• • External links Website My Little Pony: Friendship Is Magic is a Canadian-American created by for. The series is based on 's line of toys and animated works and is often referred by collectors as the fourth generation ('G4') of the franchise.

The series premiered on October 10, 2010, on The Hub. Hasbro selected animator as the creative director and executive producer for the show.

Faust sought to challenge the established nature of the existing My Little Pony line, creating more in-depth characters and adventurous settings; she left the series during season 2, to be replaced by as showrunner. The show follows a studious unicorn pony named Twilight Sparkle as her mentor Princess Celestia guides her to learn about friendship in the town of Ponyville. Twilight becomes close friends with five other ponies: Applejack, Rarity, Fluttershy, Rainbow Dash, and Pinkie Pie. Each of the ponies represent a different facet of friendship, and Twilight discovers herself to be a key part of the magical artifacts known as the 'Elements of Harmony'.

The ponies travel on adventures and help others around while working out problems that arise in their own friendships. The series has become a major commercial success, becoming the most highly rated original production in the Hub Network's broadcast history and leading to new merchandising opportunities for Hasbro, including books, clothing, collectible trading cards, and comics. Despite the target demographic of young girls, Friendship Is Magic has also gained a large following of older viewers, mainly young and middle-aged men, who call themselves '. Portions of the show have become part of the, and have formed the basis for a variety of.

The show has ran for 169 episodes through seven seasons with an eighth scheduled for 2018.. A spin-off feature film series,, started in 2013 and has been shown in limited theatrical screenings prior to television broadcast and home media release. A feature-length film adaptation directly based on the TV series, titled, was theatrically released on October 6, 2017 in the United States.

Celestia Medium is a fan-made alteration of the font used in the Friendship is Magic logo.

Contents • • • • • • • • • • • • • • • • • • • • • • • Origin Hasbro, Inc. Has produced several incarnations and lines of toys and entertainment related to the My Little Pony franchise, often labeled by collectors as 'generations'.

The animated series which premiered in 1992 was the toy line's most recent television series before Friendship Is Magic, featuring the pony designs of the first toy line. It was followed by various releases, which featured later designs up to the third incarnation of the franchise. Just as 's had helped to boost the new toy line, Hasbro wanted to retool the My Little Pony franchise and update it to better suit the current demographic and taste of young girls. According to Margaret Loesch, CEO of Hub Network, revisiting properties that had worked in the past was an important programming decision, influenced to an extent by the opinions of the network's programming executives, a number of whom were once fans of such shows. Senior Vice President Linda Steiner also stated that they 'intended to have the show appeal to a larger ', with the concept of 'co-viewing' of parents with their children being a central theme of the Hub Network's programming. Central themes that Hasbro sought for the show included friendships and working together, factors they determined from market research in how girls played with their toys.

Developer and initial showrunner of My Little Pony: Friendship Is Magic Animator and writer Lauren Faust approached Hasbro, seeking to develop her girls' toys property 'Galaxy Girls' into an animated series. Faust, who had previously worked on and, had been pitching original animation aimed at girls for years, but had always been rejected by studios and networks because cartoons for girls were considered unsuccessful. When she pitched to Lisa Licht of Hasbro Studios, Licht showed Faust one of their recent My Little Pony animated works,, 'completely on the fly'.

Licht considered that Faust's style was well suited to that line, and asked her to consider 'some ideas where to take a new version of the franchise'. Faust was initially hired by Hasbro to create a for the show, allowing her to get additional help with conceptualization. Faust said she was 'extremely skeptical' about taking the job at first because she had always found shows based on girls' toys to be boring and unrelatable. My Little Pony was one of her favorite childhood toys, but she was disappointed that her imagination at the time was nothing like the animated shows, in which the characters, according to Faust, 'just had endless tea parties, giggled over nothing and defeated villains by either sharing with them or crying'. With the chance to work on My Little Pony, she hoped to prove that 'cartoons for girls don't have to be a puddle of smooshy, cutesy-wootsy, goody-two-shoeness'.

To do this, she incorporated into the design of the characters and the show many elements that contradicted idealized stereotypes of girls, such as diverse personalities, the message that friends can be different and can get into arguments but still be friends, and the idea that girls should not be limited by what others say they can or cannot do. Elements of the characters' personalities and the show's settings were based on her own childhood imagination of the ponies' adventures, in part inspired by the animated shows that her brothers would watch while growing up, such as and; she considered that she was making Friendship Is Magic 'for me as an eight-year-old'. Faust still aimed for the characters to be 'relatable' characters, using stereotypical 'icons of girliness' (such as the waif or the bookworm) in order to broaden the appeal of the characters for the young female audience.

Faust stated that as she provided Hasbro with more of her ideas for the show, she was inspired by their positive response to the non-traditional elements. Faust had initially pitched the show to include 'adventure stories' in a similar proportion to 'relationship stories', but recognizing the younger target audience, as well as the difficulty of basing complex plots on the adventure elements, she trimmed back this content, focusing more on exchanges between the characters. The show still incorporates episodic creatures intended to be frightening to children, such as and, but it places more emphasis on the friendships among the characters, displayed with a comedic tone. By the time the show was approved, Faust had developed three full scripts for the series. Faust began to work out concept sketches, several of which appeared on her page, including ponies from the original series (Twilight, Applejack, Firefly, Surprise, Posey and Sparkler), which later provided the core for the main cast of the show. Hasbro approved the show with Faust as Executive Producer and asked her to complete the pitch bible. In order to do so, Faust brought in Martin Ansolabehere and, who had worked on other animated shows with her.

