A stage-four cancer diagnosis once sounded like the end of the road – after all, there is no stage five. When Joe Biden’s prostate cancer was recently labelled “aggressive” and described as having spread to his bones, many assumed the worst. Yet today, thanks to astonishing advances in cancer science, a stage-four label need not mean imminent death.
“Stage four means the cancer has spread to another part of the body further away from where it started,” explains Dr Ben O’Leary, a clinical oncologist at the Royal Marsden and a researcher at The Institute of Cancer Research (ICR). “Most stage-four cancers still can’t be cured, but our deeper understanding of how cancers evolve and grow means many people are living longer. In some cases, we now see responses, and yes, even cures, that weren’t thought possible 10 years ago.”
What’s driving this optimism? Five types of cancer offer a snapshot of progress.
Skip to:
- Prostate cancer
- Blood cancers
- Breast cancer
- Bladder cancer
- Lung cancer
Prostate cancer
By the age of 80, half of men harbour cancer in their prostate, though it proves fatal in only a small minority. Even so, around 12,000 men die of metastatic prostate cancer each year in the UK.
Dr Anna Wilkins of the ICR and Royal Marsden says metastatic prostate cancer most often spreads to the bones. “On scans, you can see up to 50 spots all over the skeleton. But there has been big progress in new drugs.”
Total testosterone blockade
Standard treatment reduces testosterone, the hormone that fuels tumour growth. Abiraterone, developed at the ICR, goes further by blocking its precursor hormones, extending survival significantly.
Liquid radiotherapy
This exciting development involves injecting patients with a radioactive liquid. Cancer cells “drink” more of the liquid than healthy cells and the resulting burst of radiation destroys bone metastases. Liquid radiotherapy drug Radium-223 is already available on the NHS, while the even more potent Lutetium-177 PSMA is available privately and awaiting National Institute of Health and Care Excellence (Nice) appraisal.
Multimodal first strikes
“We now combine hormone drugs – and sometimes chemotherapy – immediately after diagnosis,” says Dr Wilkins. Even resistant cancers respond to this approach. Treating the original tumour with radiotherapy, even in metastatic cases, also boosts survival: “It’s as if you’re silencing a mothership that coordinates the metastases,” she says.
While there is no cure yet, Dr Wilkins says, these approaches are turning stage-four prostate cancer into a condition many men will live with, not die from.
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Blood cancers
Staging in blood cancers such as leukaemia or lymphoma is less about tumour size and more about specific genetic mutations within the cancer, which can determine how the cancer responds to treatment. “Unlike solid tumours, blood is already everywhere all at once,” explains Dr Sarah Gooding of Oxford University Hospitals. “So, when staging the cancer we look at how badly the disease is affecting the body and how hard it is to treat.”
T-Cell engagers
In relapsed multiple myeloma, a type of blood cancer that affects the bone marrow, where blood cells are produced, T-cell engagers (TCEs) are transforming treatment. These immunotherapy drugs lock tumour cells to immune T-cells, triggering the immune system to kill its prey. Response rates of more than 60 per cent are typical, and says Dr Gooding, new agents are arriving so fast that by the time resistance sets in, even better options may be available.
Antibody-Drug Conjugates incoming
The ADC belantamab mafodotin targets a protein found on the surface of myeloma cells, causing them to die. It has recently been approve by Nice for NHS use in relapsed myeloma patients.
CAR-T therapies
CAR-T therapy, which involves genetically modifying a patient’s own immune system T-cells to attack cancer, has revolutionised the treatment of some blood cancers. It is now approved for several relapsed lymphomas which develop in the lymphatic system, including diffuse large B-cell lymphoma and mantle cell lymphoma. Trials are underway to assess its effectiveness in more forms of blood cancer, including myeloma and certain leukaemias.
Re-educating leukaemia cells
Menin inhibitors are used in acute myeloid leukaemia. These new drugs can force cancer cells to become normal cells again. “Cancer is in the midst of a revolution,” says Dr Gooding. “Our next challenge is how healthcare systems afford the flood of innovative drugs.”
Breast cancer
One in seven women will be diagnosed with breast cancer in their lifetime. Of those, around a third will eventually progress to secondary, or metastatic, disease – typically spreading to the bones, liver, lungs or brain. Though still considered incurable once it reaches this stage, treatment has progressed rapidly in recent years.
“There is a growing belief in oncology that within five to 10 years some types of metastatic breast cancer could be managed as a chronic disease,” says Dr Simon Vincent of the charity Breast Cancer Now.
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Targeted therapy and “smart” chemotherapy
Perhaps the most significant strides have been made in HER2-positive breast cancer, a form that affects around 15 per cent of patients. It is driven by a gene mutation that leads to an overproduction of HER2 proteins on breast cell surfaces. These proteins signal cells to grow uncontrollably. The diagnosis used to carry a grim prognosis, but that changed in the 1990s with the advent of targeted drugs including trastuzumab (Herceptin), which blocks HER2 activity.
