ASCO 2019: Intensified Up-Front Therapy for Prostate Cancer: The Revolution Continues with ENZAMET

Chicago, IL (UroToday.com) The presentation of ENZAMET, overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial, by Christopher Sweeney, MBBS, was followed by Tanya B. Dorff, MD, of City of Hope Cancer Center, who provided a discussion of this highly anticipated phase 3 trial demonstrating an OS benefit for enzalutamide vs non-steroidal anti-androgen among men with mHSPC. Following Dr. Sweeney’s presentation, ENZAMET was immediately published in the New England Journal of Medicine.1

Dr. Dorff notes that the Revolution in Prostate Cancer Therapy began in 2015 – before CHAARTED was published2 we “saved arrows in our quiver:” SWOG9916 and TAX327 found that docetaxel prolonged median survival ~2 months in mCRPC. In CHAARTED, up front docetaxel increased median OS by 13.6 months, which was simultaneously confirmed in STAMPEDE.3 It became evident that hitting prostate cancer hard and early was critical to long-term control.

The Revolution continued in 2017 with the addition of up-front abiraterone. Previously, abiraterone acetate plus prednisone in mCRPC prolonged survival with an HR of 0.65 post-docetaxel (COU-301)4 and HR 0.75 pre-docetaxel (COU-302).5 Up-front abiraterone increased median OS with an HR 0.62 in LATITUDE6 and improved 3-year survival from 76% to 83% (HR 0.63) in STAMPEDE.7

Dr. Dorff notes that with the reporting of ENZAMET, the Revolution is now validated. Enzalutamide previously improved survival in mCRPC with a hazard ratio (HR) of 0.63 post-docetaxel (AFFIRM)8, and HR 0.71 in the pre-docetaxel setting (PREVAIL).9 Furthermore, enzalutamide delayed metastasis by a median 22 months in non-metastatic CRPC (PROSPER).10 ENZAMET showed a 3-year OS increase from 72% to 79% and a HR for OS of 0.67 (95%CI 0.52-0.86).

ASCO2019_Dorff_ENZAMET_1.png
Dr. Dorff notes that there are several statistical aspects of interest with regards to ENZAMET:
  • The OS benefit in ENZAMET was similar to previous mHSPC studies, despite using a more active control (bicalutamide, flutamide, or nilutamide)
  • The control arm performed better than assumed (72% OS at 3-years, whereas the assumption, was 65%)
  • Only 50% of planned events have occurred
  • These results are supported by the ARCHES11 finding of PFS benefit with up-front enzalutamide
  • There is proof of concept support from TITAN12: OS benefit in mHSPC achieved with another next-generation AR antagonist apalutamide
Whether up-front intensification is well-tolerated is an important consideration. In LATITUDE, the abiraterone group had a grade 3/4 adverse event rate of 63%; enzalutamide had its usual side effect profile that has been described in other studies, including hypertension (grade 3/4 adverse events 43%), fatigue (grade 3/4 adverse events 31%), and cardiac disorders (grade 3/4 adverse events 29%). Dr. Dorff provides an excellent slide assisting clinicians with regards to how to choose between the up-front agents:

ASCO2019_Dorff_ENZAMET_2.png
Dr. Dorff poses the question, Why not combine (sequence) chemotherapy and androgen receptor targeted therapy in mHSPC? Interestingly, there was less benefit seen in patients treated with docetaxel up-front in ENZAMET, and no study has shown the synergy of AR-targeted therapy plus docetaxel, although the combination of full doses is safe. Second, there is less benefit seen in high volume patients, as 70% received docetaxel whereas <40% of low volume patients received docetaxel. Finally, dedicated trials will answer whether there is an advantage to using both (ie. ARAMIS with darolutamide, PEACE1 with abiraterone).

Several other considerations are important, as noted by Dr. Dorff. When ENZAMET was assessed by the ASCO Net Health Benefit it scored 33; a Net Health Benefit score of ≥46 is defined as substantial, whereas a value ≤41 is defined as low value. Interestingly, ENZAMET scored similarly to other mHSPC studies. Second, no biomarkers are currently available to select mHSPC patients for abiraterone vs enzalutamide vs docetaxel. AR-V7 shows some promise in selecting between AR-targeted therapy and docetaxel in mCRPC, but does not differentiate likelihood of response with abiraterone vs enzalutamide; AR-V7 is rarely present in mHSPC. Third, novel circulating tumor cell biomarkers may be of interest in that CTC heterogeneity is associated with shorter duration of response with AR-targeted therapy. But whether CTC heterogeneity is commonly present in mHSPC is still to be fully determined. Additional questions that remain to be answered and are currently under investigation include (i) Should we treat the primary? (ii) Should we use metastasis-directed therapy (ie. SBRT)? (iii) Is continuous therapy still necessary?

Dr. Dorff concluded this discussion of ENZAMET with several remarks:
  • Hitting prostate cancer hard and early is critical for long-term cancer control
  • There is no strong evidence of benefit for doing both docetaxel and enzalutamide
  • Multiple options for up-front intensification include abiraterone, docetaxel, apalutamide, or enzalutamide – currently there is no evidence that one is superior to the others
Clinical trial information: NCT02446405

Presented by: Tanya B. Dorff, MD, Medical Oncologist and Associate Clinical Professor, City of Hope Cancer Center, Los Angeles, California

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med 2019 June 2 [Epub ahead of print].
  2. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015;373(8):737-746.
  3. 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. 2016;387(10024):1163-1177.
  4. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.
  5. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148.
  6. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-360.
  7. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377(4):338-351.
  8. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187-1197.
  9. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371(5):424-433.
  10. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018 Jun 28;378(26):2465-2474.
  11. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. Phase 3 study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial. J Clin Oncol 37, 2019 (suppl 7S; abstr 687).
  12. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med 2019 May 31 [Epub ahead of print].