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  • Asia-Pacific stocks mixed as Japan ushers in new leadership

    Asia-Pacific stocks mixed as Japan ushers in new leadership

    Mount Fuji and the Shinjuku skyline in Tokyo, Japan, on Friday, Feb. 14, 2025. Photographer: Kiyoshi Ota/Bloomberg via Getty Images

    Bloomberg | Bloomberg | Getty Images

    Asia-Pacific markets fell Wednesday as investors assessed trade data from Japan and its new government.

    Japanese exports in September snapped four months of declines, climbing 4.2% year on year, as shipments to Asia saw robust growth, partially offsetting the drop in exports to the U.S.

    Exports, however, missed analysts’ expectations of a 4.6% rise, according to median estimates in a Reuters poll of economists.

    Prime Minister Sanae Takaichi and her new cabinet were sworn in on Tuesday, with her former rival in the ruling Liberal Democratic Party’s leadership race, Shinjiro Koizumi, named defense minister and Satsuki Katayama becoming Japan’s first female finance minister.

    Japan’s Nikkei 225 was down 1.26%, leading losses in Asia, while the Topix index lost 0.18%. Shares of SoftBank plunged over 10%, building on their 0.26% drop on Tuesday. Shares had gained 8.5% on Monday.

    On Tuesday, the Nikkei briefly set a new intraday record of 49,945.95, before retreating after Takaichi won the parliamentary vote to become Prime Minister.

    South Korea’s Kospi index was down 0.26%, while the small-cap Kosdaq fell 0.25%. Shares of LG Chem soared as much as 10% after Palliser Capital urged the chemicals company to revamp its board and buy back shares, according to a Reuters report.

    Australia’s S&P/ASX 200 started the day down 0.73%, pulling back from earlier gains on Tuesday after rare earth stocks briefly rallied on news of a U.S.-Australia critical minerals agreement.

    Hong Kong Hang Seng index futures were at 25,919, lower than the last close of 26,027.55.

    Indian markets are closed for a holiday.

    Overnight in the U.S., the Dow Jones Industrial Average set a new closing record, boosted by strong earnings reports from companies such as Coca-Cola and 3M, while the S&P 500 was relatively unchanged.

    The 30-stock index gained 0.47% to close at 46,924.74, and briefly topped 47,000 during the session.

    The broad market S&P 500 closed just above the flatline at 6,735.35, while the tech-heavy Nasdaq Composite lagged, falling 0.16% to 22,953.67.

    —CNBC’s Sean Conlon and Pia Singh contributed to this report.

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  • Why supermarket prices really became sky high in the UK

    Why supermarket prices really became sky high in the UK

    Faisal Islam profile imageFaisal IslamEconomics editor

    BBC A treated image showing several glasses of orange juice on a colorful background BBC

    There has been more than a bitter twang in the glasses at British breakfast tables. Only five years ago, a typical supermarket own-label carton of orange juice could be bought for 76p for 1 litre. It now costs £1.79.

    That’s a rise of 134% since 2020, and it’s up 29% just in the past year.

    In cafes and restaurants it’s a similar story – with £3.50 to £4 now a standard price point for a glass of basic OJ.

    One colleague was outraged to be sent a bill for £9 for a glass of hangover-busting orange juice and lemonade at an unassuming little restaurant in Kent. Asked why so much, she was told that the orange juice – albeit freshly squeezed – accounted for £5.30 of the price.

    Yet as costs have surged, the taste is changing too, with certain manufacturers substituting oranges for mandarins to cut costs.

    The public is, if you like, being freshly squeezed.

    A chart showing how some orange juice prices have increased. For example, in October 2020 an own label ambient smooth juice was £0.76 and in October 2025 was £1.79 - marking a 134% increase

    There are all sorts of reasons for this: disease among crops, extreme weather, over-reliance on supply from a single nation, new rules for packaging and complexities around trade wars and Brexit.

    All of this is compounded by grocery price inflation which, after hitting 17.5% in 2023, came down (to around 5.7% in August) but is rising once again. New figures for overall inflation will be released later today.

    It is a perfect storm.

    Yet the problem is not isolated to orange juice – track the prices of all sorts of other groceries in supermarket aisles and you’ll see a similar pattern. And so understanding what has happened to orange juice offers a glimpse into how our overall grocery bills suddenly seem so expensive.

    It all prompts the question: is this storm a passing one, or are prices set to remain stubbornly high – and should brace for them staying that way permanently?

    The Bing Crosby effect

    Where else to start but in the orange groves of Florida where the industrialisation of OJ began as an initiative of the US Army during World War Two.

    The US government was seeking a source of transportable Vitamin C for troops that didn’t taste like turpentine.

