New drug treatments are helping patients with advanced prostate cancer to live longer.
The course of Jim Kiefert’s life took an unexpected turn 26 years ago during a routine physical examination. Along with the usual blood work, his doctor offered to perform a test that was new back then, the prostate-specific antigen (PSA) test, which measures the PSA level in the blood and can, if the level is high, indicate the presence of prostate cancer.
His test revealed a serum PSA concentration of 39 nanograms per milliliter (ng/mL); most healthy men have a PSA level below 4.
“Not only did they find out that I had prostate cancer, but it had also spread to the seminal vesicles,” Kiefert says. “So I began to do research on what to do from that point.”
Jim Kiefert had a PSA test when the screening measure was brand-new, and it led to his diagnosis with prostate cancer. [Photo by Shauna Bittle]
Kiefert, of Olympia, Wash., had surgery to remove his prostate gland and underwent 35 sessions of external beam radiation therapy. But his PSA level was still high. “At that point, the doctor called me and my wife into his office and told us that the major treatments for prostate cancer had failed, and it had spread,” Kiefert recalls. “He said that I probably had one to three years left to live, and I should go home and get my life in order.”
Kiefert decided to not follow his doctor’s advice. “Instead,” he says, “I started my journey of becoming an informed and empowered patient.”
More than two decades later, Kiefert, who will turn 77 in September, still has not gotten his affairs in order. Instead, the retired school superintendent has defied his initial diagnosis. In addition to using standard medical therapies and entering clinical trials, he has made changes to his lifestyle and diet.Less than 10 years ago, the cupboard was relatively bare when it came to treating advanced prostate cancer. But new drug strategies have been developed, including immunotherapy, hormone therapy and chemotherapy. Biologically targeted agents are in development. Although these agents are generally not curative, studies have shown they can slow disease progression, improve quality of life and extend overall survival.
“For a man with advanced prostate cancer who has been through a gamut of therapies, the moment when he sees a rise in his PSA can be one of the scariest times in his life,” says Edwin Posadas, medical director of the urologic oncology program at Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute in Los Angeles. “There was a time when we didn’t have anything with known efficacy to offer. It wasn’t until 2004 that oncologists had the first FDA-approved drug that impacted survival after progression through initial hormone therapy.”
Since 2010, the U.S. Food and Drug Administration (FDA) has approved six new agents for prostate cancer. Five of these approvals were based on an improvement in survival.Male hormones, known as androgens, which include testosterone, play a pivotal role in the development, growth and pathology of prostate cancer. As most cases of prostate cancer are fueled by androgens, hormone therapy, also known as androgen deprivation therapy, has long been a component of treatment. Simply put, the goal of hormone therapy is to lower the levels of androgens, which in turn can shrink the cancer and put the brakes on its growth.
Hormone therapy is generally used if surgery and radiation are not options or if the cancer remains or returns following those treatments. In addition, hormone therapy combined with radiation is used as a first-line therapy for men who have a high risk of their cancer recurring or if it has metastasized. Sometimes hormone therapy is used before radiation to shrink the tumor, potentially making the treatment more effective.
The collection of drugs in this class is expanding, and now patients have several options.
Luteinizing hormone—releasing hormone (LHRH) agonists, or analogs, block release of LHRH, a key hormone released by the pituitary gland that stimulates the testicles to produce testosterone. These agents, which are injected or placed as small implants under the skin, include Lupron (leuprolide), Zoladex (goserelin), Vantas (histrelin) and Trelstar (triptorelin).
LHRH antagonists are a newer class of drugs that can reduce testosterone levels more quickly without causing a “flare,” an initial short-term rise in testosterone, as the agonists do. Firmagon (degarelix), the only approved therapy in this class, is administered monthly by injection.
Anti-androgens, such as Eulexin or Drogenil (flutamide), Casodex (bicalutamide) and Nilandron (nilutamide), can block the action of androgens made by the testicles and/or adrenal glands. When paired with an LHRH agonist, these daily pills can help prevent testosterone flare.
Ketoconazole, an anti-fungal, also blocks the production of androgen (and the steroid cortisol) in men with prostate cancer, and is sometimes administered to those who haven’t responded well to other hormonal therapies — although it’s not approved by the FDA for that indication, or for the treatment of any cancer, for that matter.
Newer therapies that work by a different mechanism have recently become available, and they could prove to be more effective than older drugs. Zytiga (abiraterone) inhibits enzymes produced by the adrenal glands — selectively those enzymes that are responsible for making androgens. Zytiga received FDA approval in 2012 to be used for metastatic disease that has become resistant to other treatments. This is known as castration-resistant prostate cancer (CRPC).
