Combination Therapy with Docetaxel for Metastatic Castration-Resistant Prostate Cancer – New Drugs with New Promise?

When docetaxel first emerged on the prostate cancer scene, the world celebrated our first agent that offered an overall survival benefit for patients with metastatic castration-resistant prostate cancer.1,2  Although, there are now many more agents regulatory approved for metastatic castration-resistant prostate cancer, docetaxel remains an important “tool in our toolbox” in our attempts to improve survival and quality of life for our patients.

For the next decade after docetaxel’s approval for metastatic castration-resistant prostate cancer, the field saw multiple combination therapy trials with docetaxel without any success.  This included multiple randomized, phase 3, controlled trials, with no therapeutic agents affording the ability to offer a survival improvement when added to docetaxel.3-11

A couple of agents (e.g. DN-101 and lenalidomide) even found a statistically significant survival decrement when the agent was combined with docetaxel.  Mechanisms of action of these various agents were distinct, ranging from antiangiogenesis (e.g. bevacizumab, lenalidomide, and aflibercept), apoptotic induction (e.g. custirsen), SRC kinase inhibition (e.g. dasatinib), high dose calcitriol (e.g. DN-101), endothelin receptor antagonism (e.g. atrasentan and zibotentan) and immunotherapeutic approaches (e.g. GVAX).

One can ask the obvious question, “why the lack of success?”  A simple answer is that these older agents were not efficacious enough to contribute overall survival benefit when added to docetaxel over docetaxel alone.  Perhaps there was a lack of synergism or even additive properties when added to docetaxel?  Perhaps there could have even been antagonism?  The survival decrement observed in 2 of the trials above could certainly support the latter assumption.10,11  The answer to our failures also lays in basic clinical trial design and biostatistics principles.  When you already have one active agent, like docetaxel, your statistical bar to improve upon that is obviously going to be higher than if you have no active agent or a minimally active agent as the control to compare your novel therapeutic to. Ultimately, these are the challenges of taking a pragmatic approach to drug development.  A combination with docetaxel offered a regulatory strategy for new drug development and a registrational pathway.  Unfortunately, the lack of success of this strategy of combination with docetaxel in prostate cancer has earned the non-complimentary nickname of being the “graveyard” of new drug development. 

Fortunately, more recent strategies with docetaxel, moving the agent earlier into the castration-sensitive disease state, has led to outstanding benefit for our patients.12,13  Yet again, when combined with a potent androgen receptor antagonist, there was no benefit observed in a subgroup analysis of approximately 40% of patients who were receiving docetaxel and where enzalutamide was added in the ENZAMET trial, Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET).14  Surprisingly, there was an increase in docetaxel-associated adverse events, making one believe that there is likely some pharmacologic interaction ongoing to potentiate those side effects.  We will soon see more similar data from the readout of the ARASENS trial, A phase 3 trial of darolutamide in combination with docetaxel for men with metastatic hormone-sensitive prostate cancer (mHSPC) (ARASENS), where all patients received androgen deprivation therapy and docetaxel for metastatic castration-sensitive prostate cancer, and the randomization entailed receipt of darolutamide or not (NCT02799602).

This leads us to the newer wave of trials that are actively enrolling for combination with docetaxel in the metastatic castration-resistant prostate cancer disease state.  As an optimist and medical oncologists should be such, I am hopeful that with newer, promising therapeutic agents, that we can see better outcomes.  Some of these combinations include agents already regulatory approved, offering survival benefit of their own (e.g. radium-223).  Other trials include checkpoint inhibitors, that have offered benefit in countless malignancies, hoping to break into the prostate cancer realm.  Let’s hope for some winners with this next wave of trials!

Highlighted docetaxel combination therapy trials for metastatic castration-resistant prostate cancer patients

  • Randomized Phase 3 trial of Nivolumab or Placebo in combination with docetaxel (CHECKMATE 7DX) (NCT04100018)
  • Phase 2 trial of Nivolumab in combination with rucaparib, docetaxel or enzalutamide (CHECKMATE 9KD) (NCT03338790)
  • Randomized Phase 3 trial of Pembrolizumab or Placebo in combination with docetaxel (KEYNOTE-921) (NCT03834506)
  • Randomized Phase 3 trial of Masatinib or Placebo in combination with docetaxel (NCT03761225)
  • Phase 1 trial of fractionated docetaxel with radium-223 (NCT03737370)
  • Randomized Phase 3 trial of docetaxel with radium-223 vs. docetaxel alone (NCT03574571)
Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium

References

  1. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. N Engl J Med 2004; 351:1502-12.
  2. Petrylak DP, Tangen CM, Hussain MH, et al.  Docetaxel and Estramustine Compared With Mitoxantrone and Prednisone for Advanced Refractory Prostate Cancer. N Engl J Med  2004; 351:1513-20.
  3. Quinn DI, Tangen CM, Hussain M, et al.  Docetaxel and Atrasentan Versus Docetaxel and Placebo for Men With Advanced Castration-Resistant Prostate Cancer (SWOG S0421): A Randomised Phase 3 Trial. Lancet Oncol 2013; 14:893-900.
  4. Fizazi K, Higano CS, Nelson JB, et al.  Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer.  J Clin Oncol  2015; 31:1740-7.
  5. Small EJ, Gerritsen WR, Rolland F, et al. A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel versus docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer (CRPC) 2009 ASCO Genitourinary Cancers Symposium 2009; Abstract 7.
  6. Tannock IF, Fizazi K, Ivanov S, et al. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol 2013; 14:760-8.
  7. Kelly WK, Halabi S, Carducci M, et al. Randomized, Double-Blind, Placebo-Controlled Phase III Trial Comparing Docetaxel and Prednisone With or Without Bevacizumab in Men With Metastatic Castration-Resistant Prostate Cancer: CALGB 90401. J Clin Oncol  2012; 30:1534-40.
  8. Chi KN, Higano CS, Blumenstein B, et al.  Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial. Lancet Oncol 2017; 18:473-85.
  9. Araujo JC, Trudel GC, Saad F, et al. Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol 2013; 14:1307-16.
  10. Petrylak DP, Vogelzang NJ, Budnik N, et al. Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial, Lancet Oncol 2015; 16:417-25.
  11. Scher HI, Jia X, Chi K, et al. Randomized, Open-Label Phase III Trial of Docetaxel Plus High-Dose Calcitriol Versus Docetaxel Plus Prednisone for Patients With Castration-Resistant Prostate Cancer. J Clin Oncol 2011; 29:2191-8.
  12. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer.  N Engl J Med  2015; 373:737-46.
  13. James ND, Sydes MR, Clarke NW, 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. Lancet  2016; 387:1163-77.
  14. Davis ID, Martin, AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med 2019; 381:121-31.
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