    Hulton Archive/Getty Images Full-length portrait of Marilyn Crane posing with Minute Maid's 'Mechanical Man' made from aluminum cans of orange juice Hulton Archive/Getty Images

    Orange juice from concentrate was commercialised by Minute Maid

    Orange juice is nearly 90% water. So gently evaporating the water off the juice and freezing the concentrate, allowed for transportability of a much better tasting product when water was later re-added.

    WW2 ended before the troops got to try it, but it ended up being commercialised by what became the American soft drink giant, Minute Maid.

    It was popularised by Bing Crosby, who, as a significant shareholder, would sing in ads and radio show jingles about frozen orange juice being “better for your health”.

    Western consumption of orange juice surged.

    TV Times/ Getty Images/ Screen Archives A dual image showing Bing Crosby dressed as Santa Claus on the set of his holiday special Bing Crosby's White Christmas (left) and Bing as he poses in an armchair (right) TV Times/ Getty Images/ Screen Archives

    Minute Maid orange juice was popularised by Bing Crosby

    Flash forward to today and an estimated 2.5 billion gallons of orange juice are drunk each year – with about a tenth of that in the UK, where the market is still growing.

    Drought, disease and flooding

    At an industrial unit in the Essex town of Basildon, green steel drums of frozen orange concentrate arrive from Brazil, overseen by Maxim McDonald.

    His firm Gerald McDonald and Co is named after his grandfather, a pioneer who was importing orange concentrate as far back as the 1940s from what was then British-mandate Palestine.

    Today it produces juices and blends them, then sells them to supermarkets and restaurant suppliers.

    But prices reached extraordinary heights in global markets, rising from $1(75p) to $1.50 (£1.12) per lb over the last decade, to a record $5.30 per lb by the end of last year.

    This followed five years of poor crops, owing to severe drought and a disease called citrus greening (caused by a bacteria spread by insects). Brazil had its worst crop since 1988. In some parts of its citrus belt, two thirds of orange trees are affected.

    “Around September of last year the price shot up to crazy levels,” Maxim tells me. “At the worst time I was being offered $7 a kilo.

    “For such a major commodity to go from $2 to $7 is insane, but it took a while to filter through to consumers.”

    Until 2023 the rise in orange juice prices was disguised among food inflation in general, explains Philip Coverdale, an industry expert at consultancy firm GlobalData.

    Producers have tried to look beyond South America but it’s not easy – the supply of oranges has been sown up by Brazil, even more so than, say, the Saudis have cornered the market for crude oil.

    Morocco, Egypt and South Africa grow oranges too but their supplies are more limited. Spain also grows them, but Valencia and Seville oranges are mostly exported as fruit, rather than concentrate. (Plus Spain too suffered from weather-related production slumps, including the floods in Valencia last October.)

    AFP via Getty Images A man recovers oranges from a tree, with the ground flooded below AFP via Getty Images

    Spain has suffered from weather-related production slumps

    Even within Brazil the market is concentrated in the hands of huge industrialised conglomerates.

    In a truly competitive market the price would settle again – but it hasn’t, nor does the industry expect it to. This is a phenomenon that is common to many other ordinary groceries too whose prices have risen.

    Oranges becoming less sweet

    Florida is the other traditional exporter of oranges, but output from the Sunshine State over the past year has been the lowest since the Great Depression, amid a high number of hurricanes and long-term problems caused by citrus greening.

    One problem with greening is that it reduces sugar content, making oranges less sweet.

    “Not many are buying Florida oranges any more unless it is a requirement to label the juice ‘Florida Orange’,” says Maxim McDonald.

    “It’s very difficult to get oranges out of Florida [because of the shortages] and it’s too expensive.”

    VW Pics/Universal Images Group via Getty Images Close up of oranges hanging on a tree with the backdrop of a historic church in the rural town of Carrion de los Cespedes, Seville, Spain VW Pics/Universal Images Group via Getty Images

    Spain also grows oranges – but Valencia and Seville oranges are mostly exported as fruit, rather than concentrate

    One of the leading suppliers to Tropicana sold off some of its land earlier this year to build homes.

    Tropicana itself, the marquee US brand for orange juice, had to restructure its debts this year. Pepsi has also sold most of its stake in it.

    One of Tropicana’s recent product innovations in the US has been to launch an “essentials” brand of orange juice “blends” – combining orange, apple and pear juice – at a lower price.

    Similar trends can be seen on British shelves. Orange is being mixed with mango, mandarins and clementine juice. Mango purée is especially cheap right now, driven by a good harvest in India. Mandarin concentrate, meanwhile, is cheaper than its orange equivalent because there is less demand for it.

    These developments save money, but also maintain the traditional sweetness of the taste.

    Tariffs: War on the orange

    Then there is the added impact of the recent spike in trade tensions with the US since President Trump introduced new tariffs.

    Oranges, it transpires, have been at the centre of it.

