Bloomberg 长篇特写复盘罗氏乳腺癌口服药 giredestrant，无新增临床或审批事实

Cancer upended Ulrike Isselhard’s life for about a year as breast-removal surgery and two rounds of chemotherapy sapped her energy, optimism and shoulder-length hair. But now she’s working full time again, riding her bike more than 2 miles to the office. She credits an experimental pill she takes every morning.

“My life is exactly like it was before I got sick,” says the mother of three from Bamberg, Germany. “Except I no longer need to wear a bra.”

Isselhard joined a clinical trial at the nearest university hospital to gain access to the new treatment, called giredestrant. Roche Holding AG, the Swiss drugmaker behind the medicine, transformed breast-cancer care once before in the first two decades of the century with a targeted therapy called Herceptin — a revolution that saved so many lives it got its own movie — and says it can do it again, this time with a daily pill.

The pitch is this: an easy-to-take drug developed in-house for women by women, which can prevent cancer from growing or returning without the harrowing side effects of older treatments, improving quality of life as patients get younger and juggle work and even sometimes motherhood.

For Thomas Schinecker, the chief executive of the usually cautious Roche, the new drug will turn into its biggest success ever, eclipsing Herceptin’s $7 billion sales peak.

There’s a lot at stake for the Swiss firm. Once known as the breast-cancer company, Roche has lost the lead in the booming market for oncology treatments, dropping to fifth position last year. It missed out on at least one deal opportunity that would have secured a blockbuster, and one of the main giredestrant clinical trials failed this year, narrowing the pool of potential patients.

What’s more, AstraZeneca Plc and other rivals are working on similar medicines. Astra has become a cancer powerhouse, snagging market share from Roche, and unlike giredestrant its competing product has already secured a first regulatory clearance. Analysts’ estimates for the Roche drug reflect the duality, with some pegging peak annual revenue at $2.5 billion and others going as high as $14.5 billion.

Breast tumors cause the most cancer deaths in women, with victims getting younger. The business of treating them and other forms of cancer is massive, and expected to more than double to surpass $398 billion in 2030, overshadowing even the obesity-drug rush.

“When I finished university in 2006, there were basically three drugs to treat breast cancer,” says Claudia Rauh, a senior physician in the Zurich University Hospital’s department of gynecology. “Now we see new therapies every six months.”

Not all are revolutionary. Fewer than half of the cancer drugs approved since 2000 that Bloomberg News reviewed based on their FDA labels had been shown to extend patient survival for any of their approved uses by April 2025.

For Donald McDonnell, a Duke University professor who helped pioneer the science behind this new class of drugs, it’s too early to tell whether Roche’s giredestrant and other so-called selective estrogen receptor degraders are truly transformative. The studies available don’t yet show whether patients actually live longer. Cancer trials often focus first on an easier metric that tells whether the drug slows tumor progression.

What’s clear is that one in eight women in the US will be diagnosed with breast cancer in her lifetime, and projections show disturbing growth. By 2050, there will be 3.6 million new cases a year worldwide, marking a 40% surge over roughly three decades. Scientists don’t entirely understand why it strikes increasingly young — a trend mirrored in other types such as bowel cancer — although they suspect lifestyle changes.

Breast cancer often runs in families. It was the case for Ulrike Isselhard: her two sisters have also had it.

Isselhard found out in 2021 after a routine ultrasound. Her tumors — one in each breast — were fueled by the hormone estrogen, making her eligible for giredestrant. Her experience with the Roche medicine so far matches the best-case scenario.

When she was diagnosed, a client advised going to the university hospital in Erlangen, a half hour from her home in the medieval city of Bamberg. A month later, both Isselhard’s breasts were removed there and after 10 days in the hospital she went on holiday to France’s Île de Ré with her family. When she returned to Germany, she found out she would also need chemotherapy.

“Chemo was awful,” she recalls. She tried to continue seeing friends once a day but now equates what she was doing to “shuffling from one park bench to the next.”

Isselhard had to take almost eight months off work and lost her hair. She bought two wigs — a brown everyday one, and a bright blue one to cheer up herself and her family on bad days. After two rounds of chemotherapy, she says she was excited to return to her job as an insurance broker for doctors’ practices in April 2022. Around the same time, she started a six-week course of radiation therapy.

With the tumors gone, doctors looked for a medicine to prevent a recurrence. They proposed tamoxifen, an older treatment that blocks the effects of estrogen in breast tissue but comes with menopause-like side effects, or enrolling in a clinical study to get the experimental giredestrant, whose efficacy and effects were still largely undocumented. She chose the latter after being told it contained “more active ingredients against cancer.” She was often nauseated at first, but then found out she needed to take the pill with food. After that, she experienced only joint pain, which she says she managed by largely cutting sugar from her diet.

