Doctor consulting with a patient, working on diagnostic examination.

Despite improved treatment options for patients progressing on standard hormone treatment, metastatic prostate cancer still remains a deadly disease.

For men with metastatic hormone-sensitive prostate cancer (mHSPC), starting standard androgen deprivation therapy (ADT), the median overall survival (OS) is approximately 45 months. However, for patients with higher-volume disease, the median survival was less (35.1 and 32.2 months, respectively).[1]

ADT has long been the gold standard for patients with mHSPC, however, the treatment of the disease was revolutionized with the addition of docetaxel or abiraterone.[2]

In clinical trials, novel anti-androgen enzalutamide has showed improved clinical activity. For example, improved radiographic progression-free survival (rPFS) and overall survival (OS) was observed among men with chemotherapy-na?ve metastatic castration-resistant prostate cancer at the prespecified interim analysis of the double-blind, randomized, phase III PREVAIL study (NCT01212991). Overall, data from longer follow-up showed that enzalutamide continued to provide benefit over placebo in patients with metastatic castration-resistant prostate cancer. [3]

ARCHES trial
The Phase III ARCHES trial (NCT02677896) evaluating enzalutamide (XTANDI?; Astellas Pharma and Pfizer) plus androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC) met its primary endpoint. These results confirm that adding enzalutamide to the treatment regiment significantly improve radiographic progression-free survival (rPFS) versus ADT alone. [4]

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The preliminary safety analysis of the ARCHES trial appears consistent with the safety profile of enzalutamide in previous clinical trials in castration-resistant prostate cancer (CRPC).

Prostate Cancer
In men with prostate cancer, the disease is considered metastatic once the cancer has spread outside of the prostate gland to other parts of the body, such as the bones, lymph nodes, bladder and rectum.[5] Men are considered hormone (or castration) sensitive if their disease still responds to medical or surgical treatment to lower testosterone levels.[6] Approximately 38,000 men in the U.S. develop metastatic hormone-sensitive prostate cancer (mHSPC) every year.[7][8]

ARCHES study design
The Phase III, randomized, double-blind, placebo-controlled, multi-national trial enrolled 1,150 patients with metastatic hormone-sensitive prostate cancer (mHSPC) at sites in the United States, Canada, Europe, South America and the Asia-Pacific region.

Patients in the ARCHES trial were randomized to receive enzalutamide 160 mg daily or placebo and continued on a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or had a history of bilateral orchiectomy.

Photo 1.0: Mace Rothenberg, MD, Chief Development Officer, Oncology, Pfizer Global Product Development.

The ARCHES trial included patients with both low- and high- volume disease and both newly diagnosed patients with mHSPC and patients who had prior definitive therapy and subsequently developed metastatic disease.

The trial also included some patients who had received recent treatment with docetaxel for mHSPC, but whose disease had not progressed. The primary endpoint of the trial was radiographic progression-free survival (rPFS), defined as the time from randomization to the first objective evidence of radiographic disease progression as assessed by central review, or death, whichever occurs first.

“While [enzalutamide] is currently approved for both metastatic and non-metastatic CRPC, there still remains a need for more treatment options for men with metastatic hormone-sensitive prostate cancer,” noted Mace Rothenberg, MD, Chief Development Officer, Oncology, Pfizer Global Product Development.

“With these top-line results, we believe [enzalutamide] has the potential to help men whose disease has progressed outside the prostate gland, but still responds to treatment to lower testosterone,” he added.

Photo 2.0: Senior Vice President and Global Therapeutic Area Head, Oncology Development, Astellas Pharma

“The results from ARCHES demonstrate a statistically significant improvement in a key marker of disease progression ? radiographic progression-free survival,” explained Steven Benner, MD, Senior Vice President and Global Therapeutic Area Head, Oncology Development, Astellas.

“Based on the top-line results of ARCHES, we look forward to discussing the data with relevant health authorities to potentially support expanding the indication for [enzalutamide],” he concluded.

Regulatory Status
[Enzalutamide] is currently approved in the U.S. and Japan for the treatment of CRPC and in the EU for the treatment of metastatic and high-risk non-metastatic CRPC. Since its initial approval in 2012, [enzalutamide] has been prescribed to more than 330,000 men worldwide.[9]

Pfizer and Astellas are also evaluating enzalutamide in the EMBARK trial (NCT02319837), in men with high-risk non-metastatic HSPC.[10]

The collaboration between Pfizer and Astellas stems from an global agreement between Medivation, which is now part of Pfizer, and Astellas to jointly develop and commercialize enzalutamide. Based on this agreement, signed in October 2009, the companies jointly commercialize enzalutamide in the United States, while Astellas has responsibility for manufacturing and all additional regulatory filings globally, as well as commercializing the agent outside the United States.

[1] Gravis G, Boher JM, Joly F, Souli? M, Albiges L, Priou F, Latorzeff I, et al. Androgen Deprivation Therapy (ADT) Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial. Eur Urol. 2016 Aug;70(2):256-62. doi: 10.1016/j.eururo.2015.11.005. Epub 2015 Nov 21.
[2] Feyerabend S, Saad F, Li T, Ito T, Diels J, Van Sanden S, De Porre P, et al. Survival benefit, disease progression and quality-of-life outcomes of abiraterone acetate plus prednisone versus docetaxel in metastatic hormone-sensitive prostate cancer: A network meta-analysis. Eur J Cancer. 2018 Nov;103:78-87. doi: 10.1016/j.ejca.2018.08.010. Epub 2018 Sep 12.
[3] Beer TM, Armstrong AJ, Rathkopf D, Loriot Y, Sternberg CN, Higano CS, Iversen P, et al. Enzalutamide in Men with Chemotherapy-na?ve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol. 2017 Feb;71(2):151-154. doi: 10.1016/j.eururo.2016.07.032. Epub 2016 Jul 28.
[4] A Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC) (ARCHES) – (NCT02677896)
[4] American Society of Clinical Oncology. ASCO Answers: Prostate Cancer (2018). Last Accessed November 13, 2018
[5] Prostate Cancer: Types of Treatment (03-2018). Las Accessed November 7, 2018.
[6] Scher HI, Solo K, Valant J, Todd MB, Mehra M et al. Prevalence of Prostate Cancer Clinical States and Mortality in the United States: Estimates Using a Dynamic Progression Model. PLoS One. 2015; 10(10): 1-2.
[7] Siegel RL, Miller KD, Jemal A, Cancer statistics, 2018. CA Cancer Journal for Clinicians. 2018;68:7?30.
[8] Data on file. Northbrook, IL: Astellas Inc.
[9] Safety and Efficacy Study of Enzalutamide Plus Leuprolide in Patients With Nonmetastatic Prostate Cancer (EMBARK) – (NCT02319837)

Last Editorial Review: December 20, 2018

Featured Image: Doctor consulting male patient, working on diagnostic examination on men’s health. Courtesy: ? 2010 – 2018 Fotolia. Used with permission. Photo 1.0: Mace Rothenberg, MD, Chief Development Officer, Oncology, Pfizer Global Product Development. Courtesy:? ? 2010 – 2018 Pfizer. Used with permission. Photo 2.0: Steve Benner, MD, Astellas Portrait Sessions. Courtesy:? ? 2010 – 2018 Todd Rosenberg Photography/Astellas Pharma. Used with permission.

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