Forward March: Push Continues for Immunotherapy in Prostate Cancer

The immunotherapy Keytruda (pembrolizumab), through a clinical trial, “gave me my life back.” — GARY TANKERSLEY, patient

The immunotherapy Keytruda (pembrolizumab), through a clinical trial, “gave me my life back.” — GARY TANKERSLEY, patient

Could the same drug that revolutionized melanoma and lung cancer treatment be used to help men with a deadly form of prostate cancer?

“That’s the hope,” says Julie Graff, M.D., prostate cancer oncologist and researcher with the OHSU Knight Cancer Institute and Portland VA Medical Center. She’s heading up a phase 2 clinical trial of a drug called Keytruda (pembrolizumab) in men with metastatic prostate cancer whose disease had progressed on hormone therapy. Keytruda is a form of immunotherapy known as a checkpoint inhibitor; it blocks a protein called PD-1, thus freeing up the immune system to attack the cancer.

Results to date from the trial of Keytruda plus the hormonal therapy Xtandi (enzalutamide), which is still ongoing, are “remarkable,” says Graff. Within months of treatment with Keytruda, prostate-specific antigen (PSA) levels in the blood, an early measure of treatment effect, plummeted in three out of 10 men enrolled in the trial (from 46, 71 and 2,503 ng/mL, respectively, to less than 0.1 ng/mL in all three cases); drugs currently available to treat metastatic, castration-resistant prostate cancer rarely result in PSA levels lower than 0.2 ng/mL after Xtandi or Zytiga (abiraterone) have stopped working. The three patients who responded to Keytruda had no disease progression for 30, 55 and 16 weeks, respectively, and two of the three gained such relief from cancer pain that they were able to stop taking opiate pain medication.

“It gave me my life back,” said 67-year-old Gary Tankersley, from North Plains, Oregon, who is part of the trial.

Tankersley was diagnosed with prostate cancer in 2004. Over the years, he says he “tried everything, but nothing worked.” By the time he entered the trial, his PSA level had “skyrocketed,” he says, and he was homebound with cancer-related bone pain. “I got up, sat in a chair and looked out the window, then went to bed, then did it again the next day. And that was a good day,” he says.

Less than two months after starting on Keytruda, Tankersley’s PSA had “plummeted,” he says, and his pain is now manageable with Tylenol. He now walks several miles a day, tends to his farm in the foothills northwest of Portland, Oregon, and recently spent a week hustling through Disneyland with his wife and 7-year-old daughter and “loving every minute of it.”

Why did the treatment work so well for some patients? Men on the study took Xtandi along with Keytruda, and investigators are hypothesizing that treatment with this potent suppressor of androgen may enhance response to immunotherapy in some men. The researchers also found genomic characteristics in responders that can be studied to determine if they may help predict which future patients with prostate cancer will fare well on immunotherapy. These characteristics included microsatellite instability (a problem that interferes with DNA’s ability to repair itself) and the expression of PD-L1, a protein related to PD-1 that helps to hold the activity of the immune system in check.

Though Tankersley’s exceptional response is rare, it is illustrative of the progress being made in a disease that is expected to be diagnosed in 180,890 men this year alone, and in one of every seven men during his lifetime. Since 2010, half a dozen new treatments for prostate cancer have been approved by the U.S. Food and Drug Administration. Treatment innovations, in combination with earlier detection of the disease, have boosted the 10-year survival rate of prostate cancer to 98 percent, according to the American Cancer Society.

New agents are not emerging in just the immunotherapy realm. In the area of hormonal therapy, a staple of prostate cancer care, new drugs including apalutamide and ODM-201 are being explored. Further, anti-angiogenesis drugs, which kill the blood vessels that feed a tumor, are being explored by scientists as a potential new form of treatment for the disease.

Novel ideas about the application of older therapies are being investigated, too. Among them is the addition of chemotherapy to radiation and hormonal therapy in newly diagnosed advanced cases of prostate cancer — something that looks promising, but isn’t yet employed routinely.

“Many treatments exist for men with prostate cancer, and we are supporting several others in clinical trials that appear to be beneficial, whether you’ve just been diagnosed with early-stage prostate cancer, your cancer has returned after treatment or you have more advanced disease,” said Jonathan Simons, M.D., president and CEO of the Prostate Cancer Foundation.