    US exports of orange juice to Canada have slumped to a 20-year low after Canada put counter-tariffs on US exports. The former PM Justin Trudeau warned that Canadians might have to “forgo Florida orange juice”.

    The Trump administration has also settled on a 10% tariff on orange juice coming from Brazil, which will feed into US supermarket prices.

    In 2024, the UK eliminated tariffs on some imports produced from fruit grown outside Britain. But tariffs on certain sweeter, cheaper varieties and blends were not part of this.

    And while the tariff cuts might have helped, they were vastly outweighed by the increase in the underlying price.

    Getty Images US President Donald Trump Getty Images

    The Trump administration has put a 10% tariff on orange juice coming from Brazil

    Then there are new regulations around packaging, further adding to the pressures.

    The rules, known as Extended Producer Responsibility, are aimed at improving recycling rates, with a weight-based fee. All juice producers will be impacted, especially those still using glass bottles.

    In August a Bank of England report said that high food price inflation is driven partly – and among other things – by these regulations.

    Did the West fall out of love with OJ?

    In Brazil, the orange harvest has recovered somewhat – this is the greatest hope for a return to normal prices. Yet it coincides with sinking demand: global consumption of orange juice is now down 30% from a peak two decades ago.

    Though this may be partly down to the high prices, in certain parts of the world there has also been a shift in perception about the sugar content and health benefits or otherwise of fruit juice.

    “When young children are not regularly given juice from an early age, they are less likely to be regular juice drinkers in later years,” suggests Philip Coverdale at GlobalData.

    Demand is increasing in countries with growing middle classes, such as China, South Africa, and India. But elsewhere other more exotic fruit juices such as mango, pear and pomegranate are growing in popularity.

    AFP via Getty Images Farm workers spread plant food on the orange trees in the ALG Estates Citrus farm in Citrusdal, South Africa AFP via Getty Images

    South Africa grows oranges but its supplies are small

    Ultimately, however, orange juice is a staple that supermarkets have long been used to selling at low prices. And the price spikes to £2 a carton could, with for example better weather, simply reverse.

    “The volatility in the harvest appears to have reduced,” says Giles Hurley, UK CEO of Aldi, “Our buying team are doing everything they can to ensure that that saving is passed on to consumers.”

    Others in the supply chain are less convinced, given that much of the frozen concentrate was bought at last year’s high prices. Plus, the stranglehold of the small number of giant producers who control the market remains.

    As for the citrus greening, some major commercial producers, including Coca-Cola, which owns Minute Maid and Innocent, have contributed to a project to Save the Orange, using artificial intelligence to find a way to combat it.

    It’s a long-term project – and even if fruitful, it may be some time before the effect – if at all – filters through to grocery bills.

    But the story of orange prices does also show how an upward price shock gets transmitted around the world far more quickly than a downward one.

    Chocolate, coffee, butter and beef

    Oranges are not the only food that has seen a price spike, of course. The price of beef and veal is up almost 25% in a year. Butter is up almost 19%, and chocolate and coffee 15% and milk over 12%, all according to the Office for National Statistics.

    This all suggests that, more generally, there may be something else at play. And that for all the food and drink spikes, the consumer was actually protected from the worst of it for a period – and now it is pay back time.

    “It might be the retailers didn’t full pass through the cost increase in the first place and therefore it’s a way of recouping some of the margin they would otherwise have got,” says Steve McCorriston, Professor of Agricultural Economics at the University of Exeter.

    EPA - EFE/REX/ Shutterstock A woman shops at a supermarket, facing rows of orange juiceEPA – EFE/REX/ Shutterstock

    Do consumers need to simply accept the fact that the UK will be increasingly exposed to food price shocks?

    Ultimately, though, trying to unpick the precise reason for why our food and drink costs what it does is very difficult – other factors that influence price can go undetected.

    “What we don’t know much about is how these supply chains tend to work in practice. It’s difficult to uncover relationships between retailers and manufacturers or farmers and the use of contracts.”

    There is also a broader question that goes well beyond orange juice: do consumers in the UK need to simply accept the fact that as a densely populated small country with limited agriculture, a changing climate means the UK will be increasingly exposed to food price shocks?

    A 2024 government report on food security noted: “The UK continues to be highly dependent on imports to meet consumer demand for fruit, vegetables and seafood…

    “Many of the countries the UK imports these foods from are subject to their own climate-related challenges and sustainability risks.”

    And so it could be that this is only the start of a wild ride on what we pay for our food and drink.

    Top image credits: Daniel Grizelj/ Tetra Images/ Getty Images

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  • Holiday optimism and a ‘KPop Demon Hunters’ deal aren’t enough for Mattel’s stock after earnings miss

    Holiday optimism and a ‘KPop Demon Hunters’ deal aren’t enough for Mattel’s stock after earnings miss

    By Bill Peters

    Shoppers have yet to see the full impact of price increases on store shelves, one analyst says

    Mattel reported quarterly results on Tuesday.

