Prostate cancer is the second most common cancer in men and the fourth most commonly occurring cancer worldwide, with 1.3 million new cases in 2018.1 Prostate cancer is considered to be castrate-sensitive (castration-sensitive prostate cancer [CSPC]) if it responds to medical or surgical treatment to lower a patient’s testosterone levels. Androgen-deprivation therapy (ADT) has been the cornerstone of therapy for men with CSPC since the 1940s.2 However, most metastatic CSPC (mCSPC) cannot be cured by ADT, and re‐emerges as metastatic castration-resistant prostate cancer (mCRPC) after around 2 years. In addition, the prognosis for men presenting with men with mCSPC, which accounts for around 4% of prostate cancer cases in the Western world, is poor.3,4 This condition has a variable presentation and clinical course, ranging from indolent to aggressive and rapidly fatal.4
The treatment landscape for metastatic prostate cancer has evolved in recent years. In 2004, the FDA approved docetaxel, the first chemotherapy for metastatic prostate cancer that showed a survival benefit. More recently, the introduction of novel androgen receptor targeted therapies abiraterone acetate (Zytiga®; Janssen, Beerse, Belgium) and enzalutamide (Xtandi®; Pfizer, New York, NY, US), has further improved treatment outcomes.5,6 However, until recently, androgen receptor targeted agents were not approved for the treatment of mCSPC. Two recent studies, STAMPEDE, and LATITUDE, have shown that the addition of abiraterone acetate has improved outcomes for patients with mCSPC7,8 and, as a result, the combination of abiraterone acetate and ADT has received FDA approval for mCSPC and become the new standard of care. It is therefore unsurprising that enzalutamide has been investigated in the same indication. Enzalutamide is currently approved in the US and Japan for the treatment of CRPC and in the EU for the treatment of metastatic and high-risk non-mCRPC.
Data from the phase III ARCHES study were presented at the 2019 Genitourinary Cancers Symposium, which was held on 14– 16 February 2019 in San Francisco, CA.9 In this study, 1,150 men were randomly assigned to receive to enzalutamide plus ADT (n=574) or placebo plus ADT (n=576). Patients were stratified by disease volume (according to the CHAARTED criteria)10 and prior docetaxel therapy. The primary endpoint was radiographic progression-free survival (rPFS) assessed centrally or death within 24 weeks of treatment discontinuation. Secondary endpoints included time to prostate-specific antigen (PSA) progression, PSA and radiographic responses, and overall survival (OS). Among the participants, 67% had distant metastasis at initial diagnosis, 63% had high volume disease, and 18% had received prior docetaxel therapy. At a median follow-up of 14.4 months, patients in the enzalutamide group showed improvements in rPFS compared to ADT alone (not reached versus 19.4 months, hazard ratio [HR] 0.39). There were also significant improvements in rPFS in prespecified subgroups of disease volume, pattern of spread, region and prior docetaxel (HR 0.24–0.53). Secondary endpoints showed that enzalutamide plus ADT reduced the risk of PSA progression (HR=0.19; p<0.0001) and reduced the risk of starting a new antineoplastic therapy (HR=0.28; p<0.0001) compared to the placebo plus ADT group. Undetectable PSA and objective response rates were also higher in the enzalutamide plus ADT group compared with ADT alone (68.1% versus17.6%; p<0.0001 and 83.1% versus 63.7%; p<0.0001, respectively). Treatment with enzalutamide plus ADT did not significantly reduce the risk of deterioration in urinary symptoms compared to ADT alone. OS data were immature and not reported. 9
At the time of reporting, only 84 deaths had occurred, with a statistically non-significant 19% reduction in deaths in favour of enzalutamide (HR 0.81, p=0.33). Preliminary analysis suggests that the safety profile of enzalutamide was consistent with that reported in other studies. Grade 3–4 adverse events (AEs) were reported in 24.3% of the enzalutamide group versus 25.6% of patients taking placebo, and no unexpected AEs occurred. Withdrawal as a result of AEs were reported in 7.2% of the enzalutamide treated patients and 5.2% of the placebo-treated patients.9
Lead author Andrew Armstrong, Director of Research in the Duke Cancer Institute’s Center for Prostate and Urologic Cancers, said: “The ARCHES trial demonstrated that Xtandi plus standard hormonal therapy delayed disease progression, and if approved, has the potential to be an important treatment option for men with prostate cancer that has spread but has not yet become hormone resistant,”11