Faust credits Rudish for the inspiration of the pegasus ponies controlling the weather in Equestria, as well as the character of Nightmare Moon during this period. Faust also consulted Craig McCracken, her husband and also an animator and creator of The Powerpuff Girls and Foster's Home for Imaginary Friends. After seeing the initial version of the pitch bible, Hasbro requested more character designs from Faust's team; subsequently, Faust brought aboard Dave Dunnet and Lynne Naylor to further refine the background and character styles. On completion of the pitch bible, Hasbro and Faust began looking at studios for the animation. Studio B Productions (renamed to DHX Media on September 8, 2010, after its parent company, along with DHX's other subsidiaries ) had previously worked on -based animations and on shows that featured a large number of animals, and Faust felt they would be a good selection. Studio B requested that Jayson Thiessen be the director, a choice Faust agreed with. She, Thiessen, and James Wootton led the completion of a two-minute short to pitch the final product to Hasbro, resulting in the company's sanctioning the full production.

Faust estimates that from being initially asked to develop the show until this point took roughly one year. Production The show is developed at Hasbro Studios in Los Angeles, where most of the writing staff is located, and at Vancouver in Vancouver, British Columbia, for the animation work. A sample from the episode 'Call of the Cutie', containing pencil sketches of the main characters, rendered backgrounds to establish settings, and instructions for the Flash animators, such as the shot shown in the second panel Faust's initial writing staff at Hasbro Studios included several writers who had worked with her on her previous shows and were approved by Hasbro. These included, Cindy Morrow,,,,, and. The writing process began with Faust and Renzetti coming up with broad plots for each show.

The two would then hold a brainstorming session with each episode's writer, allowing the writer to script out scenes and dialogue. Faust and Renzetti then worked with the writer to finalize the scripts and assign some basic storyboard instructions. Hasbro was involved throughout this process and laid down some of the concepts to be incorporated into the show. Examples of Hasbro's influence include having Celestia be a princess rather than a queen, making one of the ponies focused on fashion, and portraying toy sets in relevant places within the story, such as Rarity's boutique. In some cases, Hasbro requested that the show include a setting, but allowed Faust and her team to create its visual style, and Hasbro then based the toy set on it; an example is the Ponyville schoolhouse. Faust also had to write to the standards that Hasbro required of the show, making the crafting of some of the situations she would have normally done on other animated shows more difficult; for example, Faust cited having one character call another an 'egghead' as 'treading a very delicate line', and having one character cheat in a competition as 'worrisome to some'. Each episode also generally includes a moral or life lesson, but these were chosen to 'cross a broad spectrum of personal experiences', and not just to suit children.

Because intellectual property issues had caused Hasbro to lose some of the rights on the original pony names, the show includes a mix of original characters from the toy line and new characters developed for the show. Jayson Thiessen, supervising director (left), and Shaun Scotellaro ('Sethisto'), the founder of the fansite, at 2011 Completed scripts were sent to Studio B for pre-production and animation using. Thiessen's production team was also allowed to select key personnel subject to Hasbro's approval; one of those selected was art director Ridd Sorensen. The Studio B team would storyboard the provided scripts, incorporating any direction and sometimes managing to create scenes that the writers had believed impossible to show in animation. The animators would then prepare the key character poses, layout, background art, and other main elements, and send these versions back to the production team in Los Angeles for review by Hasbro and suggestions from the writers.

Thiessen credited much of the technical expertise in the show to Wooton, who created Flash programs to optimize the placement and posing of the pony characters and other elements, simplifying and economizing on the amount of work needed from the other animators. For example, the ponies' and tails are generally fixed shapes, animated by bending and stretching them in curves in three dimensions and giving them a sense of movement without the high cost of individual animated hairs.

The storyboard artists and animators also need to fill in background characters for otherwise scripted scenes as to populate the world. According to writer Meghan McCarthy, many of the small nods to the fandom, pop culture references, or other would be added at this point by the studio. Once the pre-production work was approved and completed, the episode would then be animated. Though Studio B performed the initial animation work, the final steps were passed to Top Draw Animation in the, an animation studio that Studio B had worked with in the later part of season one and beyond.

The voice casting and production is handled by Voicebox Productions, with as the series' voice director. Faust, Thiessen, and others participated in selecting voice actors, and Hasbro gave final approval. The voice work is performed prior to the animation, with the animators in the room to help provide direction; according to Libman, this allows herself and the other actors to play the character without certain limitations. Libman noted that for recording her lines as the hyperactive Pinkie Pie, 'I learned that I can go as over the top as I want and they [the animators] rarely pull me back.' Daniel Ingram at Everfree Northwest 2012 The series' background music is composed by William Kevin Anderson, and composes the songs, which are only included if they would make sense in the episode's script.