    Mattel Inc. on Tuesday said it expects a decent holiday season, but shares still dropped after the toymaker’s third-quarter earnings report missed Wall Street’s expectations.

    The results arrived as toymakers and retailers gear up for the key holiday-shopping stretch – and as they both try to cushion the impact of tariffs, which have made imports more expensive and threatened to push prices higher for inflation-weary consumers.

    For the third quarter, Mattel reported sales of $1.74 billion. That was down 6% year over year, led by a drop in North America, and below FactSet analyst estimates for $1.83 billion. The company’s adjusted earnings per share came in at 89 cents, below forecasts for $1.06.

    Mattel shares (MAT) dropped around 6% in after-hours trading Tuesday.

    Chief Executive Ynon Kreiz said that since the start of the fourth quarter, orders from U.S. retailers had grown as stores try to stock up for the holiday season. So had point-of-sale trends and consumer demand overall.

    “Looking into the balance of the year, we expect a good holiday season for Mattel and strong top-line growth in the fourth quarter,” he said.

    Against that backdrop, Mattel said it was sticking with its full-year outlook. The company expects adjusted earnings per share of $1.54 to $1.66 for the full year.

    Mattel’s results also landed as it tries to become more of a gaming and entertainment company, along with one that sells classic toys like Hot Wheels, Barbie dolls and action figures.

    Netflix Inc. (NFLX) on Tuesday said it was partnering with Mattel and rival Hasbro Inc. (HAS) to roll out toys for “KPop Demon Hunters,” the streaming service’s megahit film. On Monday, Mattel said it had renewed a multiyear licensing agreement to make Disney’s (DIS) Princess and “Frozen” toys.

    Some analysts expect holiday spending to cool slightly this season, as consumers stay selective on purchases and wrestle with tariff-related anxieties. In May, Mattel said it planned to raise prices in the U.S. “where necessary” as it grappled with the Trump administration’s trade wars.

    During Mattel’s earnings call Tuesday, Kreiz said Mattel’s U.S. business during the third quarter was “challenged” by changes in the way retailers are ordering toys that shifted orders to the fourth quarter. More retailers, management said during the call, were opting to let Mattel handle imports and warehousing before taking in items – a more “just-in-time” approach to shipping, as retailers look for more flexibility in committing to orders.

    UBS analyst Arpine Kocharyan said in a research note Monday that Mattel and Hasbro, as larger players in the toy industry, were in better shape than their rivals heading into the holidays. But she noted that the toy companies have largely acknowledged that shoppers have yet to see the full impact of price increases on store shelves.

    Kocharyan said the industry was also running up against issues trying to move production out of China, a country that it has relied on for manufacturing and which the U.S. has targeted in its global trade war.

    “The process of taking production out of China has been bumpier than anticipated for the industry,” she said.

    “Buyers note supply-chain problems and issues with uninterrupted supply, while suppliers highlight disappointing production processes due to a lack of infrastructure in markets such as Vietnam and India and others,” she added.

    -Bill Peters

    This content was created by MarketWatch, which is operated by Dow Jones & Co. MarketWatch is published independently from Dow Jones Newswires and The Wall Street Journal. 

    
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    Copyright (c) 2025 Dow Jones & Company, Inc.

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  • ALMA Captures Spiral-Shaped Gas Streamer Guided by Magnetic Fields in Star-Forming Region

    ALMA Captures Spiral-Shaped Gas Streamer Guided by Magnetic Fields in Star-Forming Region

    This streamer of gas is channeling matter from the surrounding cloud of a star-forming region in Perseus directly onto a newborn binary star system called SVS 13A.

    An artist’s impression of the SVS 13A system. Image credit: NSF / AUI /…

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  • Letter: Matcha matchmaking

    Letter: Matcha matchmaking

    In an age of fierce geopolitical tension, it’s easy to lump all Chinese exports into the same category: state-subsidised oversupply flooding western markets.

    However, nothing could be further from the truth when it comes to matcha. As your Big Read shows (“Can Japan satisfy the world’s thirst for matcha?”, October 10), the enormous surge in demand for matcha in the UK and the rest of the world is causing some serious global shortages.

    This trend compelled me to turn to China as a source of supply.

    As a business owner, I found Chinese matcha to be a great commercial delight. I discovered matcha of comparable grade to Japan’s, for half the price, sometimes even less.

    And as a certified tea sommelier, I found Chinese matcha intriguing. Though there was a fair share of pretty rubbish matcha, if one looks there are certainly gems that rival what Japan has to offer. Perhaps not the grand cru of matcha, but premier cru it certainly is.

