Better Calculating the Aggressiveness of Prostate Cancer

THIBEAUX LINCECUM, shown playing with his twin sons at home, wishes his original urologist had reacted more aggressively to his prostate cancer symptoms. - PHOTO BY BOB RIVES

THIBEAUX LINCECUM, shown playing with his twin sons at home, wishes his original urologist had reacted more aggressively to his prostate cancer symptoms. - PHOTO BY BOB RIVES

Thibeaux Lincecum wishes he’d fired his urologist more than a decade ago. Lincecum, 46, visited his specialist three years ago, when he noticed a precipitous drop in his semen volume over just a few months. (He’d seen the same doctor a decade before for urinary urgency — another possible symptom of prostate cancer.) He asked for a prostate-specific antigen (PSA) test — a standard blood test that is often used to screen for prostate cancer, but is controversial due to its lack of specificity in detecting the disease — yet the doctor gave in only when he learned there was a family history. He ordered tests from two different labs, and both came back high enough to warrant investigation. He dismissed the results and prescribed antibiotics.

Finally, Lincecum decided his doctor “was an idiot.” His next urologist needed only to do a digital rectal exam to express concern and schedule a biopsy. The results were brutal: a maximum Gleason score of 10, indicating an extremely high level of abnormal cells and growth, and a prostate nearly solid with cancer. The only bright side was no sign — yet — of metastatic disease.

Lincecum was done waiting. When he tried to schedule surgery immediately and was offered a first appointment three weeks out, he began calling around for an earlier time slot. One receptionist noted his biopsy results, consulted a doctor and booked him for early the next morning. Between his age and advanced disease state, Lincecum fit the profile for a clinical trial, so after a radical prostatectomy, he enrolled in what would become the first of many.

His dilemma outlines the fundamental challenge of prostate cancer. It’s often said that men don’t die of prostate cancer, they die with it. This is, in many cases, quite true. But it’s also true that prostate cancer is the second-leading cause of cancer-related death in American men. This is because some men present with aggressive cancer, a higher PSA and higher Gleason scores. They are at greater risk of developing metastases, and their disease is often more resistant to treatment.

“It goes all the way from very low risk to very difficult to treat. There is no disease where risk stratification is more important,” explains urology department head Christopher Kane, M.D., of Moores Cancer Center at the University of California San Diego. “Prostate cancer is one of the most complicated diseases in medicine.”

WHICH DISEASE WILL PROGRESS?

If you look at 70-year-old men dying of other causes, more than half of them have microscopic, low-grade disease that, under today’s classification system, is called prostate cancer. “The death risk of those men, from prostate cancer, is well under 1 percent,” says Kane. He believes that this low-grade, low-volume prostate cancer — the result of normal aging — should probably be called something different.

Oncologists struggle to precisely define low-risk prostate cancer. According to National Comprehensive Cancer Network guidelines, the characteristics of low-risk disease include a Gleason grade of 3+3, a PSA under 10 ng/mL and low-volume disease that the doctor can’t feel. “If you meet that criteria, among the various treatment options, the recommended strategy is active surveillance,” says Kane. “Not a potential option, but now THE recommended strategy.” Active surveillance is not to be confused with watchful waiting for either the development of clear metastatic disease or cancer-related symptoms. Active surveillance is more aggressive, beginning with initial classification of low-risk patients according to a specific criterion, and including systematic monitoring with PSA screening, biopsies, physical exams and possibly imaging — and, when needed, a quick shift to aggressive intervention.

Active is the key word. A proportion of men with apparently indolent disease will, over time, either develop more aggressive disease, or will experience a more aggressive disease that was there at diagnosis, but missed. “Following men over time is really important,” says Kane. If you have very low-risk prostate cancer, and you don’t blow off your follow-up appointments, your 10-year prostate cancerspecific mortality is about half of 1 percent.

The biggest challenge remains figuring out which disease will progress and which will remain indolent. Fairly new genetic tools are available, including three tests to analyze tumors: Decipher, Prolaris and Oncotype DX for Prostate Cancer.

“Those three tests have been shown to do a good job of risk stratifying,” says Kane. “They can really help us decide who has indolent prostate cancer and who should be followed.” There are also some methods of risk stratification that are still being studied. Single-nucleotide polymorphism, or cancer susceptibility gene mutation testing (such as looking for BRCA mutations) would uncover any inherited genetic mistakes associated with more or less promising prognoses. Assessing the androgen gene receptor in a man’s plasma might predict whether he will respond well to the hormonal drugs Zytiga (abiraterone) or Xtandi (enzalutamide). Detecting the presence of AR-V7 (an androgen receptor splice variant) in circulating tumor cells could signal that a man with castration-resistant prostate cancer will have a less-than-robust response to hormonal drugs. Finally, what's living in someone’s microbiome, or gut, may affect treatment outcomes.

Predictions will improve as the understanding of prostate cancer genetics continues to emerge, but for now, only a minority of patients are treated with the help of genomic testing and targeting. The work of breaking down the whole population of prostate cancer into subtypes, and figuring out which ones respond best to which drugs, is just beginning. “The promise of genomic testing is to be more individualized, not just for the patients who have advanced and recurrent disease, but right when a man is initially diagnosed,” Kane says. “We have a lot of work to do.”