ACTIVE SURVEILLANCE

Several options are detailed below.In the not-so-distant past, the use of active surveillance — an approach that involves closely monitoring a patient’s cancer over time and foregoing immediate treatment — was largely resisted by prostate cancer doctors. Today it is the standard of care for most patients with low-risk tumors, which grow slowly and rarely pose a health threat.

“The goal is to spare patients from treatment that they don’t need and that can cause lasting quality-of-life effects,” said Matthew Cooperberg, M.D., M.P.H., who specializes in treating patients with urologic cancers at the University of California, San Francisco.

Patients undergoing active surveillance should be regularly monitored with PSA testing every three to six months, digital rectal examinations at least every year, and prostate biopsies. Treatment, such as surgery or radiation, is given if the cancer begins to grow, with the goal, Cooperberg says, “to cure the cancer.”

Not everyone is a candidate for active surveillance, though, and determining who is and who is not is not always clear-cut. “Men who appear to have low-risk disease, for example, but have imaging findings that show otherwise might be encouraged to begin treatment right away,” Cooperberg says.

SURGERY

Cooperberg hopes that, one day in the near future, new tools will not only allow doctors to better identify prostate cancer patients for whom active surveillance is the best way to manage low-risk disease, but also to tailor the level of surveillance according to an individual patient’s cancer. “Active surveillance is not a one-size-fits-all solution,” he says. “Nothing is, when it comes to cancer.”The goal of surgery in men with prostate cancer is to try to eliminate a tumor before it spreads outside the prostate. During surgery, all or some of the prostate is removed, as well as a margin of healthy tissue that surrounds it. Two surgical approaches are commonly used:

Radical prostatectomy, sometimes called an open prostatectomy, is a complex surgical procedure in which the surgeon makes a large incision in the lower abdomen and then removes the prostate. The seminal vesicles (the small glands that help produce semen), and a short segment of the urethra, which passes through the prostate, are also removed. The surgeon either uses the tools directly or uses a computer to precisely move robotic arms that hold the tools.

A laparoscopic prostatectomy is a less invasive surgery in which the surgeon makes several smaller incisions and uses long surgical tools to remove the prostate and surrounding tissues. As with radical prostatectomy, doctors may or may not perform robot-assisted surgery.

RADIATION THERAPY

Although a laparoscopic prostatectomy usually causes less bleeding and pain, the sexual and urinary side effects are similar to those associated with a radical prostatectomy. Both procedures may cause temporary or permanent impotence (the inability to get an erection) and urinary incontinence (the inability to control the flow of urine.) Sometimes a nerve-sparing technique, which spares the erectile nerves that run alongside the prostate, can be used to increase the chance of maintaining sexual function. Even if the nerves cannot be spared, it is sometimes possible to surgically attach, or graft, nerves from other parts of the body to the ends of the cut erectile nerves. However, surgeons won’t know until the time of the procedure if nerve sparing is possible.Radiation therapy often is used as the exclusive treatment for prostate cancer that is contained within the prostate or the tissues surrounding it, but the technique also can be used as part of a larger treatment regimen for more advanced prostate cancers. It involves the use of high-energy beams or radioactive seeds to eliminate tumors. The most common types are:

IMRT, or image-guided radiation therapy, is a kind of external radiation that projects radiation from a machine outside of the body. It tailors the radiation dose to the precise shape of the tumor to avoid or reduce exposure of healthy tissue and limit the side effects of treatment.

Brachytherapy, or internal radiation, involves placing tiny radioactive seeds inside of the prostate. It allows doctors to deliver higher doses of radiation to more specific areas of the body.

Proton therapy is a new kind of external radiation that targets even the most difficult to treat and reach tumors and is designed to allow higher doses of radiation to be delivered to the prostate with fewer side effects.

HORMONE THERAPY

The type of radiation therapy used varies based on the disease. Patients with early-stage disease often have a choice between surgery and radiation, with similar anticipated outcomes. For larger or more aggressive tumors, radiation therapy may be used in combination with hormone therapy. Radiation also may be used to treat prostate cancer tumors that are not completely removed or that come back after surgery.Hormone therapy, also called androgen deprivation therapy, blocks testosterone production or blocks testosterone from interacting with the tumor cells. The majority of prostate cancers are hormone-sensitive, which means that male hormones (androgens), such as testosterone, fuel the growth of the cancer. These medications reduce the tumor size or make it grow more slowly. Hormone therapy may be given in different ways:

CHEMOTHERAPY

Hormone therapy alone: Hormone therapy is sometimes used alone in men with advanced, high-grade tumors or in patients with cancer that already has spread beyond the prostate to other parts of the body. It is also the standard treatment for men whose cancer has come back after being treated with radiation therapy or surgery.Adjuvant and neoadjuvant hormone therapy: Hormone therapy that is given after surgery or radiation to eliminate any remaining cancer or reduce the chance that cancer will return is called adjuvant hormone therapy. Men with early-stage prostate cancer who have an intermediate or high risk of recurrence often receive adjuvant hormone therapy after radiation therapy or surgery. Sometimes these men also have hormone therapy before surgery or radiation; this is called neoadjuvant hormone therapy. Studies have shown that men who have adjuvant hormone therapy after prostatectomy live longer without having a recurrence than men who have surgery alone, but they do not live longer overall. Men who have adjuvant hormone therapy after radiation therapy live longer overall and without having a recurrence than men treated with radiation therapy alone.Chemotherapy is the use of drugs to destroy cancer cells. Several kinds of chemotherapy are used to treat prostate cancer, and others are in various phases of clinical trials.

“Both surgery and radiation really only treat the pelvis and the prostate itself. When you add on hormone therapy or chemotherapy, then you begin to get the cells that might have escaped and caused the disease to spread,” says Graff.

Until recently, chemotherapy was used only to relieve symptoms associated with advanced or metastatic disease. Today, it is used to prolong the lives of men with prostate cancer that no longer responds to hormone therapy. The standard chemotherapy for prostate cancer is Taxotere (docetaxel) combined with a steroid called prednisone. If Taxotere does not work (or stops working), Jevtana (cabazitaxel) is often the next chemotherapy used.

Chemotherapy may also benefit some patients when given in addition to standard therapies. One 2015 clinical trial, for example, showed that Taxotere improved survival when given alongside standard hormone therapy in patients with newly diagnosed advanced prostate cancer not previously treated with hormone therapy; men who received the addition of Taxotere plus standard therapy lived on average 10 months longer than those who did not. In another clinical trial, the addition to Taxotere was shown to improve four-year survival when given alongside hormone therapy and radiation to patients with high-risk localized prostate cancer; in the study, also reported in 2015, the four-year survival rate was 93 percent for men treated with the standard treatment of hormone therapy and radiation plus Taxotere compared to 89 percent when treated with the standard treatment alone.

RADIOPHARMACEUTICALS

Graff stresses that more evidence is needed before recommending the addition of Taxotere to standard therapies. “It does indeed delay the time to the cancer returning and keep the cancer from returning, but we don’t know yet if it saves lives in the long run,” she says. In the meantime, it’s up to the patient and provider to decide. “It’s not really a clear decision right now.”Xofigo (radium-223) is a first-in-class alpha-emitting radiopharmaceutical that was approved in 2013 to treat metastatic castration-resistant prostate cancer with bone metastases, on the grounds that it improved overall survival and progression-free survival in a clinical trial.

IMMUNOTHERAPIES

Now, trials are investigating the success of the drug when used in combination with hormonal therapies such as Zytiga or Xtandi.These treatments empower the immune system, the body’s natural defense system, to fight cancer. Several immune-based therapies are being used to help men who have prostate cancer, including those with advanced or recurrent disease.

Vaccines: Unlike preventive vaccines, which protect people from developing particular diseases, an FDAapproved vaccine called Provenge (sipuleucel-T) is given to people who have already developed prostate cancer. Provenge is for men with advanced, metastatic prostate cancer that does not get better with hormone therapy and with minimal or no symptoms. It’s made from a man’s own immune cells, mixed with a protein that helps the medication specifically reach prostate cancer cells. Other vaccines are being studied in clinical trials.

Checkpoint inhibitors, approved in several cancers but not yet in prostate cancer, prevent cancer cells from turning off some types of immune cells, called T cells. This allows T cells to infiltrate a tumor and kill cancer cells. Keytruda, the drug that Tankersley is receiving, is an example of this type of checkpoint inhibitor. It targets the immune checkpoint protein PD-1, which is on the surface of some immune system cells. Another checkpoint inhibitor called Yervoy (ipilimumab) targets the immune checkpoint protein CTLA-4 on certain immune cells. Yervoy is already used to treat melanoma, and is now being tested in men with advanced prostate cancer.