    So perhaps China turning its hand to this rediscovered agricultural export may end up bringing good to the world — or at least to Gen Z and yuppy millennials, who will no longer have to pay £5 for a cup of matcha.

    Raphael Chow
    Managing Director & Co-founder, Brut Tea, London W1, UK

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  • CISA urges immediate patching of exploited Windows SMB client vulnerability

    CISA urges immediate patching of exploited Windows SMB client vulnerability

    The U.S. Cybersecurity and Infrastructure Agency has issued a warning relating to an actively targeted Microsoft Windows vulnerability that can be found in unpatched versions of Windows 10, Windows 11 and Windows Server.

    Tracked as

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  • Capital One puts credit risk worries to rest, delivers a strong quarter and new buyback

    Capital One puts credit risk worries to rest, delivers a strong quarter and new buyback

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  • Soil sample study offers clues on lunar water evolution

    Soil sample study offers clues on lunar water evolution

    Chinese scientists studying a 2-gram lunar soil sample from the Chang’e 6 mission have identified rare CI chondrite impact residues, providing new insights into mass transfer in the inner solar system and offering new…

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  • Inside Alana Hadid’s backyard wedding in LA—where sisters Bella and Gigi were barefoot bridesmaids – Vogue Australia

    1. Inside Alana Hadid’s backyard wedding in LA—where sisters Bella and Gigi were barefoot bridesmaids  Vogue Australia
    2. Inside Alana Hadid’s Backyard L.A. Wedding—Where Sisters Bella and Gigi Were Barefoot Bridesmaids  Vogue
    3. Alana Hadid gets…

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  • PADCEV™ (enfortumab vedotin-ejfv) Plus KEYTRUDA® (pembrolizumab) sBLA Granted FDA Priority Review for Treatment of Certain Patients with Muscle-Invasive Bladder Cancer

    PADCEV™ (enfortumab vedotin-ejfv) Plus KEYTRUDA® (pembrolizumab) sBLA Granted FDA Priority Review for Treatment of Certain Patients with Muscle-Invasive Bladder Cancer

    Results from the pivotal EV-303 trial demonstrated that, when used before and after surgery, the combination reduced the risk of recurrence, progression or death by 60% and the risk of death by 50% in cisplatin-ineligible patients with muscle-invasive bladder cancer

    If approved, PADCEV plus KEYTRUDA could fundamentally change the treatment approach for patients with this disease

    TOKYO, Oct. 22, 2025 /PRNewswire/ — Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, “Astellas”) today announced that the U.S. Food and Drug Administration (FDA) accepted for priority review a supplemental Biologics License Application (sBLA) for PADCEV™ (enfortumab vedotin-ejfv) in combination with KEYTRUDA® (pembrolizumab) as a neoadjuvant treatment (before surgery) and then continued after radical cystectomy as adjuvant treatment (after surgery) for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy.

    Under the Prescription Drug User Fee Act (PDUFA), the FDA has set a target action date of April 7, 2026.

    The sBLA submission was based on results from the pivotal Phase 3 EV-303 clinical trial (also known as KEYNOTE-905) evaluating PADCEV, a Nectin-4 directed antibody-drug conjugate, in combination with KEYTRUDA, a PD-1 inhibitor, as neoadjuvant and adjuvant treatment versus surgery alone, the current standard of care. Detailed results from EV-303, which showed the combination reduced the risk of recurrence, progression or death by 60% and the risk of death by 50% compared to surgery alone, were presented at the 2025 European Society of Medical Oncology (ESMO) Congress. The safety results in EV-303 were consistent with those previously reported for this combination, and no new safety signals were identified.

    About the EV-303/KEYNOTE-905 Trial
    The EV-303 trial (also known as KEYNOTE-905) is an ongoing, open-label, randomized, three-arm, controlled, Phase 3 study evaluating neoadjuvant and adjuvant PADCEV in combination with KEYTRUDA or neoadjuvant and adjuvant KEYTRUDA versus surgery alone in patients with MIBC who are either not eligible for or declined cisplatin-based chemotherapy. Patients were randomized to receive either neoadjuvant and adjuvant KEYTRUDA (arm A), surgery alone (arm B) or neoadjuvant and adjuvant PADCEV in combination with KEYTRUDA (arm C).1

    The primary endpoint of this trial is event-free survival (EFS) between arm C and arm B, defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes radical cystectomy (RC) surgery or failure to undergo RC surgery in participants with residual disease, gross residual disease left behind at the time of surgery, local or distant recurrence as assessed by imaging and/or biopsy or death due to any cause. Key secondary endpoints include overall survival (OS) and pathologic complete response (pCR) rate between arm C and arm B, as well as EFS, OS and pCR rate between arm A and arm B.1

    For more information on the global EV-303 trial, go to clinicaltrials.gov.