“One of the most significant developments has been the recognition that, even in castration-resistant prostate cancer, testosterone is still driving growth,” says Bruce Roth, an oncologist at the Washington University School of Medicine in St. Louis, Mo. “We now know that testosterone is coming from a number of sources, one being the adrenal gland, and recognize that prostate cancer can make its own testosterone.”
Another drug, Xtandi (enzalutamide), is a newer type of anti-androgen that works by a different mechanism than others in its class. It blocks androgen receptor signaling and has been shown to have a significant effect on median overall survival in men with CRPC whose disease has progressed after chemotherapy. In 2014, the FDA approved expanded use of this oral medication when a study showed that it also delayed tumor progression and prolonged lives in men who used the drug before receiving chemotherapy.
On the horizon, new therapies are undergoing clinical trials. Among these are galeterone (TOK-001) and ARN-509, which interfere with the androgen signaling pathway. Early results are promising. The clinical trial for another drug, orteronel (TAK-700), was stopped early because although this drug, along with prednisone, extended the period before cancer progression, it did not improve overall survival.
But some researchers still see the potential of TAK-700, and are testing it in a different combination. SWOG, formerly the Southwest Oncology Group, is conducting a large, phase 3 study comparing an LHRH agonist and an anti-androgen medication (bicalutamide) with an LHRH agonist and TAK-700. This study is still in its early stages.
Even though prostate cancer tumors generally respond to hormone therapy, resistance to these agents typically develops, occurring over a wide range of time among individual patients. Hormone therapy also carries some unwanted side effects, which can include hot flashes, loss of bone density, weight gain, erectile dysfunction and fatigue. One potential method of minimizing these side effects is a strategy known as intermittent therapy, which stops and restarts treatment depending on the levels of PSA in the blood.
Several studies have shown that intermittent therapy might give patients some relief from side effects but is not as effective in controlling cancer and may be more suitable for those without metastases. As a result, continuous therapy remains the standard of care for those with metastatic disease. Intermittent therapy needs to be adjusted to the individual patient.
Kiefert eventually chose intermittent therapy following his initial treatment. He also made significant changes in his lifestyle: He modified his diet and no longer eats red meat or dairy. Instead, he opts for fresh fruits and vegetables. Kiefert also exercises regularly, biking, gardening and playing in the lake at his home with his grandkids and great-grandkids.
Realizing that his emotional outlook and stress levels also contribute to his health, Kiefert learned mind-body techniques to keep negative thoughts at bay. He left his job and went to one that “he looked forward to going to each morning,” a move that helped make his life less stressful.
Kiefert stayed off of therapy for about seven years, and when his PSA level began to rise, he looked into hormone therapies. “There wasn’t a protocol for intermittent therapy at that time,” Kiefert says. “But that was the way I wanted to do it. I monitored my own testosterone.”
It wasn’t until his PSA level began to rise a little too much that he decided to resume therapy. “The best advice I received as to when to start therapy again was when I reached the panic point,” Kiefert says. “When that happened, I did what I had to do.”Amid all of the buzz about personalized medicine and genomic therapy, chemotherapy is often considered “old school.” But prostate cancer treatment is one area where the old methods are finding new success.
The chemotherapy drug docetaxel (known as Taxotere, but also available as a generic) has become a treatment for patients with CRPC, but recently researchers questioned whether it improved survival if it was given earlier, during hormone therapy and before the cancer became resistant. The CHAARTED trial showed that using docetaxel early, along with hormonal therapy, resulted in better overall survival, especially in patients who had more extensive metastases. These findings were supported by the STAMPEDE study, sponsored by Cancer Research UK and presented at the 2015 American Society of Clinical Oncology annual meeting, which found that combining docetaxel early in treatment with standard hormone therapy improved survival by 10 months, specifically in men with newly diagnosed advanced prostate cancer that had not previously been treated with hormone therapy.
If docetaxel proves ineffective for patients with CRPC or stops working, a second chemotherapy agent, Jevtana (cabazitaxel), is another option. Jevtana was approved in 2010 for the treatment of patients with CRPC in combination with prednisone, but only after patients had been previously treated with docetaxel.
“Chemotherapy is not going away in prostate cancer,” Posadas says. “It is a viable and important strategy, and we are going to keep coming back to it because it helps patients.” Despite the concerns about chemotherapy toxicity, treatment with drugs such as docetaxel has been shown to improve quality of life as well as survival for symptomatic patients.Immunotherapy boosts the ability of the body’s immune system to identify and target cancer cells.