“I’m so glad I chose giredestrant,” she says. “I’ve spoken to people who stopped taking tamoxifen because the side effects were so severe.”

Isselhard was eligible because her tumors were hormone receptor-positive, meaning they needed estrogen to grow. That’s the most common form of breast cancer, and also the target of the entire class of medicines known by their acronym SERDs, which cut off the tumor’s growth signal by binding to its estrogen receptors and damaging them.

To regain its lead, Roche will need to face off with Astra, which vaulted into a corner of the market that had largely been the Swiss firm’s purview in 2019 with a licensing deal worth as much as $6.9 billion — and has been gaining market share, reaching third position ahead of Roche last year.

Since Herceptin’s emergence as the first cancer mega-blockbuster early in the century, chronicled in a TV movie called Living Proof, Roche has dominated the market for an aggressive form of the disease fueled by a growth-promoting protein called HER2.

Herceptin, by blocking those tumor-stimulating effects, transformed the cancer from a likely death sentence into a treatable disease. It also sealed Roche’s identity as the company going after HER2, which turned into a franchise spanning different stages and treatment approaches over the years, with medicines like Perjeta and Kadcyla.

“Roche defined HER2,” according to Rauh, the Zurich hospital physician.

The Swiss drugmaker’s cancer empire started coming under pressure as Herceptin and another key therapy neared the end of their patent protection in the mid to late 2010s. Roche needed new growth drivers, yet it didn’t seize a licensing opportunity with Daiichi Sankyo Co. — a decision that delivered a major advantage to rival Astra by giving it a future blockbuster right on Roche’s own HER2 turf.

Roche “just did not show any interest” when Daiichi came looking for a partner for an experimental drug combination now called Enhertu that could target cancer cells directly by attaching to the HER2 proteins on the tumor, recalls Antoine Yver, the Japanese firm’s former oncology research chief. “They could not see that it was completely transforming HER2.”

Astra wasn’t convinced either at first, but eventually CEO Pascal Soriot, the former Roche executive who turned the UK drugmaker into a major cancer player, did see the potential and struck an agreement with Daiichi, flying to Japan to seal the deal.

Enhertu is one of the world’s fastest-growing cancer medicines, according to Bloomberg Intelligence, generating about $5 billion in sales in the last fiscal year. It beat Roche’s Kadcyla in a head-to-head breast trial and it’s now also approved for gastric and lung tumors.

“Roche shouldn’t have lost Enhertu,” says Thilo Schroeder, a managing partner at Nextech Invest AG.

It wasn’t the only miss. In 2018, the company’s Chugai Pharmaceutical Co. division opted to not keep developing an experimental weight-loss pill, licensing it to Eli Lilly & Co. instead. The product, now called Foundayo, is touted as one of the booming obesity market’s potential next-generation blockbusters.

Roche’s CEO argues it has other ways to close the escape routes tumors use to adapt and grow. Cancer is increasingly a battle on multiple fronts, and the Swiss firm has about 30 oncology medicines in its pipeline, including one just approved to tackle a mutation in a gene called PI3K that can promote cancer growth.

Roche’s dealmaking did have one spectacular early success: its investment in California’s Genentech, begun in 1990 and completed with a $47 billion buyout in 2009. Like Herceptin, that’s where giredestrant was born. The medicine doesn’t target HER2 but the most common breast cancer — the hormone-fueled one affecting Isselhard.

Around 2013, a biotech called Seragon Pharmaceuticals led efforts to try to disable women’s estrogen receptors rather than just block them. Roche bought the company for $725 million, but the Seragon medicines didn’t work out, underscoring the risks inherent to drug development.

The lead product caused too many side effects and another required swallowing about seven pills a day, according to Sandra Milan, a project team leader at Genentech in South San Francisco.

“No way women are going to stay on this drug long enough to see the benefit,” Milan recalls thinking. Milan knew about that firsthand: she was diagnosed with breast cancer at age 40 and had to stop taking the older hormone therapy tamoxifen because — even as a highly motivated patient — she couldn’t bear the side effects.

So she and two other female scientists focused on the homegrown product that would become giredestrant. Gina Wang, the chemist in charge, describes her approach as involving some reverse-engineering. Rather than focus on the cancer effect first, she and her team first designed a medicine that the body could absorb well as a pill. Only afterwards did they build its cancer-fighting properties, she says.

“I knew we needed to think outside the box and try something different” given the failures in the field, says Wang, who first started working on estrogen-receptor modulators during her postdoctoral work at RTI International, a research institute in North Carolina.