    About Muscle-Invasive Bladder Cancer
    Bladder cancer is the ninth most common cancer worldwide, diagnosed in more than 614,000 people each year globally, including an estimated 85,000 people in the U.S.2,3 MIBC represents approximately 30% of all bladder cancer cases.4 The standard treatment for patients with MIBC is neoadjuvant cisplatin-based chemotherapy followed by surgery, which has been shown to prolong survival.5 However, up to half of patients with MIBC are not eligible to receive cisplatin and face limited treatment options, typically undergoing surgery without any systemic treatment.6  

    About PADCEV™ (enfortumab vedotin)
    PADCEV™ (enfortumab vedotin) is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.7 Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4-expressing cells, followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).8

    PADCEV plus KEYTRUDA is approved for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC) regardless of cisplatin eligibility in the United States, the European Union, Japan and a number of other countries around the world. PADCEV is also approved as a single agent for the treatment of adult patients with la/mUC who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy or are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.8

    PADCEV (enfortumab vedotin-ejfv) U.S. Indication & Important Safety Information

    BOXED WARNING: SERIOUS SKIN REACTIONS  

    • PADCEV can cause severe and fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later.
    • Closely monitor patients for skin reactions.
    • Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.
    • Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.

    Indication  
    PADCEV™, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC).  

    PADCEV, as a single agent, is indicated for the treatment of adult patients with locally advanced or mUC who:  

    • have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or
    • are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.

    PADCEV Important Safety Information  

    Warnings and Precautions  

    Skin reactions Severe cutaneous adverse reactions, including fatal cases of SJS or TEN occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later. Skin reactions occurred in 70% (all grades) of the 564 patients treated with PADCEV in combination with pembrolizumab in clinical trials. When PADCEV was given in combination with pembrolizumab, the incidence of skin reactions, including severe events, occurred at a higher rate compared to PADCEV as a single agent. The majority of the skin reactions that occurred with combination therapy included maculo-papular rash, macular rash and papular rash. Grade 3-4 skin reactions occurred in 17% of patients (Grade 3: 16%, Grade 4: 1%), including maculo-papular rash, bullous dermatitis, dermatitis, exfoliative dermatitis, pemphigoid, rash, erythematous rash, macular rash, and papular rash. A fatal reaction of bullous dermatitis occurred in one patient (0.2%). The median time to onset of severe skin reactions was 1.7 months (range: 0.1 to 17.2 months). Skin reactions led to discontinuation of PADCEV in 6% of patients.  

    Skin reactions occurred in 58% (all grades) of the 720 patients treated with PADCEV as a single agent in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 34% had pruritus. Grade 3-4 skin reactions occurred in 14% of patients, including maculo-papular rash, erythematous rash, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. The median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 8 months). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=75), 24% of patients restarting at the same dose and 24% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 3.1% of patients.  

    Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. For persistent or recurrent Grade 2 skin reactions, consider withholding PADCEV until Grade ≤1. Withhold PADCEV and refer for specialized care for suspected SJS, TEN or for Grade 3 skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.  

    Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C ≥8% were excluded from clinical trials. In clinical trials of PADCEV as a single agent, 17% of the 720 patients treated with PADCEV developed hyperglycemia of any grade; 7% of patients developed Grade 3-4 hyperglycemia (Grade 3: 6.5%, Grade 4: 0.6%). Fatal events of hyperglycemia and DKA occurred in one patient each (0.1%). The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. The median time to onset of hyperglycemia was 0.5 months (range: 0 to 20 months). Hyperglycemia led to discontinuation of PADCEV in 0.7% of patients. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. Of the patients who initiated insulin therapy for treatment of hyperglycemia, 66% (23/35) discontinued insulin at the time of last evaluation. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV.  

    Pneumonitis/Interstitial Lung Disease (ILD) Severe, life-threatening or fatal pneumonitis/ILD occurred in patients treated with PADCEV. When PADCEV was given in combination with pembrolizumab, 10% of the 564 patients treated with combination therapy had pneumonitis/ILD of any grade and 4% had Grade 3-4. A fatal event of pneumonitis/ILD occurred in two patients (0.4%). The incidence of pneumonitis/ILD, including severe events, occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of any grade pneumonitis/ILD was 4 months (range: 0.3 to 26 months).  

    In clinical trials of PADCEV as a single agent, 3% of the 720 patients treated with PADCEV had pneumonitis/ILD of any grade and 0.8% had Grade 3-4. The median time to onset of any grade pneumonitis/ILD was 2.9 months (range: 0.6 to 6 months).  

    Monitor patients for signs and symptoms indicative of pneumonitis/ILD such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients who develop Grade 2 pneumonitis/ILD and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis/ILD.  

