite convincing comparison of the two approaches, as presented at ESMO this year, showing they provide similar benefit (except for failure-free survival). So I would argue that we may not necessarily need a phase 3 comparing docetaxel and abiraterone at this point. In fact, as many other approaches are emerging (e.g.enzalutamide is being evaluated in the same setting; combination of docetaxel and abiraterone; targeted therapies), we will soon face new questions to be answered. Happy to discuss further if you wish: mcaitano@coh.org
Manuel Maia

Abiraterone versus docetaxel in the castrate sensitive setting.

All the recent data has been well summarized here. I have an opinion which we can discuss upon. Before Abiraterone in the castrate sensitive setting, Docetaxel was standard. Abiraterone in the LATTITUDE and STAMPEDE trials has been compared against placebo. I think the ideal study is to do a comparison of abiraterone against docetaxel in the castrate sensitive setting, as Docetaxel was standard before. More over Docetaxel is much cheaper, albeit slightly more toxic. Atleast a non-inferiority trial between abiraterone and docetaxel is more valid than a comparison of abiraterone with placebo.
Dr Gumdal Vishesh
g.vishesh@gmail.com

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