We may have turned the corner. We’re not there yet, but wow, are we hopeful! At the Prostate Cancer Foundation, our goal has always been to put ourselves out of business by curing this terrible disease. Not just by catching it early, or by curing cancer that’s confined to the prostate or cancer that’s spread just beyond it, but by tackling the most devastating prostate cancer there is – cancer that has metastasized, cancer that has invaded the bones, cancer that got better for a while on hormonal therapy but came back with a vengeance when the hormonal therapy stopped working. Cancer that breaks hearts and destroys lives. Our goal is to go after that very worst kind of cancer, and conquer the heck out of it.
It’s been happening in other cancers: Tumors that should have killed people with lung cancer, melanoma, kidney or bladder cancer have melted away instead, thanks to new drugs called checkpoint inhibitors. It’s a new kind of immunotherapy that takes the blinders off of the body’s great warriors, T cells, and allows them to recognize the cancer that’s been growing – invisibility-cloaked in plain sight – from the immune system soldiers that have the power to defeat it.
Immunotherapy has not previously lived up to expectations in prostate cancer, for reasons that scientists still don’t fully understand. But there are points of light, and an especially bright one just appeared in a study by scientists in Oregon and at Johns Hopkins, published in the online journal, Oncotarget. The results with this particular type of checkpoint inhibitor, called a PD-1 inhibitor, were so dramatic, and so unexpected, that the investigators decided to publish the early results.
Oncologist Julie Graff, M.D., at the Knight Cancer Institute of Oregon Health & Science University, explains: “PD-1 inhibitors on their own have not seemed to have much of an effect on prostate cancer.” But Graff and colleagues saw two exceptions to the rule, two men with “castrate-resistant prostate cancer” (their hormonal therapy stopped working) who responded exceptionally well to immunotherapy: their PSA went away, and their cancer appeared to be undetectable. “We wondered whether enzalutamide, which targets the androgen receptor, might stimulate the immune system to make the PD-1 inhibitor work better.”
The team designed a study of 28 men who are taking enzalutamide but whose cancer is still progressing. The men continue to take enzalutamide as they receive four doses of a PD-1 inhibitor called pembrolizumab. The first 10 patients were enrolled from March 2015 to January 2016. Their ages ranged from 61 to 80, and their PSA ranged from a little over 4 ng/ml to nearly 2,503.
Here’s what happened to them: in three men, the disease did not change; it did not get noticeably better, but it didn’t get noticeably worse, either. Four men did not have any evidence of a benefit, and one of these men died of his cancer. So that’s seven men; what about the other three? Their response blew the investigators away: Their PSA – including the man with the PSA of nearly 2,503 – dropped to the undetectable range of less than 0.1 ng/ml. Two of these men had been on narcotics for pain, and stopped taking them. One man’s liver metastases went away. “These three men had a complete response,” says Graff. “Their tumors shrank radiographically” – meaning that they couldn’t be seen in imaging – “in the lab” – their PSA falling to nearly nothing – “and clinically,” with the need for pain medication going away. “None has had a recurrence.”
The men are still on enzalutamide; the investigators don’t know whether it’s safe to stop it. “The first patient is 62 weeks out” of the last dose of pembrolizumab,” says Graff. “He’s had this very robust response for more than a year. Maybe he’s cured, I don’t know. We still have a lot of questions: what led to those responses? Can we identify men straight away who should be given this treatment?”
PD-1 inhibitors are not without their own side effects, which can include loss of thyroid function, muscle inflammation, and other treatable complications. In studies of other cancers, some people have not been able to complete the treatment for these reasons – however, some of them had enough of a response that new options were suddenly on the table. For example, in some people, cancer that was inoperable has shrunk enough to become treatable with surgery. For others – as seen in this study – the cancer didn’t get any worse, it just went into a holding pattern.
The 28th patient in this study is currently being treated, and then the team will analyze the results of this next batch of patients. Some points they will be considering for future investigation:
Does timing matter? If enzalutamide and pembrolizumab were started at the same time, would that make a difference?
What will biopsies show? Not all of the men had a tumor that could be biopsied, but Graff hopes to learn more from looking at the “tumor microenvironment” – what’s happening deep within cells that might make them more susceptible to this treatment.
What can be learned from other cancers? Some colon cancer patients who have responded well to pembrolizumab have something called “microsatellite instability.” When their DNA gets damaged, it doesn’t get fixed properly; at fault are “mismatch repair enzymes.” Maybe men with prostate cancer who respond well have this same genetic smoking gun.
Is there anything else that might “prime the pump,” to maximize the PD-1 inhibitor’s effect? In prostate cancer, what happens to the immune system is similar to what happens to Sleeping Beauty’s kingdom: it takes a long nap. Oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation, describes it this way: “The T cells that should be fighting the cancer are mostly in a state of dormancy. They’re stuporous, because prostate cancers have something on their surface that puts them to sleep. They’re not dead, just sleepy.” Here, the cancer is subverting a normal and essential process that happens to every pregnant woman, so that she doesn’t make an immune reaction to her child. “It turns out that enzalutamide may actually improve the ability of T cells to work, so when the sleeping pill gets turned off by the PD-1 inhibitor, the body can attack the cancer.”
Are there other immune checkpoints that could be targeted, besides PD-1? “This work will give us real clues for targets that we can pick out with precision immunotherapy,” says Simons, “so we know which patients will respond, and which genes can be activated.”
Terms to know from this article:
Treatment that adds, blocks, or removes hormones. For certain conditions (such as diabetes or menopause), hormones are given to adjust low hormone levels. To slow or stop the growth of certain cancers (such as prostate and breast cancer), synthetic hormones or other drugs may be given to block the body's natural hormones. Sometimes surgery is needed to remove the gland that makes hormones. Also called hormone therapy, hormone treatment, or endocrine therapy.
Immunotherapy is a type of treatment that boosts or restores the immune system to fight cancer, infections and other diseases. There a several different agents used for immunotherapy; Provenge is one example.
A doctor who specializes in treating cancer. Some oncologists specialize in a particular type of cancer treatment. For example, a radiation oncologist specializes in treating cancer with radiation.
A type of hormone that promotes the development and maintenance of male sex characteristics.
prostate-specific antigen (PSA): A substance produced by the prostate that may be found in an increased amount in the blood of men who have prostate cancer, benign prostatic hyperplasia, or infection or inflammation of the prostate.
A mass of excess tissue that results from abnormal cell division. Tumors perform no useful body function. They may be benign (not cancerous) or malignant (cancerous).