MARK STEELE has taken more than a dozen new drugs during his ongoing fight against prostate cancer. - PHOTO BY DAVEY MORGAN

MARK STEELE has taken more than a dozen new drugs during his ongoing fight against prostate cancer. - PHOTO BY DAVEY MORGAN

HORMONAL DRUGS ARE A MAINSTAY

One of our major weapons against prostate cancer is a salvo of drugs used to manipulate androgens, male hormones including testosterone. As part of the male reproductive system, prostate tissue is particularly sensitive to these hormones, and testosterone can help fuel prostate cancer at certain stages of the disease; androgen deprivation therapy (ADT) tries to shut those pathways down. Unfortunately, most men don’t like the way it feels, since low testosterone can lead to lower energy levels, including diminished libido, decline in sexual function and other body changes. Prostate cells have different pathways activated by testosterone, so shutting it down completely is pharmacologically difficult. The cancer makes it even harder, spinning off various mutations affecting androgen action that make the disease resistant to ADT. Prostate cancer that doesn't respond to ADT is called castration-resistant disease. While it seems counterintuitive, sometimes high-dose testosterone can help keep advanced prostate cancer in check and counteract its resistance to ADT.

“Right now, I’m on this high-dose testosterone, so I’m feeling pretty good,” laughs Mark Steele, an Atlanta retiree of 70. He’s a few weeks out from the five-year anniversary of his diagnosis, and is planning a party to mark the occasion. They haven’t been easy or disease-free years, but he faces that with a nonchalant, fighting spirit.

Steele’s disease came on fast. When he was 64, his PSA was under 2 (4 or higher is considered abnormal) and, as for evidence of disease, he was all-clear. By the time he was 65, his PSA had leapt to 29, the disease metastatic and already beyond surgery. “Drugs have been my best friend for the last five years,” he says. He often compares notes with a good friend from his tour in Vietnam who is a few years ahead of him with prostate cancer: “We say jokingly — but also quite seriously — if we live long enough, we’re going to be saved by the new drugs.”

He’s had a lot of them — more than a dozen — including a variety of testosterone modulators and two of the more promising approvals of the last five years: androgen inhibitors Zytiga and Xtandi. Zytiga was the most successful for him. Given with prednisone, it was first approved by the Food and Drug Administration in February of 2011 for patients with metastatic disease after chemotherapy, increasing median overall survival from 11 months with just prednisone to 15 months with the combination. By December of 2012, it had also been approved for patients with metastatic disease prior to chemotherapy. In the study on which that approval was based, Zytiga increased median overall survival from 30 to 35 months for those who took prednisone only compared with those who took the Zytiga combination.

Steele got 18 months out of Zytiga before the cancer progressed, and then he moved on to Xtandi. It was first approved in 2012 for metastatic castration-resistant disease, and in 2014 its use was also expanded into firstline treatment.

Steele got another year out of Xtandi, then underwent proton beam radiation and, last spring, began a targeted drug, the PARP [poly(ADP-ribose) polymerase] inhibitor Lynparza (olaparib), which disables certain DNA repair enzymes, making it difficult for cancer cells to propagate. But his PSA is rising again, and he figures chemotherapy is probably next in what he knows will be a steep challenge. If his cancer had been diagnosed today, his treatment schedule might have been quite different. In the past year, several trials have reported an encouraging bump in survival when either Zytiga or chemotherapy (docetaxel), along with ADT, is used soon after diagnosis.

For Zytiga plus ADT, two trials showed this early intervention lowered the risk of death by almost 40 percent for men with newly diagnosed metastatic prostate cancer. For docetaxel, two large randomized trials showed survival improvements of about a year (10 and 13.6 months) when the chemotherapy was added to androgen deprivation therapy, instead of the usual practice of using chemotherapy later. The benefit was even higher for those with more disease, and whose cancer was metastatic at initial diagnosis.

“We can use a lot of these drugs a lot earlier,” says Susan Slovin M.D., Ph.D., a prostate cancer specialist at Memorial Sloan Kettering Cancer Center in New York City. Being able to use Zytiga and docetaxel so much earlier is potentially paradigm-shifting, as the patients do much better in terms of disease control. “While chemo is not for every patient, a unique subset with a lot of disease seemed to do very well,” she adds. “We’ve never had this kind of flexibility before.” This timing discovery is exciting, but also emphasizes the challenge of using the drugs correctly. For example, another recently approved drug, the radiopharmaceutical Xofigo (radium 223 dichloride), offers yet another option for patients with bone metastases, yet it’s not universally appropriate, even for that subset of patients. “There are a lot of new drugs that have hit the market, and they have really been challenging in terms of how we strategize them,” says Robert Dreicer, M.D., a prostate cancer specialist and deputy director of the University of Virginia Cancer Center.