The production team identifies specific parts of the episode where they want music cues, allowing Anderson to create appropriate music for each. Ingram works alongside Anderson's compositions to create vocal songs that mesh with the background music while filling out the show's fantasy setting.

The composition of the music and songs far precedes the broadcast of the episode; for example, songs for the show's third season that began airing in November 2012 were composed in 2011. Ingram considered that songs from previous shows of My Little Pony were 'a little bit dated' and decided to bring more interesting work to the Friendship Is Magic series. Such changes include making songs with more emotional depth than typical for children's animation, and tending to write songs that can be enjoyed musically outside of the context of the episode.

Ingram's songs have 'became bigger and more epic, more Broadway and more cinematic over time' with Hasbro blessing the effort to try 'something groundbreaking for daytime television', according to Ingram. Lyrics and overall musical themes may be suggested by the writers; two examples include songs written by Amy Keating Rogers, who is a self-professed fan. The song 'The Art of the Dress' in the first-season episode 'Suited for Success' is inspired by 'Putting it Together' from the musical, while the season one finale's song, 'At The Gala', is based on Sondheim's. A large musical number in the episode 'The Super Speedy Cider Squeezy 6000' paid homage to the song ' from Meredith Willson's musical,. Before the show was approved, Hasbro and Faust had planned for episodes to be 11 minutes long, to which Faust conformed in her first full-length script, 'The Ticket Master', which was part of the pitch bible. However, Faust preferred more traditional 22-minute episodes, and Hasbro eventually agreed to this. The initial production stages were very tight, requiring a schedule twice as fast as Faust had previously experienced, and frequent remote communication between the Los Angeles writing offices and the animation studio in Vancouver.

At times, the two teams would hold 'writer's summits' to propose new ideas for characters and situations, at which the animation team would provide suggestions on visuals, body language, and characterization. Faust estimates that the time to complete one episode was one year; at one point, the team was simultaneously working on various stages of all 26 episodes of the first season, and when the second season was approved, that number rose temporarily to 32.

Episodes then aired about a month after completion. Thiessen explained that they had pushed to start work on the second season as soon as the first was completed, to prevent staff turnover. After the airing of the first season's finale, Faust announced that she had left the show, and would be credited in the future as Consulting Producer. Her involvement in the second season consists mainly of story conception and scripts, and the involvement ceased after the second season. Despite leaving, she still has high hopes for the staff members, stating that 'the gaps I have left are being filled by the same amazing artists, writers, and directors who brought you Season 1.

I'm certain the show will be as entertaining as ever'. In an interview with, Faust stated her reasons for leaving were a combination of a hectic production schedules and a lack of creative control she had with the series. According to her husband McCracken, Faust's departure was due to the fact that as a toy company-driven show, 'there were things she wanted to do with that series that she just wasn't able to do', and that there is 'still some frustration with' not being able to bring some of her ideas to screen. Main article: Premise Friendship Is Magic takes place in the land of, populated by varieties of ponies including variants of and, along with other sentient and non-sentient creatures. The central character is Twilight Sparkle, a unicorn mare sent by her mentor Princess Celestia, ruler of Equestria, to the town of Ponyville to study the magic of friendship. In the show's opening episode 'Friendship Is Magic', Twilight resents this assignment, as she is more concerned about the foretold appearance of Nightmare Moon, the evil sister of Celestia. When Nightmare Moon does appear, vowing everlasting night and causing Celestia to disappear, Twilight sets off with five other ponies – Applejack, Fluttershy, Pinkie Pie, Rainbow Dash, and Rarity – to obtain the Elements of Harmony and defeat Nightmare Moon.

Before Twilight can activate the Elements, Nightmare Moon appears and shatters them. In a flash of inspiration, Twilight realizes that each of her new friends represents one of the Elements of Harmony (Honesty, Loyalty, Laughter, Generosity, and Kindness), and that she herself is the final piece, Magic. The magical power of the ponies' friendship reverts Nightmare Moon to a repentant Princess Luna. Celestia reappears, reunites with her sister Princess Luna, and decrees that Twilight shall stay in Ponyville to continue studying the magic of friendship, much to the happiness of Twilight and her new friends. Later episodes follow Twilight and her friends dealing with various problems around Ponyville, including interpersonal problems between friends and family, as well as more adventurous stories involving creatures like dragons and hydras, and having to save Equestria from villainous characters. At the end of each episode, Twilight sends a report back to Celestia explaining what she learned about friendship from these adventures. This part of the formula is abandoned in 'Lesson Zero', the second-season episode in which Twilight is convinced to be less rigid in her perceived duties; after this, all the principals contribute reports, although the formality is disregarded when appropriate.