In late 2018, early tests validated her approach. “We started seeing just a much more improved toxicity profile, and we started to see tumor shrinkage,” says Milan who worked closely with Wang and a third scientist, Ciara Metcalfe, who led the biology behind the drug. “All of us in the team were just jumping out of our skin the minute we heard about the first patient having clinical benefit.”

Milan found herself having to make the case to management for pressing ahead with the drug’s expensive scientific development as Roche faced the patent cliff for Herceptin and another cancer blockbuster called Avastin, which she says “felt like I was doing my thesis defense all over again.”

At the time, there was one SERD medicine on the market — Astra’s fulvestrant — but it required patients getting two often painful injections in the buttocks at least once a month. The medicine’s annual sales barely topped $1 billion.

Milan convinced the Swiss company to go all in with a $1.2 billion commitment to the experimental giredestrant just before the pandemic, when only 50 patients had been treated. Roche didn’t have much of a head start on Astra but it took a risk, opting to move to the third and most expensive stage of clinical tests in some indications before it had results for intermediate trials.

The biggest breakthrough came last November, when a study with over 4,000 patients with early-stage tumors showed that giredestrant was better than existing hormone-targeting therapy at preventing cancer’s return. The risk of invasive-disease recurrence or death was cut by 30% on the Roche medicine. That’s significant because cancer tends to return for a third of women on the older therapies. And many — like Milan herself — simply have to stop treatment because they can’t tolerate it.

Roche shares surged almost 20% on the announcement. Milan had a necklace made for her team that reads “Giredestrant Shero” to celebrate how her largely female team had turned the once-backup molecule into a potential lifesaver.

A few months later, there was a surprise setback. Another key trial in thousands of women whose cancer had advanced or metastasized didn’t benefit — at least not in a way that was statistically significant. Astra has since said its rival drug failed in a similar setting. Despite falling when the study results were published, Roche shares have gained about 19% this year.

Analysts slashed their giredestrant revenue estimates without giving up on the drug. Many argue the sales potential comes largely from it being a so-called adjuvant therapy offered after surgery to avoid a recurrence, not as an initial treatment.

Alan Hippe, Roche’s chief financial officer, figures the market potential is about $15 billion overall, with adjuvants making up two thirds. The US Food and Drug Administration is due to make a decision by the end of November for giredestrant in that indication.

“This is really going to be the new standard of care as a backbone therapy for 70% of breast-cancer patients,” CEO Schinecker told Bloomberg Television earlier this year.

Astra is going after the same group of patients, with a key clinical trial reading expected only from 2030. A Lilly pill from the same class called imlunestrantis already available, as is one with a different mechanism from Italy’s Menarini group, but for now they are on sale for somewhat niche indications.

“Giredestrant will have a major impact simply because it is the first drug of its kind in early breast cancer,” says Peter Fasching, a senior physician at Erlangen University Hospital, where Isselhard is followed. “Once a doctor has become familiar with one product and has treated 10 or 20 patients with it, it becomes an established routine in terms of what they tell the next patient.”

Others say that the other three contenders are coming too close on giredestrant’s heels to give it time to really conquer the market. Roche argues the pill will be quickly adopted because it can offer a quality-of-life boost to millions of women, is simple to take and well tolerated.

Michael Leuchten, an analyst at Jefferies, is skeptical about the side effects. In Roche’s main successful trial, patients reported roughly as much joint pain, hot flashes, headaches and fatigue as with older treatments, though far fewer volunteers stopped treatment than on tamoxifen or another class of medicines called aromatase inhibitors.

“I know Roche is saying it’s milder, it’s better tolerated,” Leuchten says. “I don’t know where that argument is coming from.” He’s one of the most bearish analysts on giredestrant, with a peak annual sales estimate at $2.5 billion.

Roche may face an uphill battle with insurers on costs. The new pill will likely be priced around $300,000 a year in the US, according to some analysts, whereas the hormone treatments it aims to displace are generics that cost as little as a few hundred dollars a year. On the drugmaker’s European home turf, Roche is one of several pressuring governments to pay more for medicines, but the context of ballooning public-health spending means costs are under scrutiny and the onus is on drugmakers to prove significant benefits. One of Roche’s arguments is that patients can take giredestrant themselves, at home, avoiding expensive doctor and hospital visits.

“You’re talking about changing the standard of care from a drug that’s a couple of hundred dollars a month to something that’s likely to be a lot more expensive,” says McDonnell.

On an individual level, the difference could be invaluable.

Every week day now, Ulrike Isselhard’s alarm sounds at 10:30 am and her colleagues shout across the open-plan office: “Ulli you have to take your pill!’’ On the weekends, her husband reminds her, and brings it over when she’s gardening. She insists it’s not a burden.

“I’d be happy to continue taking it for the rest of my life,” she says. “Taking the pill is just like wearing my bike helmet. I wouldn’t stop doing that either.”