    Peripheral neuropathy (PN) When PADCEV was given in combination with pembrolizumab, 67% of the 564 patients treated with combination therapy had PN of any grade, 36% had Grade 2 neuropathy, and 7% had Grade 3 neuropathy. The incidence of PN occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of Grade ≥2 PN was 6 months (range: 0.3 to 25 months).  

    PN occurred in 53% of the 720 patients treated with PADCEV as a single agent in clinical trials including 38% with sensory neuropathy, 8% with muscular weakness and 7% with motor neuropathy. Thirty percent of patients experienced Grade 2 reactions and 5% experienced Grade 3-4 reactions. PN occurred in patients treated with PADCEV with or without preexisting PN. The median time to onset of Grade ≥2 PN was 4.9 months (range: 0.1 to 20 months). Neuropathy led to treatment discontinuation in 6% of patients.  

    Monitor patients for symptoms of new or worsening PN and consider dose interruption or dose reduction of PADCEV when PN occurs. Permanently discontinue PADCEV in patients who develop Grade ≥3 PN.  

    Ocular disorders were reported in 40% of the 384 patients treated with PADCEV as a single agent in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 30% of patients, and blurred vision occurred in 10% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.7 months (range: 0 to 30.6 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.  

    Infusion site extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 720 patients treated with PADCEV as a single agent in clinical trials, 1% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.  

    Embryo-fetal toxicity PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.  

    ADVERSE REACTIONS  

    Most common adverse reactions, including laboratory abnormalities (≥20%) (PADCEV in combination with pembrolizumab)  
    Increased aspartate aminotransferase (AST), increased creatinine, rash, increased glucose, PN, increased lipase, decreased lymphocytes, increased alanine aminotransferase (ALT), decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection and decreased platelets.  

    Most common adverse reactions, including laboratory abnormalities (≥20%) (PADCEV monotherapy)  
    Increased glucose, increased AST, decreased lymphocytes, increased creatinine, rash, fatigue, PN, decreased albumin, decreased hemoglobin, alopecia, decreased appetite, decreased neutrophils, decreased sodium, increased ALT, decreased phosphate, diarrhea, nausea, pruritus, increased urate, dry eye, dysgeusia, constipation, increased lipase, decreased weight, decreased platelets, abdominal pain, dry skin.  

    EV-302 Study: 440 patients with previously untreated la/mUC (PADCEV in combination with pembrolizumab)  
    Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab. The most common serious adverse reactions (≥2%) were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Fatal adverse reactions occurred in 3.9% of patients treated with PADCEV in combination with pembrolizumab including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%).  

    Adverse reactions leading to discontinuation of PADCEV occurred in 35% of patients. The most common adverse reactions (≥2%) leading to discontinuation of PADCEV were PN (15%), rash (4.1%) and pneumonitis/ILD (2.3%). Adverse reactions leading to dose interruption of PADCEV occurred in 73% of patients. The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were PN (22%), rash (16%), COVID19 (10%), diarrhea (5%), pneumonitis/ILD (4.8%), fatigue (3.9%), hyperglycemia (3.6%), increased ALT (3%) and pruritus (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 42% of patients. The most common adverse reactions (≥2%) leading to dose reduction of PADCEV were rash (16%), PN (13%) and fatigue (2.7%).  

    EV-103 Study: 121 patients with previously untreated la/mUC who were not eligible for cisplatin-containing chemotherapy (PADCEV in combination with pembrolizumab)  
    Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab; the most common (≥2%) were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), sepsis (3.3%), pneumonia (3.3%), hematuria (3.3%), pneumonitis/ILD (3.3%), urinary retention (2.5%), diarrhea (2.5%), myasthenia gravis (2.5%), myositis (2.5%), anemia (2.5%), and hypotension (2.5%). Fatal adverse reactions occurred in 5% of patients treated with PADCEV in combination with pembrolizumab, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis/ILD (0.8%). Adverse reactions leading to discontinuation of PADCEV occurred in 36% of patients; the most common (≥2%) were PN (20%) and rash (6%). Adverse reactions leading to dose interruption of PADCEV occurred in 69% of patients; the most common (≥2%) were PN (18%), rash (12%), increased lipase (6%), pneumonitis/ILD (6%), diarrhea (4.1%), acute kidney injury (3.3%), increased ALT (3.3%), fatigue (3.3%), neutropenia (3.3%), urinary tract infection (3.3%), increased amylase (2.5%), anemia (2.5%), COVID19 (2.5%), hyperglycemia (2.5%), and hypotension (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 45% of patients; the most common (≥2%) were PN (17%), rash (12%), fatigue (5%), neutropenia (5%), and diarrhea (4.1%).  