In the fourth season, with the request for reports no longer applicable, the six resolve to keep a collective personal journal in which they record their thoughts about life for posterity. Another focus of the show is the Cutie Mark Crusaders, a trio of much younger mares consisting of Apple Bloom, Sweetie Belle, and Scootaloo, who are obsessed with finding their 'cutie marks', an iconic symbol that magically appear on a pony's flank once they have discovered their special talent in life. The show regularly features episodes centered on the Crusaders, who have yet to receive their cutie marks and are teased by other young ponies as 'blank flanks'. In response, they desperately hurry to try to discover their talents and receive their own cutie marks, often doing so in comical fashions. Although the episodes are designed to stand alone, the series features continuity and overall, with several key elements of the series changing; one such change is the evolution of Twilight herself, who spends the first three seasons learning about friendship and is subsequently granted wings by Celestia to become an and a princess in the finale '. In the finale ', she discovers that she is the Princess of Friendship and starts living in a magic castle after the destruction of her library home from previous seasons.

Other crucial events impacting the series are the Cutie Mark Crusaders finally obtaining their cutie marks in the episode 'Crusaders of the Lost Mark'; the same season's introduction of Starlight Glimmer, a villainous character who redeems herself and becomes Twilight's pupil in the season finale 'The Cutie Re-Mark'; and Rainbow Dash fulfilling her lifelong dream of joining the elite Wonderbolts flight team in the episode 'Newbie Dash'. Each season typically has a theme and overall story arc: a theme throughout the, for example, is ponies' preparation for the Grand Galloping Gala that occurs in the final episode of that season. In season 4, the Mane Six must find six keys to a mysterious box revealed after they relinquish the Elements of Harmony to their original source, the Tree of Harmony, to save Equestria; in the season finale, it is revealed that they had already obtained the keys, in the form of gifts they received during the season from people they helped.

Cast and characters. The cast of Friendship Is Magic, presented as a poster at the 2011. Major characters include (mid-front row, starting sixth from left) Rainbow Dash, Pinkie Pie, Applejack, Twilight Sparkle, Fluttershy, Spike and Rarity. The poster also includes minor characters and those named by the fandom, including Derpy, DJ Pon-3, and Doctor Hooves. Main article: In total, 169 episodes have been produced and broadcast. See also: Friendship Is Magic is associated with the of My Little Pony toy line, having figurines and playsets based on it.

A section of the Hasbro website gives information about Friendship Is Magic for children and their parents, including character backgrounds, videos, and interactive games and media. Due in part to the older fans, Hasbro has come to see My Little Pony as a 'lifestyle' brand, with over 200 licenses in 15 categories of products, including clothing, houseware, and digital media. The brand grossed over 650 million USD in retail sales in 2013, and one billion USD annually in retail sales in 2014 and 2015., a theatrical animated film of the television series, was released on October 6, 2017 in the United States, distributed. The film is directed by series supervising director and written by showrunner, and is financed by ' film subdivision, Allspark Pictures. Reception Critical reception The series has received positive reviews from critics.

Todd VanDerWerff of favorably noted its 'sheer and utter joyfulness' and lack of, unlike many other shows that garnered a cult following of parents and adults. He complimented the characters' stylized appearance, the stories' relative complexity for children's television, and the solid jokes which make the show enjoyable for parents as well as children. He gave the series a B+. The show has been critically praised for its humor and moral outlook by Brian Truitt of USA Today. Genevieve Koski of The A.V. Club later commented that Friendship Is Magic is an example of a show that, while considered 'girly', has been able to tap into the nerd culture to allow it to gain wider acceptance than other comparable forms. Emily Ashby of, an organization focusing on the parenting aspect of children's media, gave the show a rating of four out of five stars, emphasizing its messages of friendship, tolerance and respect, but advised parents to be wary of the 'influence the characters might have on their kids' desires, since it's rooted in a well-known product line of books, toys, and just about everything in between.'

Liz Ohanesian, for, said that the show is 'absolutely genuine in its messages about friendship but never takes itself too seriously'. Matt Morgan, writing for 's ' column, praised the show for having 'rebooted the long-time Hasbro property while managing to lace it with geeky undertones' and being one of the few 'girl-focused shows that a geeky dad can appreciate with his daughter'. Critic Robert Lloyd called the show 'smarter and sassier and more aesthetically sophisticated' than any of the previous My Little Pony cartoons, and praised its ability to appeal to both children and their parents, in that it is 'smart and sprightly and well-staged, and never horribly cute'. Listed Friendship Is Magic as one of the top sixty animated shows of all time in a September 2013 list.

Kathleen Richter of believed that Friendship Is Magic did little to change the nature of older animations for girls, which she considered 'so sexist and racist and.' For example, she suggested that, through the character of Rainbow Dash, the show was promoting the stereotype that 'all feminists are angry, tomboyish lesbians.' She also considered that the only darker-colored ponies shown to date were in positions of servitude towards the 'white pony overlord.' Lauren Faust responded to these claims by stating that while Rainbow Dash was a tomboy, 'nowhere in the show is her sexual orientation ever referenced' and 'assuming [tomboys] are lesbians is extremely unfair to both straight and lesbian tomboys', and further stating that 'Color has never, ever been depicted as a race indicator for the ponies.'