Is chemotherapy or Zytiga better overall when doing an early intervention? Will different patients experience different benefits? “We don’t know that one is better than the other,” says Dreicer. In addition to considering the differences in patient eligibility in each of the trials, the treatment choice may be governed by other factors, ranging from side-effect profiles and the patient’s pre-existing conditions all the way to cost. “There is not a definitive answer,” Dreicer says. “It’s still progress, because we’re improving survival and have more options.” With less clear evidence about how to do things, clinical experience matters. Because prostate cancer is common, it’s frequently treated in community hospitals, but its complexity is daunting. “The knowledge base is impossible for anybody to keep up with,” warns Dreicer, so seeking out a second opinion, at least to confirm a treatment paradigm, is becoming increasingly important.

“Some cancers have very well-defined treatment courses,” he adds. “Prostate cancer is not one of those diseases.”

OTHER AVENUES FOR TREATMENT

Hormone therapy targets hormonal receptors to slow prostate cancer, but the more specifically targeted therapy that matches a particular genetic target to a precisely designed drug is only just coming into focus in prostate cancer. For patients with BRCA1 and BRCA2 mutations, as well as mutations in ATM, CHEK2, PALB2, FANCA and HDAC2, a new generation of drugs, PARP inhibitors, offers significant hope. In fact, recent studies have shown that, in those with metastatic disease, upwards of 10 percent of patients may harbor one of these inherited mutations, even in the absence of a family history.

The DNA repair routine is so deeply coded in human cells that even cancer cells repair some of their own damaged DNA. PARP inhibitors block these repair enzymes in some cancer cells, helping to kill them. Though they appear to have the best chance of working in patients with known mutations in BRAC1, BRCA2 and some of the other DNA repair genes, they may also work on some patients without these mutations. Figuring out these exceptions to the rule will help researchers get even closer to a more complete targeted therapy approach.

Already approved for treating ovarian cancer with BRCA-mutation roots and shown to be more effective than chemotherapy in breast cancer with BRCA mutations, Lynparza has been given clearance for use in accelerated clinical trials because of an early study in which one-third of 49 patients with advanced prostate cancer showed at least some response to the drug. Response was 87.5 percent among the 16 participating patients who had DNA-repair mutations.

PARP inhibitors are the first real crack in the genomic profile of prostate cancer that will hopefully allow oncologists to begin carving it into subtypes, matching specific treatments to known genetic profiles of disease. Unfortunately, the other hot frontier of cancer treatment, immunotherapy, has less exciting news to report when it comes to prostate cancer. Slovin feels this frustration intensely, especially every time she sees Keytruda (pembrolizumab) advertisements on TV. “Drives me batty,” she acknowledges.

The success of Keytruda and related checkpoint inhibitors in melanoma, lung and other cancers has led to a broad effort to test their worth in just about every other cancer type. For other genitourinary cancers like bladder cancer, the response has been significant: five checkpoint inhibitors have been approved to treat that disease since last year. But results in prostate cancer have been underwhelming, at best.

An immunostimulant, a vaccine called Provenge (sipuleucel- T, or sip-T), was approved in 2010 for men with lowvolume metastatic disease. It is trained to match a patient’s immune system, but seems to be struggling to find its treatment niche. “We really have no firm data to suggest that, if you give sip-T, you are changing the immune milieu substantially,” Slovin says. As with other recently approved drugs, it may be necessary to find an appropriate pharmaceutical partner, which will involve further research.

TAKING CONTROL

With any cancer, it can be hard to reconcile the experiences of its most forward-thinking doctors and its most frustrated patients. With unprecedented choices and rising survival rates, Kane calls prostate cancer “one of the solid tumors we’ve made the most progress on in the last 10 years.” Lincecum tries to channel that positive attitude, but knows those breaks haven’t fallen his way. He wages his battle in full public view, hoping that other men learn from his bad luck and experience.

And he talks openly about the difficult choices that men with this disease must face. Surgery was the clinically recommended choice with his diagnosis, but he’s not sure he made the right decision. “Sometimes I think I’d be happier keeping my erectile function and dying earlier,” he admits.

But still he fights, enjoying his young twin boys and trying to erase the deficit left by the doctors who didn’t read his PSA correctly or comprehend the dark side of his urinary complaints. “It’s just like my second job, learning about prostate cancer. It just never stops,” he says. From his Maryland home, he regularly contacts the experts at Johns Hopkins University, the National Institutes of Health and Georgetown University. He’s always looking for a treatment edge, and currently he’s waiting for the bureaucratic wheels to turn on a phase 1 bone marrow transplant trial. If approved, he’d be the first patient enrolled. “This cancer is not going to go away with normal treatment,” he says plainly. “I need to do something radical.”

It’s a spirit that Steele understands, and even wears on a blue rubber wrist band: NEVER GIVE IN. “I’ll never be cured, but (I’ll do what) I can (to) live a longer life, with quality of life,” he says.

In his support group, he counsels newly diagnosed men, trying to replace their deer-in-the-headlights look with temper and resolve. “You’ve got time. Study. You make the decision. Once you make it, don’t look back,” he advises. “The best thing you can do is start getting educated. If you really want to live, you’ve got to take control of your fate. You’ve got to understand what’s going on.”