Until this study, no data existed supporting the benefits of sequential use of docetaxel and ADT with a second-generation androgen receptor pathway inhibitor. Enzalutamide has proven effective in a broad population of men with mCSPC regardless of age, pattern of spread, disease burden or prior chemotherapy use. Based on these results, enzalutamide is likely to receive regulatory approval for men with mCSPC. The choice of whether to use abiraterone acetate or enzalutamide is likely to depend on their side effect profile. Recent head-to head studies in patients with mCRPC suggest that abiraterone acetate plus prednisone is should not be used as initial therapy for men with diabetes, poor glucose control, heart failure, or fluid overload. The use of abiraterone acetate can result in hypokalaemia and requires monitoring of potassium levels and liver function tests. In addition, enzalutamide is not recommended in men with seizures, on seizure-lowering medications, or taking medications with epileptogenic potential and fatigue. For patients without these issues, the choice is likely to be a matter of physician preference.12
In summary, the ARCHES study has given us another therapeutic option for mCSPC. Further work will be needed to determine which patients will be the best candidates for androgen receptor targeted therapies. Since combined approaches have proven effective in men with mCRPC, the use of additional systemic agents, including PARP inhibitors, immunotherapy and other combination approaches, may further improve on outcomes in mCSPC.13,14
1. World Cancer Research Fund (WCRF): Prostate Cancer Statistics. 2018. Available at: www.wcrf.org/dietandcancer/cancer-trends/prostate-cancer-statistics (accessed 20 March 2019).
2. Huggins C, Stephens RE, Hodges CV. Studies on prostate cancer II. The effects of castration on advanced carcinoma of the prostate. Arch Surg. 1941;43:209–23.
3. American Cancer Society: Survival rates for prostate cancer. 2019. Available at: www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/survival-rates.html (accessed 20 March 2019).
4. Mosillo C, Iacovelli R, Ciccarese C, et al. De novo metastatic castration sensitive prostate cancer: State of art and future perspectives. Cancer Treat Rev. 2018;70:67–74.
5. Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target. Lancet Oncol. 2009;10:981–91.
6. Shiota M, Eto M. Current status of primary pharmacotherapy and future perspectives toward upfront therapy for metastatic hormone-sensitive prostate cancer. Int J Urol. 2016;23:360–9.
7. 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.
8. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377:352–60.
9. 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. 2019;37 (7S):abstr: 687.
10. Eggener S. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Department of Medicine; Department of Biostatistics and Computational Biology; Dana-Farber Cancer Institute, Boston; Harvard Medical School, Boston; Johns Hopkins University, Baltimore; University of Wisconsin Carbone Cancer Center; School of Medicine and Public Health; Madison; Fox Chase Cancer Center, Temple University Health System, Philadelphia; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis; Mayo Clinic, Rochester, MN; University Hospitals Case Medical Center, Seidman Cancer Center; Cleveland Clinic Taussig Cancer Institute; Both in Cleveland; University of Virginia Cancer Center, Charlottesville; Comprehensive Cancer Centers of Nevada, Las Vegas; Siteman Cancer Center, Washington University School of Medicine, St. Louis; NorthShore University Health System, Evanston, IL; University of Michigan Comprehensive Cancer Center, Ann Arbor; Rutgers Cancer Institute of New Jersey, New Brunswick.N Engl J Med. 2015 Aug 20;373(8):737-46. [Epub 2015 Aug 5]. doi: 10.1056/NEJMoa1503747. Urol Oncol, 2017;35:123.
11. Uro Today. Phase 3 ARCHES Trial Shows XTANDI® (enzalutamide) Significantly Improved Radiographic Progression-Free Survival in Men with Metastatic Hormone-Sensitive Prostate Cancer. 2019. Available at: www.urotoday.com/conference-highlights/asco-gu-2019/asco-gu-2019-press-releases/110194-phase-3-arches-trial-shows-xtandi-enzalutamide-significantly-improved-radiographic-progression-free-survival-in-men-with-metastatic-hormone-sensitive-prostate-cancer.html (accessed 20 March 2019).
12. The ASCO Post. Abiraterone or Enzalutamide for Newly Diagnosed Metastatic Castrate-Resistant Prostate Cancer? 2018. Available at: www.ascopost.com/issues/august-10-2018/abiraterone-or-enzalutamide-in-prostate-cancer/ (accessed 22 March 2019).
13. Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018;19:975–86.
14. Cordes LM, Gulley JL, Madan RA. Perspectives on the clinical development of immunotherapy in prostate cancer. Asian J Androl. 2018;20:253–9.
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