Amid Amidi, writing for the animation website, was more critical of the concept of the show, calling it a sign of 'the end of the creator-driven era in TV animation'. Amidi's essay expressed concern that assigning a talent like Faust to a toy-centric show was part of a trend towards a focus on profitable genres of animation, such as toy tie-ins, to deal with a fragmented viewing audience, and overall 'an admission of defeat for the entire movement, a -waving moment for the TV animation industry.' Ratings Friendship Is Magic originally premiered with an average viewership of 1.4 million per month, but expanded to 4 million per month by the end of the first season, making it the highest-rated of any Hasbro offering at the time. Reports that the viewership doubled between the first and the second season. The Hub Network reported that ', an episode on the theme of Valentine's Day, which aired on February 11, 2012, in the middle of the second season, was the show's most-viewed episode ever, and the second highest of any program of the Hub network; its viewership exceeded 150% of that of the previous year. This was surpassed by the two-part season two finale, 'A Canterlot Wedding', airing in April 2012, marking the broadcast as the highest viewership for the Hub Network to that date.

Awards and nominations Friendship Is Magic was nominated for three British Columbia for Animation, 'Best Program', 'Best Direction', and 'Best Overall Sound'. Additionally, the songs 'Becoming Popular (The Pony Everypony Should Know)' (from season 2 episode 9, 'Sweet and Elite') and 'Find A Pet Song' (from season 2 episode 7, 'May the Best Pet Win!' ), both written by Daniel Ingram, were nominated, but did not win, for 'Outstanding Original Song—Children's and Animation' at the. The show was named the best animated show for the 2011–12 television season in a user poll on the website.

Marcel Duperreault, Todd Araki, Jason Fredrickson, and Adam McGhie received a 2014 Leo Award for their work on 'Power Ponies' for 'Best Overall Sound in an Animation Program or Series' on June 1, 2014. Main article: Despite Hasbro's target demographic of young girls and their parents, My Little Pony: Friendship Is Magic has become a cultural and Internet phenomenon, with many male fans between 13 and 35. The response from the Internet has been traced to cartoon and animation fans on the Internet board, responding to Amidi's negative essay regarding the show and current trends in animation. As a result of the discussion on 4chan, interest in the show spread throughout other parts of the Internet, creating a large fanbase and a multitude of creative works, fan sites, and conventions. The fanbase has adopted the name 'brony' (a of 'bro' and 'pony') to describe themselves. The older fanbase had come as a surprise to Hasbro and staff members involved with the show. They have appreciated and embraced the fandom, adding nods to the fans within the show and the toys, while, early on, allowing the creative elements of the fandom to flourish without legal interference.

Other Director was inspired by the visuals of Friendship Is Magic, which his daughters had watched frequently, in creating a short for 's 2014 educational/documentary web series, 'We the Economy', using cartoon in the same style as the show to explain about. In early 2016, Hasbro was sued by Font Brothers over Hasbro's use of the font 'Generation B' for much of its product packaging and marketing with the Friendship Is Magic show and toyline, including the 'Friendship Is Magic' text in the show's logo. Font Brothers claim that Hasbro has been using this font in an unlicensed manner and is seeking up to $150,000 for each violation of its use. Dialogue from a My Little Pony: Friendship Is Magic episode was brought up during the by a member of the Convention to defend against accusations of plagiarism. See also Wikiquote has quotations related to: • • •. • Big Jim [@TheBiggestJim] (11 March 2016).

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Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Enzalutamide in Metastatic Prostate Cancer before Chemotherapy Tomasz M. Beer, M.D., Andrew J. Armstrong, M.D., Sc.M., Dana E. Rathkopf, M.D., Yohann Loriot, M.D., Cora N. Sternberg, M.D., Celestia S.

Higano, M.D., Peter Iversen, M.D., Suman Bhattacharya, Ph.D., Joan Carles, M.D., Ph.D., Simon Chowdhury, M.D., Ph.D., Ian D. Davis, M.B., B.S., Ph.D., Johann S.

De Bono, M.B., Ch.B., Ph.D., Christopher P. Evans, M.D., Karim Fizazi, M.D., Ph.D., Anthony M. Joshua, M.B., B.S., Ph.D., Choung-Soo Kim, M.D., Ph.D., Go Kimura, M.D., Ph.D., Paul Mainwaring, M.B., B.S., M.D., Harry Mansbach, M.D., Kurt Miller, M.D., Sarah B. Noonberg, M.D., Ph.D., Frank Perabo, M.D., Ph.D., De Phung, B.S., Fred Saad, M.D., Howard I. Scher, M.D., Mary-Ellen Taplin, M.D., Peter M.

Venner, M.D., and Bertrand Tombal, M.D., Ph.D., for the PREVAIL Investigators N Engl J Med 2014; 371:424-433 DOI: 10.1056/NEJMoa1405095. Results The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P. Figure 2 Kaplan–Meier Estimates for the Times until the Initiation of Cytotoxic Chemotherapy and an Increased Level of Prostate-Specific Antigen. Shown are secondary efficacy end points that include the time until the initiation of cytotoxic chemotherapy (Panel A) and the time until an increased level of prostate-specific antigen (PSA) (Panel B). The horizontal dashed lines indicate medians.

Hazard ratios are based on unstratified Cox regression models with treatment as the only covariate, with values of less than 1.00 favoring enzalutamide. The full definition of PSA progression is provided in Table S1 in the. Prostate cancer is the most commonly diagnosed cancer and the sixth leading cause of cancer-related death among men worldwide.