Now, newer drugs are going further. Enhertu, part of a new seek-and-destroy class of drugs known as antibody-drug conjugates (ADCs). Enhertu targets the HER2 protein to deliver a microscopic warhead of chemotherapy straight into the cancer cell. In trials, Enhertu led to tumour shrinkage in 82 per cent of women, compared to 37 per cent using the older ADC, Kadcyla.
“This concept of finding a cancer marker to attach chemotherapy directly into the cancer cells is where the big steps forward are happening,” says Dr Vincent.
Despite this, attempts to expand Enhertu’s use to metastatic patients with lower HER2 levels were blocked by Nice in 2024 due to rows over costs.
From control to cure?
In the United States, a groundbreaking trial known as SAPPHO is testing the possibility of curing metastatic HER2-positive breast cancer by using a sequence of eight already-approved drugs. Because these medications are already licensed in the UK, success could potentially translate quickly into clinical practice here – though affordability remains a key question.
Nicholas Turner, a consultant oncologist at the Royal Marsden and a team leader in Breast Cancer Now’s Research Centre at the ICR, believes that 10 to 15 per cent of metastatic HER2-positive patients may already be cured by current anti-HER2 treatments. “It’s just that we haven’t been treating people long enough to know if their remission is permanent,” he says.
Triple combinations for hormone-positive disease
Roughly 80 per cent of breast cancers are “fed” by oestrogen. These cancers tend to respond well to hormone-blocking therapies initially, but resistance often develops. Researchers are now turning to triple-combination treatments to overcome this hurdle.
In the INAVO120 trial, doctors combined inavolisib with two other drugs, palbociclib and fulvestrant, in patients whose tumours carried the PIK3CA mutation which impacts the growth and spread of cancer cells and which is present in 40 per cent of cases. The result? Tumour shrinkage in 63 per cent of patients and progression delayed from seven months to 17 months.
BRCA and beyond
Olaparib, a PARP inhibitor first developed for BRCA-mutated breast cancers, has been another major leap. The drug works by suppressing an enzyme called PARP which plays a crucial role in DNA repair. The drug exploits weaknesses in cancer cells’ DNA repair mechanisms, leading to their death. It was first used in ovarian cancers with the same mutation. “The beauty of targeting gene mutations,” says Dr Vincent, “is that drugs can work across different cancer types which have the same mutation.”
Immunotherapy for triple-negative breast cancer
Triple-negative breast cancers – so named because they lack HER2 and hormone receptors – were once the most aggressive and hard to treat form. But immunotherapy is offering new hope. Drugs called checkpoint inhibitors prevent cancer cells dialling down our immune response. This means our own immune killer cells can more easily recognise and attack malignant cells. One checkpoint inhibitor, pembrolizumab, is showing positive results in triple-negative breast cancer, especially when used alongside chemotherapy or surgery. Several trials are underway to determine the best timing and combination strategies.
Bladder cancer
Each year, around 5,600 people in the UK die of bladder cancer. Stage four disease – where the cancer has spread to lymph nodes, bones, lungs or liver – was once a hopeless diagnosis. Now, some patients are experiencing years of remission.
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Immunotherapy breakthroughs
Checkpoint inhibitors are producing lasting remissions in about 20 per cent of metastatic bladder cancer patients. This is a big improvement forward from the near-universal fatalism of a decade ago.
A standing-ovation drug
In trials, the drug enfortumab vedotin (EV), when paired with pembrolizumab, doubled survival in people with advanced bladder cancer compared to the previous gold-standard treatment, chemotherapy. EV targets Nectin-4, a protein found in most bladder cancers. The findings were so dramatic, they received a rare standing ovation at the 2023 European Society for Medical Oncology congress. “It’s a whole new concept,” says Dr Wilkins. “We are seeing people whose cancer has not progressed for three years. I have never wanted to see a drug approved so much in my life.” Nice is due to decide imminently on its NHS use.
Lung cancer
Still the UK’s top cancer killer, lung cancer is also being reshaped by precision medicine.
From ‘undruggable’ to druggable
KRAS mutations that can lead to uncontrollable cell growth in cancer were once considered untreatable. Now, targeted inhibitors are showing success in stabilising the disease in patients with this common gene fault. “Progress comes in small steps,” says Dr Wilkins. “But for someone with the right mutation, the right drug can really improve their outlook.”
Preventing spread with vaccines
Cancer Research UK is funding a preventative vaccine called LungVax for those at high risk. It’s also being trialled in patients previously treated for lung cancer, to catch recurrence before it starts by priming the immune system to recognise and destroy cancer cells early.
An uplifting prognosis
None of these treatments offers a guaranteed cure, and many patients still need lifelong therapy. Side effects can be gruelling. But survival rates are rising, and treatment options are expanding dramatically. Drugs and techniques that once seemed like science fiction are becoming routine.
“We are in a golden age of cancer research,” says Dr Nisharnthi Duggan, a science engagement manager at Cancer Research UK. “We understand cancer’s secrets and weaknesses much better than we ever did before. Beating cancer won’t come from one silver bullet, but combinations of all these different treatments. There’s a lot of hope.”
