The challenge of combating advanced prostate cancer can be summed up in two words: treatment resistance. Despite effective therapies that can arrest the progress of cancer that has spread, or metastasized, beyond the prostate gland, the cancer inevitably learns how to resist the effects of those treatments.
But researchers are fighting back with a host of new strategies that are helping postpone the onset of resistance. They’re also investigating new tests that could help identify men with advanced prostate cancer who would be most likely to benefit from certain treatments.
These advances offer hope that doctors may one day be able to permanently outsmart this wily adversary. In the interim, they’ve begun improving the quality of life and adding more time to the lives of men whose prostate cancer has become life-threatening.
The mainstay of initial treatment for advanced prostate cancer is hormonal therapy, also called androgen deprivation therapy (ADT). Testosterone, the predominant male hormone (or androgen), stimulates growth of prostate cancer cells. But while lowering testosterone levels with ADT is highly effective, it does not offer a cure. In time, the effect of testosterone suppression wanes and the disease progresses. At this point, a man is considered to have castration-resistant, or castration-recurrent, prostate cancer (CRPC).
Traditionally, chemotherapy has been the next step for men whose prostate cancer is no longer controlled by ADT and has spread outside the prostate. Chemotherapy works by destroying cancerous cells as they replicate. But some researchers wondered what would happen if chemotherapy was initiated at the same time as ADT instead of waiting for ADT to fail. Could this help a man live longer? And if so, how long?
The CHAARTED (ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) study was launched in July 2006 to answer these important questions. The trial enrolled 790 men with metastatic prostate cancer who had not yet started androgen deprivation (or androgen ablation) therapy. The men (average age, 63) were randomly assigned to receive ADT alone or ADT plus the chemotherapy agent docetaxel (Taxotere).
The study was stopped prematurely in 2012 after an interim analysis showed that men who had received the chemo-hormonal therapy survived 57.6 months, on average, compared with 44 months for those who received hormone therapy only. Interestingly, the survival difference between the two groups was even greater in men with high-volume disease (four or more bone metastases, one of which is outside the spine or pelvis).
Findings from the CHAARTED study have proven to be game changing. Indeed, the National Comprehensive Cancer Network (NCCN) has revised its most recent prostate cancer treatment guidelines to include concurrent chemotherapy-hormone therapy as an option for some men with high-volume disease who have not been treated with ADT. Some doctors may also recommend this regimen to a man who lacks metastases to the bone if he has malignancies that have spread to the liver or lung, since they are associated with a particularly poor prognosis.
Laboratory studies have suggested that ADT plus cabazitaxel (Jevtana)—a newer chemo- therapy drug in the same family as docetaxel—is an even more effective combination. Investigators have begun clinical trials to determine whether that finding may also hold true for humans. For now, however, Jevtana is currently approved only for use by men with metastatic CRPC who have already been treated with docetaxel.
Chemotherapy following hormone therapy remains an important option for many men with metastatic CRPC. In recent years, the Food and Drug Administration (FDA) has approved several treatments that can help these men delay the start of chemotherapy, thereby putting off its toxic effects. These include the immunotherapy agent sipuleucel-T (Provenge) and two new types of hormone therapy, abiraterone (Zytiga) and enzalutamide (Xtandi).
Provenge. This treatment is a pre-chemotherapy option for some men who have advanced prostate cancer that has not spread to the liver and who are experiencing few or no cancer-related symptoms, such as bone pain. Approved by the FDA in 2010, Provenge is the first anticancer vaccine therapy in our armamentarium—it’s designed to get a man’s own immune system to attack and eliminate his cancer. Results from a large clinical trial, reported in 2010 in The New England Journal of Medicine, demonstrated that Provenge extended the lives of men with CRPC by an average of four months when compared with those given a placebo.
Zytiga. This medication works by blocking the production of testosterone by the adrenal glands, the testes and the prostate tumor itself. The drug was initially approved by the FDA in 2011 for the treatment of CRPC after docetaxel therapy was no longer effective. In studies of men with metastatic CRPC who had undergone chemotherapy, those who took Zytiga or Xtandi (see below) lived four to five months longer, on average, than their counterparts who received a placebo.
The FDA now also allows Zytiga to be used before chemotherapy in men with metastatic CRPC. The expanded approval was given on the basis of a randomized double-blind study of more than one thousand men who had not yet received chemotherapy.
The study showed that the disease progressed significantly more slowly in Zytiga users than in individuals who received a placebo; progression-free survival was 16.5 months for men taking Zytiga versus 8.3 months for the placebo group. A final analysis of the data, published last year in The Lancet Oncology also showed an overall survival benefit for men who used Zytiga prior to chemotherapy compared with placebo users. In addition, pre-chemo Zytiga use helped increase the length of time before opiates were needed for pain control.
Xtandi. A highly potent androgen receptor inhibitor, Xtandi blocks testosterone receptors at three points, thereby preventing the hormone from stimulating the genes that cause prostate cancer growth. Like Zytiga, this drug was initially approved by the FDA for use in men who had already received chemotherapy. But in 2014 the FDA approved Xtandi for use prior to chemotherapy, too.
Evidence of Xtandi’s pre-chemo benefit came from the PREVAIL study, which involved more than 1,700 men with CRPC. The findings, which were reported in The New England Journal of Medicine, showed that men treated with 160 mg of Xtandi once a day for at least one year were able to postpone chemotherapy for an average of 17 months, compared with a little over five months for men who received a placebo. The advantage was so striking that the study was also ended prematurely, and men who had received a placebo were offered the treatment.
New tests: On the horizon
It’s important to note that a significant portion of men don’t respond to Zytiga or Xtandi.
There’s hope on the horizon that researchers may eventually discover tests that identify patients most likely to benefit from specific prostate cancer medicines. Such an advance would reduce the risk of needlessly exposing a man to the potential side effects and the financial expense of a drug that will not work for him.
One example comes from researchers at Johns Hopkins who recently reported that a new blood-based biomarker (a substance that can be measured to detect or monitor disease) called androgen receptor splice variant-7 (AR-V7) may help predict resistance to Xtandi and Zytiga. Their findings, reported in 2014 in The New England Journal of Medicine, showed that men whose tumor cells contained detectable levels of AR-V7 responded poorly to both of these drugs.
Another smaller study by the same group of researchers, reported in 2015 in JAMA Oncology, found no difference in response to chemotherapy between men with or without the variant.
Taken together, these findings suggest that AR-V7 might be used to help guide treatment decisions. However, additional results from larger studies are needed to clarify these findings before such testing is likely to become routine.
A promising time
If you have advanced prostate cancer, the good news is that you currently have more treatment choices than ever before. You’ll need to discuss the options with your doctor to decide which might be worth considering based on your individual circumstances.