Strategies to block androgen-receptor signaling have formed the backbone of prostate-cancer therapy since the first description of the hormonal dependence of this cancer in 1941. Advances in endocrine therapies have improved survival in men with high-risk locoregional prostate cancer. However, new hormonal agents have been shown to extend survival in men with metastatic castration-resistant disease. In most patients who are treated for advanced recurrent prostate cancer with androgen-deprivation therapy (comprising a luteinizing hormone–releasing hormone [LHRH] analogue or orchiectomy with or without an antiandrogen), disease progression occurs despite effective suppression of serum testosterone. This disease state, called castration-resistant prostate cancer, is almost always associated with increases in levels of serum prostate-specific antigen (PSA), suggesting that the disease continues to be driven by androgen-receptor signaling. Preclinical evidence suggests that androgen-receptor overexpression is sufficient to confer resistance to androgen deprivation in prostate-cancer cell lines and that levels of intratumoral androgens are often increased in patients with progressive prostate cancer. These observations have provided a clear basis for developing more effective methods to treat prostate cancer by further suppressing androgen-receptor signaling.

Enzalutamide (formerly known as MDV3100) is a rationally designed, targeted androgen-receptor inhibitor that competitively binds to the ligand-binding domain of the androgen receptor and inhibits androgen-receptor translocation to the cell nucleus, recruitment of androgen-receptor cofactors, and androgen-receptor binding to DNA. In a phase 1–2 trial, enzalutamide was found to have encouraging antitumor activity in men with castration-resistant prostate cancer, with data suggesting a greater benefit in men who had not yet received chemotherapy.

In a previous phase 3 study, enzalutamide, as compared with placebo, prolonged overall and progression-free survival, improved patient-reported quality of life, and delayed the development of skeletal-related complications in men with metastatic castration-resistant prostate cancer who had previously received docetaxel. In our study, we evaluated enzalutamide in men in whom hormonal agents are frequently administered (i.e., those who have asymptomatic or mildly symptomatic metastatic disease that has progressed despite the use of androgen-deprivation therapy) and who have not undergone chemotherapy. Study Design and Conduct The PREVAIL study was a multinational, double-blind, randomized, placebo-controlled, phase 3 trial of enzalutamide. The study was approved by the independent review board at each participating site and was conducted according to the provisions of the Declaration of Helsinki and the Good Clinical Practice Guidelines of the International Conference on Harmonisation. All patients provided written informed consent before participating in the trial. An independent data and safety monitoring committee reviewed safety data at regular intervals and reviewed the prespecified interim analysis conducted by an independent statistical group at the contract clinical research organization where the study database was held.

The study was designed by prostate-cancer experts and employees of the sponsors, Medivation and Astellas Pharma, which are codeveloping enzalutamide. Investigators at the participating centers entered the data into an electronic data-capture system that was verified for source data by monitors from a separate clinical research organization. The data analyses reported here were conducted by the sponsor and were provided to all the authors, who wrote the manuscript and made the decision to submit the manuscript for publication. These authors assume responsibility for the accuracy of the data and adherence to the study, which is available with the full text of this article at NEJM.org. A professional writer who was paid by the sponsors assisted in the preparation of the manuscript. All the authors and participating institutions have agreements with the sponsors regarding the confidentiality of the data.

Study Participants Patients were eligible if they had histologically or cytologically confirmed adenocarcinoma of the prostate with documented metastases and had PSA progression, radiographic progression, or both in bone or soft tissue, despite receiving LHRH analogue therapy or undergoing orchiectomy, with a serum testosterone level of 1.73 nmol per liter (50 ng per deciliter) or less. Continued androgen-deprivation therapy was required. Previous antiandrogen therapy and concurrent use of glucocorticoids were permitted but not required. Eligible patients had not received cytotoxic chemotherapy, ketoconazole, or abiraterone acetate, had an Eastern Cooperative Oncology Group performance status grade of 0 or 1 (no symptoms or ambulatory but restricted in strenuous activities), and were either asymptomatic (score of 0 to 1) or mildly symptomatic (score of 2 to 3), as measured on the Brief Pain Inventory Short Form question 3 (on which scores range from 0 to 10, with higher scores indicating a greater severity of pain). Patients with visceral disease, including lung or liver metastases, were eligible, as were patients with New York Heart Association class I or II heart failure. Patients with a history of seizure or a condition that could confer a predisposition to seizure were excluded, although patients taking medications associated with lowering the seizure threshold were eligible. From September 2010 through September 2012, patients were enrolled at 207 sites globally.

All patients were randomly assigned to receive either oral enzalutamide (at a dose of 160 mg) or placebo once daily with or without food. Randomization was stratified according to the study site. Treatment continued until the occurrence of unacceptable side effects or confirmed radiographic progression and the initiation of chemotherapy or an investigational agent. Treatment discontinuation because of an increase in the PSA level alone was discouraged. Study End Points Coprimary end points were radiographic progression-free survival and overall survival. Secondary end points included the time until the initiation of cytotoxic chemotherapy, the time until the first skeletal-related event, the best overall soft-tissue response, the time until PSA progression, and a decline in the PSA level of 50% or more from baseline. Prespecified exploratory end points included quality of life, as measured with the use of the Functional Assessment of Cancer Therapy–Prostate (FACT-P) scale, and a decline in the PSA level of 90% or more from baseline.

