They are among the most challenging prostate cancer patients to treat: about 150,000 men worldwide each year whose cancer is aggressive enough to defy standard hormonal therapy, but has not yet spread to the point where it can be seen on scans.
These patients enter a tense limbo which often ends too quickly with the cancer metastasizing to their bones, lymph nodes or other organs — sometimes causing intense pain.
Now, for the first time, researchers have results from two independent clinical trials showing that two different drugs help these patients — giving them about two more years before their cancer metastasizes. That means two additional years before pain and other symptoms spread and they need chemotherapy or other treatments.
“We’re going from rags to riches,” said Dr. Judd Moul, a professor of surgery and director of the Duke Prostate Center, who was not involved in either study. “Up until now, we haven’t had anything for these guys. We just had to tell them ‘We’ll keep an eye on it.’”
The studies, each involving more than 1,200 patients in countries around the world, were presented Thursday at the Genitourinary Cancers Symposium in San Francisco. They used very similar drugs — both androgen receptor inhibitors, which block testosterone from binding to prostate cancer cells and entering them.
The study of an experimental drug called apalutamide was published Thursday in the New England Journal of Medicine. The other study of a drug called enzalutamide, currently approved for treating prostate cancer that has already metastasized, has not yet been peer-reviewed for publication, the authors said.
Prostate cancer is the second most common cancer in men worldwide. The American Cancer Society estimates that in 2018, there will be about 164,690 new cases and about 29,430 deaths. Worldwide, there were 1.1 million new cases and about 307,000 deaths in 2012, according to the most recent data available from the World Health Organization.
The patients in both studies were men who had previously received some treatment for prostate cancer, such as surgery or radiation, but who later began to show rapid increases in their prostate-specific antigen or PSA, a protein associated with prostate cancer. They did not respond to the standard treatment to suppress testosterone, called androgen deprivation therapy.
Each year, about 30,000 to 50,000 American men and about 150,000 worldwide, fall into this category, called nonmetastatic castration-resistant prostate cancer. (The medical term for blocking male hormones is chemical castration.) Globally, about 200,000 of the four million men with prostate cancer are estimated to have this diagnosis, said Dr. Matthew Smith, director of the Genitourinary Malignancies Program at Massachusetts General Hospital’s Cancer Center, who co-led the apalutamide study with Dr. Eric Small, deputy director of the Helen Diller Family Comprehensive Cancer Center at University of California, San Francisco.
In the studies, two-thirds of the men took one of the androgen receptor inhibitors, while a third took a placebo. They all continued to receive androgen deprivation therapy.
In the study of men receiving apalutamide, it took, on average, 40.5 months for cancer to spread to the point where it could be detected by conventional scans. For men receiving the placebo, the cancer spread in 16.2 months, on average. In the enzalutamide study, metastasis took 36.6 months on average in men receiving that drug compared to 14.7 months with placebo.
“Delaying median time to metastases by over two years is a big deal,” said Dr. Scott Eggener, a urologic oncologist and professor of surgery at University of Chicago, who was not involved in the studies. He said the studies were also important scientifically because they show that “maximally decreasing testosterone production and its ability to bind or enter cancer cells leads to meaningful clinical improvement for these men.”
Still, he said, while the studies both show preliminary indications that the drugs might extend patients’ survival, researchers will have to follow the patients longer to know.
Both studies were funded by the companies that make the drugs. Janssen Pharmaceutical Companies of Johnson & Johnson, the maker of apalutamide, has applied for approval from the Food and Drug Administration, which has put it under priority review, Dr. Smith said.
The developers of enzalutamide, Pfizer and Astellas Pharma, have applied to the F.D.A. for approval to expand the use of the drug, marketed as Xtandi, to patients in this category, said Dr. Maha Hussain, deputy director of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University’s Feinberg School of Medicine. She co-led that study with Dr. Cora Sternberg, chief of medical oncology at San Camillo and Forlanini Hospitals in Rome.
Both drugs appear to be safe with relatively few serious side effects, experts said. Negative effects for some patients included fatigue, hypertension, rashes, fractures, falls, nausea, and mild cognitive and memory slippage.
Ron Scolamiero, 72, of Marshfield, Massachusetts, a patient of Dr. Smith’s, began taking apalutamide in 2012 for an earlier phase of the clinical trial. He still takes a four-pill dose daily.
In the drug’s initial formulation, side effects included hot flashes, diarrhea and nausea, but those diminished greatly after it was reformulated, said Mr. Scolamiero, who owns a financial services company. About 18 months ago, a tumor that developed at the site of his prostate had to be removed, but his cancer has not metastasized to other parts of his body.
“It’s controlled my cancer,” he said. “I’m so grateful.”
Still, some experts said enthusiasm about the new drugs should be tempered by other changes occurring in the prostate cancer landscape.
“I don’t want to say this is the best thing since sliced bread — it’s not,” said Dr. Oliver Sartor, medical director of Tulane Cancer Center. “You’re taking a person with no symptoms and potentially giving them side effects, definitely giving them an expensive drug. And it is unclear if this is the optimal management of these patients.”
The current list price of enzalutamide is more than $10,000 a month; a price hasn’t been set for apalutamide, which is not yet on the market
Dr. Sartor and others noted that another androgen receptor inhibitor, abiraterone, which is used to treat cancer once it metastasizes and is also produced by Janssen, is likely to go off-patent soon and will become much cheaper because generic versions will be produced. Since abiraterone operates on the same biological pathway, experts expect that it will be tried for patients with cancer that hasn’t metastasized and could end up working as well.
Increasingly sophisticated imaging techniques are allowing doctors to spot previously undetectable signs of metastasis. While some patients in these trials might have had cancer spread that was not detected by conventional scans, Dr. Smith said what matters is that they were early in the cancer trajectory and the drug helped them stay in that early state longer.
The two new studies did not compare the drugs against each other, only against a placebo. “You can look at that as being a challenge for physicians,” said Dr. Ian Thompson, Jr., president of CHRISTUS Santa Rosa Hospital-Medical Center in San Antonio. “You can also look at that as being an advantage for the patient.”
Besides giving patients options, Dr. Hussain said, having both apalutamide and enzalutamide “opens up the door for more investigation to happen to even prevent this disease stage from happening in the first place.”
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