The U.S. Food and Drug Administration has accepted a Supplemental New Drug Application (sNDA) for enzalutamide (Xtandi®; Pfizer/Astellas) to add an indication for the treatment of men with metastatic hormone-sensitive prostate cancer (mHSPC).
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. Men are considered hormone (or castration) sensitive if their disease still responds to medical or surgical treatment to lower testosterone levels. The prevalence of mHSPC in the U.S. in 2019 is estimated to be just over 40,000.
The application has also been granted Priority Review, a designation given to those applications for drugs that, if approved, may offer significant improvements in the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions when compared to standard applications. Enzalutamide is currently indicated in the U.S. for the treatment of patients with castration-resistant prostate cancer (CRPC).
ARCHES and ENZAMET trials
The submission is based on results from the
trial presented at the Genitourinary Cancers Symposium (ASCO GU), a three-day scientific and educational meeting designed to meet the needs of physicians and other members of the cancer care and research community who diagnose, treat, and study GU malignancies held in February 2019 and published in The Journal of Clinical Oncology in July.
The study evaluated the efficacy and safety of enzalutamide plus androgen deprivation therapy (ADT) versus ADT plus placebo in men with mHSPC. The primary endpoint of radiographic progression-free survival (rPFS) was met in the study.
Additionally, the submission is supported by data from ENZAMET trial, an Astellas-supported, investigator-sponsored Phase III study led by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) and sponsored by the University of Sydney.
The ENZAMET trial evaluated enzalutamide plus ADT versus ADT plus a standard non-steroidal antiandrogen therapy (bicalutamide, nilutamide or flutamide) in men with mHSPC to provide an active control. The results were presented during the Plenary Session at the annual meeting of the American Society of Clinical Oncology (ASCO) held in June 2019. The study results were simultaneously published in The New England Journal of Medicine.
The primary endpoint of overall survival (OS) was met in the ENZAMET trial. The safety analyses of the ARCHES and ENZAMET trials appear consistent with the safety profile of enzalutamide in previous clinical trials in CRPC.
The authors of the study published in the NEJM concluded that enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression.
Need for treatment
“We are pleased to receive the Priority Review designation, which reflects the need for more treatment options for men living with metastatic hormone-sensitive prostate cancer,” said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development.
“The submission is supported by a strong data package, including two Phase III trials investigating enzalutamide in men living with this form of prostate cancer,” Boshoff added.
“The complementary data from the ARCHES and ENZAMET trials in men with mHSPC take us another step closer to understanding enzalutamide’s full potential in helping address unmet needs in prostate cancer,” explained Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head at Astellas.
“Enzalutamide is a current standard of care in castration-resistant prostate cancer and we look forward to working with the FDA to potentially make [this therapeutic agent] available to men earlier in their prostate cancer journey,” Krivoshik concluded.
One of the most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in patients treated with enzalutamide during the randomized placebo-controlled trials included asthenia/fatigue, decreased appetite, hot flush, arthralgia, dizziness/vertigo, hypertension, headache and weight decreased. In the bicalutamide-controlled study, the most common adverse reactions (≥ 10%) reported in enzalutamide patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.
In the placebo-controlled study of metastatic CRPC (mCRPC) patients being treated with enzalutamide who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of enzalutamide patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of enzalutamide patients and 18% of placebo patients. In the placebo-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 44% of enzalutamide patients and 37% of placebo patients.
Discontinuations due to adverse events were reported for 6% of both study groups. In the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher adverse reactions were reported in 31% of enzalutamide patients and 23% of placebo patients. Discontinuations with an adverse event as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients. In the bicalutamide-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 39% of enzalutamide patients and 38% of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8% of enzalutamide patients and 6% of bicalutamide patients.
Data from the ARCHES and ENZAMET studies have also been submitted to the European Medicines Agency (EMA) and to the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan to potentially support an indication for enzalutamide that includes men with mHSPC.
The FDA has set a Prescription Drug User Fee Act (PDUFA) date, or target action date, in Q4 2019.
- A Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC) (ARCHES) – NCT02677896
- Randomised phase III trial of enzalutamide in first line androgen deprivation therapy for metastatic prostate cancer: ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684
- Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) – NCT02446405
- Randomised phase III trial of enzalutamide in first line androgen deprivation therapy for metastatic prostate cancer: ENZAMET EU Clinical Trials Register number, 2014-003190-42
 American Society of Clinical Oncology. ASCO Answers: Prostate Cancer (2018). Online. Last accessed August 21, 2019.
 Cancer.net. Prostate Cancer: Types of Treatment (03-2018). Online. Last Accessed August 21, 2019
 Supplement to: Scher HI, Solo K, Valant J, Todd MB, Mehra M. Prevalence of prostate cancer clinical states and mortality in the United States: estimates using a dynamic progression model. PLoS One 2015;10(10):e0139440.
 Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, Alcaraz A, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2019 Jul 22:JCO1900799. doi: 10.1200/JCO.19.00799. [Pubmed][Article]
 Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, Coskinas X, Frydenberg M, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med. 2019 Jul 11;381(2):121-131. doi: 10.1056/NEJMoa1903835. Epub 2019 Jun 2.[Pubmed][Article]