    EV-301 Study: 296 patients previously treated with a PD-1/L1 inhibitor and platinum-based chemotherapy (PADCEV monotherapy)  
    Serious adverse reactions occurred in 47% of patients treated with PADCEV; the most common (≥2%) were urinary tract infection, acute kidney injury (7% each), and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis/ILD, and pelvic abscess (0.3% each). Adverse reactions leading to discontinuation occurred in 17% of patients; the most common (≥2%) were PN (5%) and rash (4%). Adverse reactions leading to dose interruption occurred in 61% of patients; the most common (≥4%) were PN (23%), rash (11%), and fatigue (9%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common (≥2%) were PN (10%), rash (8%), decreased appetite, and fatigue (3% each).  

    EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for cisplatin-based chemotherapy (PADCEV monotherapy)  
    Serious adverse reactions occurred in 39% of patients treated with PADCEV; the most common (≥3%) were pneumonia, sepsis, and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia, and pneumonitis/ILD (1.1% each). Adverse reactions leading to discontinuation occurred in 20% of patients; the most common (≥2%) was PN (7%). Adverse reactions leading to dose interruption occurred in 60% of patients; the most common (≥3%) were PN (19%), rash (9%), fatigue (8%), diarrhea (5%), increased AST, and hyperglycemia (3% each). Adverse reactions leading to dose reduction occurred in 49% of patients; the most common (≥3%) were PN (19%), rash (11%), and fatigue (7%).  

    DRUG INTERACTIONS  
    Effects of other drugs on PADCEV (Dual P-gp and Strong CYP3A4 Inhibitors) 
    Concomitant use with dual P-gp and strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and strong CYP3A4 inhibitors.  

    SPECIFIC POPULATIONS  
    Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for 3 weeks after the last dose.  

    Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment.   

    For more information, please see the U.S. full Prescribing Information including BOXED WARNING for PADCEV here .  

    About Astellas
    Astellas is a global life sciences company committed to turning innovative science into VALUE for patients. We provide transformative therapies in disease areas that include oncology, ophthalmology, urology, immunology and women’s health. Through our research and development programs, we are pioneering new healthcare solutions for diseases with high unmet medical need. Learn more at www.astellas.com.

    About the Pfizer, Astellas and Merck Collaboration
    Seagen and Astellas entered a clinical collaboration agreement with Merck to evaluate the combination of Seagen’s and Astellas’ PADCEV™ (enfortumab vedotin-ejfv) and Merck’s KEYTRUDA® (pembrolizumab) in patients with previously untreated metastatic urothelial cancer. Pfizer Inc. successfully completed its acquisition of Seagen on December 14, 2023. KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States and Canada).

    Cautionary Notes
     In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management’s current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas ‘  intellectual property rights by third parties. Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice.

    References:

    1 National Institute of Health. National Library of Medicine. Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Participants Who Are Cisplatin-ineligible or Decline Cisplatin With Muscle-invasive Bladder Cancer (MK-3475-905/ KEYNOTE-905/ EV-303. ClinicalTrials.gov identifier: NCT03924895. Published July 24, 2019. Updated June 17, 2025. Accessed June 23, 2025. Available at: https://clinicaltrials.gov/study/NCT03924895?term=AREA%5BBasicSearch%5D(myosarcoma)&rank=3  
    2 World Bladder Cancer Patient Coalition. GLOBOCAN 2022: Bladder cancer 9th most common worldwide. Accessed June 23, 2025. Available at: https://worldbladdercancer.org/news_events/globocan-2022-bladder-cancer-is-the-9th-most-commonly-diagnosed-worldwide/
    3 American Cancer Society. Cancer Facts & Figures 2025. Accessed September 23, 2025. Available at: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2025-cancer-facts-figures.html 
    4 Bladder Cancer Awareness Network. What is Muscle Invasive Bladder Cancer? Accessed June 23, 2025. Available at: https://bcan.org/what-is-muscle-invasive-bladder-cancer/#:~:text=When%20tumors%20grow%20into%20or,Virginia%20Health%20System%20explain%20MIBC. 
    5 Funt SA, Rosenberg JE. Systemic, perioperative management of muscle-invasive bladder cancer and future horizons. Nat Rev Clin Oncol. 2017 Apr;14(4):221-234. doi: 10.1038/nrclinonc.2016.188. Epub 2016 Nov 22. PMID: 27874062; PMCID: PMC6054138.
    6 Esteban-Villarrubia J, Torres-Jiménez J, Bueno-Bravo C, García-Mondaray R, Subiela JD, Gajate P. Current and Future Landscape of Perioperative Treatment for Muscle-Invasive Bladder Cancer. Cancers (Basel). 2023 Jan 17;15(3):566. doi: 10.3390/cancers15030566. PMID: 36765525; PMCID: PMC9913718.
    7 Challita-Eid PM, Satpayev D, Yang P, et al. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res 2016;76(10):3003-13.
    8 PADCEV [package insert]. Northbrook, IL: Astellas Pharma US, Inc.

    SOURCE Astellas Pharma Inc.

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