End-point definitions are provided in Table S1 in the, available at NEJM.org. Radiographic disease was evaluated with the use of either computed tomography or magnetic resonance imaging and with the use of bone scanning. Imaging was performed at the time of screening, at weeks 9, 17, and 25, and every 12 weeks thereafter. Radiologists at a central location who were unaware of the study-group assignments determined whether there was progressive disease on the basis of Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, for soft tissue or on the basis of criteria adapted from the Prostate Cancer Clinical Trials Working Group 2 for osseous disease (Table S1 in the ). Statistical Analysis The planned enrollment was approximately 1680 patients. The coprimary end points were analyzed in the intention-to-treat population at a total type I error rate of 0.05, with an error rate of 0.001 (two-sided) allocated to radiographic progression-free survival and an error rate of 0.049 (two-sided) allocated to overall survival.

It was planned that the final analysis of radiographic progression-free survival would be conducted after the occurrence of at least 410 events at the time of the interim analysis of overall survival. The interim analysis of overall survival was to be conducted after the occurrence of approximately 516 deaths, or 67% of the 765 deaths specified for the final analysis. The final analysis of radiographic progression-free survival was performed after the occurrence of 439 events (with data cutoff on May 6, 2012); the interim analysis of overall survival was performed after the occurrence of 540 deaths with the use of a two-sided type I error rate of 0.0147. Holm's step-down procedure was applied to the analyses of the secondary end points to maintain a two-sided type I error of 5%. The results presented here are based on a cutoff date of September 16, 2013, unless otherwise specified. An updated survival analysis was performed with a data-cutoff date of January 15, 2014. Study Patients A total of 1717 patients were enrolled in the study, with 872 in the enzalutamide group and 845 in the placebo group; 1715 patients received at least one dose of a study drug (Fig.

Baseline demographic and disease characteristics were well balanced between the two groups (Tables S2 and S3 in the ). The median time that patients received a study drug was substantially longer in the enzalutamide group than in the placebo group (16.6 months vs. More patients in the enzalutamide group than in the placebo group received at least 12 months of treatment (68% vs. 18%) and continued to receive treatment as of the data-cutoff date (42% vs. Radiographic Progression-free Survival At 12 months of follow-up, the rate of radiographic progression-free survival was 65% in the enzalutamide group and 14% in the placebo group. Treatment with enzalutamide, as compared with placebo, resulted in an 81% reduction in the risk of radiographic progression or death (hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P. Overall Survival At the planned interim analysis of overall survival, the median duration of follow-up for survival was approximately 22 months.

Fewer deaths occurred in the enzalutamide group than in the placebo group (241 of 872 patients [28%] vs. 299 of 845 patients [35%]). Treatment with enzalutamide, as compared with placebo, resulted in a 29% decrease in the risk of death (hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P.

Subsequent Antineoplastic Therapy Subsequent antineoplastic treatments associated with a demonstrated survival benefit in metastatic prostate cancer were received by 40% of patients in the enzalutamide group, as compared with 70% of those in the placebo group. The two most common subsequent therapies were docetaxel (received by 33% and 57% of patients, respectively) and abiraterone (received by 21% and 46%, respectively) (Table S5 in the ). The use of abiraterone was more common in North America than in other regions. The duration and efficacy of post-progression therapies were not ascertained.

Prespecified Secondary and Exploratory End Points The superiority of enzalutamide over placebo was shown with respect to all secondary end points. The median time until the initiation of cytotoxic chemotherapy was 28.0 months in the enzalutamide group, as compared with 10.8 months in the placebo group (hazard ratio, 0.35; P.

Safety Adverse events are summarized in Table 2 Summary of Adverse Events. And Table 3 Most Common Adverse Events and Events of Special Interest. (with events occurring in at least 10% of patients in the enzalutamide group listed in the latter table). The median reporting period for adverse events was 17.1 months in the enzalutamide group and 5.4 months in placebo group, which reflected the longer exposure of patients to enzalutamide. A grade 3 or higher adverse event was reported in 43% of the patients in the enzalutamide group, as compared with 37% in the placebo group; however, the median time until the first event of grade 3 or higher was 22.3 months in the enzalutamide group and 13.3 months in the placebo group (Fig. The most common adverse events leading to death were disease progression and a general deterioration in physical health, with similar incidences in the two groups.

Adverse events that occurred in 20% or more of patients receiving enzalutamide at a rate that was at least 2 percentage points higher than that in the placebo group were fatigue (Table S6 in the ), back pain, constipation, and arthralgia. After adjustment for the length of exposure, events with a higher rate in the enzalutamide group than in the placebo group were hot flush (14 vs. 12 events per 100 patient-years), hypertension (11 vs. 7 events per 100 patient-years), and falls (11 vs.