Several approaches to immunotherapy for prostate cancer have shown promise in clinical trials in recent years, with the most notable being Provenge (sipuleucel-T). Indicated for the treatment of metastatic CRPC, it is the first therapeutic vaccine approved for any type of cancer.
Each dose is manufactured specifically for the individual patient using his own immune cells. The process involves the removal of a certain type of white blood cell, called a dendritic cell, from the patient. These cells are then exposed to an antigen specific to prostate cancer cells, along with a stimulatory molecule to activate their immunity. The final step is injecting the white blood cells, now “programmed” to attack the prostate cancer, into the patient.
The pivotal study that led to FDA approval found that Provenge increased median survival by about four months in men who had advanced disease. But not everyone is a candidate for this treatment. Those most likely to benefit from this therapy are relatively free from symptoms and have not had extensive treatment for advanced disease.
Roth points out that even though the study showed a survival benefit, it didn’t really show “objective” responses, such as a delay in tumor progression.
“I think some healthy skepticism about what patients get in terms of their treatment is reasonable,” Roth says. “And now there are other drugs like Zytiga and Xtandi that provide survival benefits that weren’t available when Provenge was approved. They also have objective responses and are in pill forms and easier for the patients. So it is something to consider when patients are choosing their different options.”
After a prostate cancer diagnosis, Jim Kiefert decided to research potential treatment strategies and drive decisions about his medical care. [Photo by Shauna Bittle]
According to Mark Stein, a medical oncologist at Rutgers Cancer Institute of New Jersey, additional research looking at Provenge combined with other therapies is indicated. Currently, two such studies are under way.
Other immunotherapy agents are nearing clinical application. Pending are results from a large, multicenter phase 3 trial to determine whether Prostvac, a series of vaccines that uses pox viruses to stimulate the immune system, contributes to overall survival in men with advanced prostate cancer. The trial is designed to investigate whether the vaccine alone or in combination with a growth factor can be effective in prolonging overall survival in men with few or no symptoms from CRPC. The treatment is administered by injection under the skin and does not involve blood collections.
A third vaccine showing promise is based on a Listeria bacterium platform. It combines the Listeria monocytogenes immunotherapy agent ADXS-PSA, which has been modified to target a prostate-specific antigen, with the checkpoint inhibitor Keytruda (pembrolizumab), which works by “releasing the brakes” on the immune system. Stein noted that Listeria-based vaccines seem to be very immunogenic, safe and able to overcome some of the mechanisms that tumors use to hide from the immune system.Unlike standard chemotherapy, targeted agents act by blocking essential biochemical pathways or proteins that are required for tumor cell growth and survival. Therefore, the development of targeted therapies requires the identification of good targets — those that are known to play a part in the growth and survival of cancer cells.
One targeted agent, custirsen (OGX-011), in combination with docetaxel and prednisone, did not extend survival, a finding that was unexpected. Previous evidence had shown that custirsen targets a protein, clusterin, which is produced in elevated levels in advanced cancers, including prostate cancer, and protects cancer cells from programmed cell death (known as apoptosis).
In a different clinical trial, custirsen is being tested in combination with Jevtana as a second-line treatment for men with CRPC. This phase 3 trial is ongoing.Some of the newer drugs are being tested in combination with established therapies. “We do see combinations of nonmedical therapies, and we’ve gone beyond the one-trick pony,” Posadas says. “The idea of being able to combine in a systemic fashion is intriguing — such as androgen deprivation and immunotherapy.”
However, Roth cautions that, with so many new drugs available, there is little existing data about the sequencing of these agents, although trials are currently under way to answer this question. “The standard approach,” says Roth, “is to use these single agents sequentially. The use of combinations of these agents should be restricted to clinical trials.”
As for personalized medicine, the goal of being able to tailor therapy to the individual is one that has not yet been fully realized. “We are not there yet for prostate cancer,” says Roberto Pili, director of genitourinary oncology at the Indiana University Melvin and Bren Simon Cancer Center. “There is research left to do. However, we have made significant advances in genetics and we are getting closer to sequencing a tumor. For example, we are learning about the type of alteration in the androgen receptor, and then telling the patient with prostate cancer which treatment will likely either work or not.”
Kiefert has proven that long-term survival is possible, using what is currently available. He participated in clinical trials for both Provenge and Xtandi, and since Xtandi’s FDA approval in 2014, he is now taking this medication. His PSA level has gone up a bit, but is holding at 8.
“I’m doing great now,” he says. “I have stayed on top of prostate cancer. Information is power, and patients need the information so that they can make the right decisions. Of course they want to listen to their physicians, but they have to realize that they are in the driver’s seat for their care.”