From the Desk of Evan Yu: "Enzalutamide and Apalutamide Now Offer Survival Benefit for Patients with Metastatic Castration-sensitive Prostate Cancer, but How Do Things Change Now and What Should We Be Doing Next?"

For patients with metastatic castration-sensitive prostate cancer, it is clear that early treatment intensification by adding agents like docetaxel or abiraterone acetate to androgen deprivation therapy (ADT) offers overall survival benefit. The CHAARTED1 and STAMPEDE2 trials both demonstrated a dramatic survival benefit with 6 cycles of docetaxel added to ADT. In the long term survival analysis of the CHAARTED trial, the benefit was confined to those patients with high volume disease, defined as ≥4 bone metastases with at least one in the appendicular skeleton and/or a visceral metastasis.3 The last time I wrote about this topic,4 2 years ago in July 2017, we had just learned from the LATITUDE5 and STAMPEDE6 trials that abiraterone acetate also provides a dramatic survival benefit when added to standard of care (SOC), generally ADT, vs. SOC alone. The survival benefit with abiraterone acetate is felt to apply to high and low volume patients alike.

At ASCO 2019, we just learned from the TITAN trial that apalutamide also offers survival benefit for patients with metastatic castration-sensitive prostate cancer when added to ADT.7 Since the trial was amended, due to the CHAARTED findings, to allow eligibility for patients who received docetaxel chemotherapy, the trial had only 11% of patients with prior exposure to docetaxel chemotherapy. The hazard ratio was 1.27, for the prior docetaxel then apalutamide plus ADT group. Not surprisingly, given the limited sample size, the confidence intervals were wide and crossed 1 in the forest plots. Hence, we were not able to discern whether the concept of “triple therapy” offers survival benefit.

The ARCHES trial results were initially presented at the 2019 Genitourinary Cancers Symposium, and the trial met its primary endpoint of a radiographic progression-free survival benefit for ADT with enzalutamide over ADT alone for the metastatic castration-sensitive prostate cancer population.8 At the ASCO 2019 update, it became apparent that approximately 18% of the population from ARCHES had received prior docetaxel and that there was a clear radiographic progression-free survival benefit to the addition of enzalutamide to this subgroup.9 Yet, overall survival data is not yet mature from this trial.

Finally, the ENZAMET trial results were presented at the plenary session of ASCO 2019.10 This trial clearly demonstrated that enzalutamide offers an overall survival benefit for patients with metastatic castration-sensitive prostate cancer. Unique to the other trials, 45% of patients in this trial received docetaxel, hence there was more statistical power to make a statement about the addition of enzalutamide to this patient population. The results confirmed that although enzalutamide offers radiographic progression-free survival benefit to ADT plus docetaxel, it does not provide an overall survival benefit. Additionally, there was more toxicity to the ADT plus docetaxel plus enzalutamide combination.

At the time of my last article on this topic, I had asked the question of whether we should combine abiraterone and docetaxel with ADT. Although we do not have exact data to answer that question, we have more information from the Enzamet trial that suggests against a “triple therapy” approach. In my opinion, I was not surprised to see enzalutamide and apalutamide both offer an overall survival benefit. These trials provide additional confirmation that the concept of potent androgen or androgen receptor inhibition offers survival benefit to our patients with metastatic castration-sensitive prostate cancer. However, I did not quite expect docetaxel chemotherapy to be quite so powerful. My take home from this new data from ASCO 2019 is that docetaxel chemotherapy is quite impressive in its efficacy, perhaps so impressive that it is tough to improve upon overall survival with androgen or androgen receptor targeted agents. As a result, I will continue to offer abiraterone for patients with low volume disease and utilize either enzalutamide or apalutamide in patients who have challenges with volume overload, liver pathology or contraindications to the prednisone that accompanies abiraterone. However, for high volume disease, I had been offering either abiraterone or docetaxel with approximately a 1:1 breakdown in patient acceptance between those two agents. Moving forward, I plan to more strongly emphasize the efficacy of docetaxel, and the advantage of a limited 6 cycle treatment duration.

We will learn more about the concept of “triple therapy” from the ARASENS trial (NCT02799602), where 100% of patients will receive ADT plus docetaxel, and the randomization is between darolutamide vs. placebo. Extrapolating from the above Enzamet data, one might hypothesize that this trial will be negative given the fact that all patients will receive docetaxel. However, darolutamide does have a rather distinct biochemical structure unique from either enzalutamide or apalutamide, and if darolutamide were to offer an overall survival benefit in the ARASENS trial, we might see a new standard of care with “triple therapy” for those patients fit enough to receive such.

Ultimately, we may have pushed our combination trials with chemohormonal agents as far as they can take us for patients with metastatic castration-sensitive prostate cancer. Hence, as a field, we must look towards unique combinations with agents that have distinct mechanisms of action and target different tumor biology. Many trials are focused on the introduction of novel immune-oncology approaches, however, targeting DNA repair mechanisms and systemic forms of radiation are also being evaluated. Please see below for details of select ongoing trials for patients with metastatic castration-sensitive prostate cancer that fit this profile by addressing other targets.

Highlighted Trials:
  • ADT + Docetaxel + PD-1 antibody REGN2810 (NCT03951831)
  • ADT + Docetaxel vs. ADT + Docetaxel + Nivolumab vs. ADT + Ipilumumab alternating with Docetaxel + Nivolumab (NCT03879122)
  • ADT + Docetaxel followed by PROSTVAC + Ipilumumab + Nivolumab followed by a neoantigen DNA vaccine (NCT03532217)
  • Rucaparib alone (TRIUMPH) for those with DNA Repair Gene Mutations (NCT03413995)
  • ADT + Stereotactic Body Radiation Therapy followed by Radium-223 (NCT03361735)
  • ADT followed by Docetaxel + PROSTVAC vs. ADT followed by sequential Docetaxel then PROSTVAC vs. ADT followed by PROSTVAC then Docetaxel (NCT02649855)

Written by: Evan Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine,  Member, Fred Hutchinson Cancer Research Center and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center

References:
1. Sweeney C et al. "Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer." New England Journal of Medicine. 2015. DOI: 10.1056/NEJMoa1503747.
2. James ND 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. 2016. doi: 10.1016/S0140-6736(15)01037-5.
3. Kyriakopoulos CE 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. 2018. doi: 10.1200/JCO.2017.75.3657.
4.Yu, Evan. 2019. "From the Desk of Evan Yu: Another advance in metastatic hormone-sensitive prostate cancer may change standard of care options but not attitude toward clinical trials". Urotoday.com. https://www.urotoday.com/clinical-trials/from-the-editor/97209-from-the-desk-of-evan-yu-another-advance-in-metastatic-hormone-sensitive-prostate-cancer-may-change-standard-of-care-options-but-not-attitude-toward-clinical-trials.html
5. Fizazi K et al. "Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer." New England Journal of Medicine. 2017. DOI: 10.1056/NEJMoa1704174.
6. James ND et al. "Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy." New England Journal of Medicine. 2017. DOI: 10.1056/NEJMoa1702900.
7. Chi KN et al. N Engl J Med 2019; Epub May 31, 2019.
8. Armstrong A et al. J Clin Oncol 37, 2019 (suppl 7S; abstr 687).
9. Armstrong A et al. J Clin Oncol 37, 2019 (suppl; abstr 5048).
10. Davis ID et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer N Engl J Med 2019; Epub June 2, 2019.
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