9 events per 100 patient-years). The most common event of grade 3 or higher in the enzalutamide group was hypertension, which was reported in 7% of the patients. The most common cardiac event was atrial fibrillation, which was reported in 2% of the patients in the enzalutamide group and in 1% of those in the placebo group. One patient in each study group had a seizure. No evidence of hepatotoxicity, as measured by adverse events or laboratory assessments, was observed in the enzalutamide group. Discussion In our study involving men with metastatic prostate cancer who had not received previous chemotherapy, enzalutamide extended the time until radiographic progression or death, improved overall survival, and delayed the initiation of chemotherapy by a median of 17 months.

The benefit of enzalutamide on radiographic progression-free survival was observed from the first assessment 2 months after randomization and conferred a relative reduction of 81% in the risk of progression or death. Consistent benefit was observed in all prespecified subgroups, including patients with visceral disease, a population with a poorer prognosis that has been excluded from other trials involving men with metastatic prostate cancer who have not received previous chemotherapy.

Enzalutamide significantly reduced the risk of death by 29% over placebo, even though patients in the placebo group had received effective post-progression therapy more frequently and earlier than those in the enzalutamide group. The benefit of enzalutamide was observed as early as 4 months after randomization and was maintained throughout the study, as depicted by the separation in the Kaplan–Meier survival curves ( ).

At the time the trial was halted, following the interim analysis, the median follow-up for survival was 22 months, approximately 8 to 10 months shorter than the estimated survival medians. Because less than 5% of the patients were at risk when the estimated medians were reached, the hazard ratio, which analyzes the differences in outcome across the entire follow-up period, is a more accurate characterization of the survival benefit and other late-occurring end points than is the estimate of the median time until the event. Health-related quality-of-life assessments can reinforce and augment objective measures such as overall survival and radiographic progression.

In this population of men with metastatic prostate cancer, deterioration in the quality of life was delayed by enzalutamide, a result suggesting that the treatment effects translated into patient-perceived benefits. The benefit of enzalutamide was achieved with a favorable safety profile.

Grade 3 or higher adverse events were more common in enzalutamide-treated patients than in placebo-treated patients (43% vs. 37%), a finding that was probably influenced by the fact that the safety-reporting period for the enzalutamide group was approximately 1 year longer than that for the placebo group. The safety profile is further illustrated by the 9-month delay in the median time until the first adverse event of grade 3 or higher in the enzalutamide group. A similar proportion of patients in each group (6%) discontinued treatment because of an adverse event. The safety profile was generally consistent with that previously reported for enzalutamide in patients who had received previous chemotherapy, with a few exceptions. Seizure, which was previously observed in the enzalutamide group among patients who had received chemotherapy, occurred in a single patient (0.1%) in each group in our study.

Both patients had a history of seizure that was unknown to investigators at the time of enrollment. Hypertension was more commonly observed in the enzalutamide group than in the placebo group (13% vs. 4%) and occurred more often in patients with a medical history of hypertension. These events were not associated with symptoms of mineralocorticoid excess or an increased risk of cardiovascular or renal sequelae and generally were managed with the use of standard therapies.

In contrast to other antiandrogens, enzalutamide was not associated with hepatotoxicity. Other adverse events that were reported more frequently in the enzalutamide group than in the placebo group included fatigue or asthenia, back pain, hot flush, and falls. Although chemotherapy has been shown to improve overall and progression-free survival in men with metastatic prostate cancer, many patients do not receive such therapy primarily because of preexisting medical conditions or associated toxic effects. Thus, there is a need for effective, convenient, and less toxic therapies. Sipuleucel-T showed an overall survival advantage in asymptomatic or mildly symptomatic men, most of whom had not received chemotherapy, but did not induce tumor responses or delay disease progression or deterioration in quality of life. Radium-223 was recently shown to extend survival in men with symptomatic castration-resistant prostate cancer and bone metastases. Abiraterone plus prednisone, which was recently compared with prednisone in patients with metastatic prostate cancer who had not received chemotherapy, improved progression-free survival, lengthened the time until a quality-of-life deterioration, delayed chemotherapy use, and was associated with a trend in favor of an overall survival benefit that did not reach statistical significance.

Treatment with abiraterone requires concomitant use of prednisone to ameliorate symptoms of mineralocorticoid excess, including fluid overload, hypokalemia, and hypertension. Multiple agents are now reported to improve survival for patients with metastatic prostate cancer that has progressed after androgen-deprivation therapy. The most effective use of these therapies (order of administration, duration of treatment, and efficacy of combinations) has not yet been defined. In conclusion, in men with minimally symptomatic or asymptomatic metastatic prostate cancer who had not received chemotherapy, enzalutamide, an oral therapy with an excellent side-effect profile, significantly delayed radiographic disease progression or death, the need for cytotoxic chemotherapy, and the deterioration in quality of life and significantly improved overall survival. Presented in part at the American Society of Clinical Oncology Genitourinary Cancers Symposium, San Francisco, January 31–February 4, 2014. Supported by Medivation and Astellas Pharma, which also funded editorial support.

Provided by the authors are available with the full text of this article at NEJM.org. Additional investigators in the PREVAIL study are listed in the, available at NEJM.org. This article was published on June 1, 2014, at NEJM.org.

We thank the patients who volunteered to participate in this study for their dedication and the study-site staff who cared for them. References • 1 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D.

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