In 1941, Charles B. Huggins, a urologist at the University of Chicago, made the seminal observation that prostate cancer was an androgen-dependent, androgen-driven disease, and that surgical or medical castration could induce significant regression. Then, as today, approximately 9 of 10 men with prostate cancer who are castrated will experience a response. But many will go on to progress to castration-resistance, with a median survival in the PSA era of roughly about 4 years.
In a wide-ranging and comprehensive review at the ASCO Genitourinary Cancers Symposium, in San Francisco, Maha Hussain, MD, FACP, FASCO, Professor of Medical Oncology at the University of Michigan, highlighted incremental progress and the challenges that remain in the care of men with hormone-naïve prostate cancer. Dr. Hussain detailed strategies that have been studied in randomized, prospective trials and have come to influence, or to change, the standard of care throughout about 75 years of progress.
Some concepts retain relevance in today’s standard of care, beginning with combined androgen deprivation, based on maximizing castration and reducing the exposure of the cancer cells to potential extra-gonadal sources of androgen with the use of gonadal suppression and peripheral blockage with an anti-androgen.
A number of international trials have been conducted using this concept, with mixed, contradictory outcomes, Dr. Hussain said. Several produced quite positive data for the use of combined androgen deprivation. Others demonstrated trends of better survival that were non-significant. Others failed to demonstrate any advantage
Whether and by how much there is a benefit to combined androgen deprivation has been the subject of debate, primarily in the 1990s. Of three meta-analyses of the time, the bottom-line message was that combined androgen deprivation conferred a benefit, primarily with non-steroidal anti-androgens. To Dr. Hussain, treatment could improve significantly with the current generation of anti-androgen agents. "I think this concept could continue to be of relevance in today’s management of prostate cancer," she added.
Another concept “near and dear to my heart” Dr. Hussain said, is that of intermittent androgen deprivation versus continuous therapy, which is attractive for many reasons. Pre-clinical data suggested that by periodically exposing a tumor to castration versus androgens, “one might be able to prolong the duration of hormonal responsiveness." That strategy, coupled with the idea of improving quality of life by reducing side effects by allowing the testicles to recover, is very attractive from a physician and patient effective. This concept has been heavily investigated in the United States and internationally, including in numerous phase III trials.
“I am focusing on two trials in particular because both trials have focused primarily on patients with hormone-naïve prostate cancer and both trials were powered to look at overall survival."
One of these trials, SWOG 9346, an Intergroup non-inferiority trial, was inspired by the concept that, even with somewhat lower survivals, if there was balance by improvements in quality of life, the approach would prove attractive.
In both trials, (recently discussed in a JCO article) continuous therapy was associated with better median survival compared to intermittent therapy. The largest of the trials, SWOG 9346, demonstrated a median survival difference of approximately 8.5 months in favor of continuous treatment. This outcome was associated with “modest at best” improvement in quality of life that, Dr. Hussain added, was, unfortunately, short-lived. Still, she added, “...from a hormonal perspective, continuous androgen deprivation is the standard of care on grounds of optimal survival outcomes."
Dr. Hussain provided an overview of the sweep of progress during the “hormone era” with highlights that have most informed clinical care.
“The first observation is that overall survival in the context of this disease has improved in the PSA era,” she said, referring to the influence of two trials—one pre-PSA and one the verge of PSA era. “Whether this is function of lead time in terms of diagnosing metastatic disease or improvement in care, or another reason, is subject to discussion. But I would say that anytime we see better survival, it is good news for patients.”
A second observation she highlighted emerged from data also from the SWOG 9346 trial, and looking at survivals between African American men and white men, saying that there appears to be a reduction in the racial gap. “Whether this is a fluke or a real observation a function of equal access to care allowing optimal outcomes, I think it is good news," Dr. Hussain remarked.
Regarding the longer-term prospects for patients with prostate cancer, even when it is metastatic, data reveal “it can be a very chronic disease.” Some clinicians have patients who are 10 to15 years out from their initial diagnosis with metastatic disease. This progress, she said, can be a stimulus for imagining how, with proper care, patients can live even longer.
“Imagine what can be done if we can shift this curve to the right. Ultimately, the only thing that is guaranteed about life is death. If we can get people to live and live longer, that I think would be something wonderful for patients, as well as for survivorship issues, and cost of therapy. What I would say is that this curve tells me that we can make this disease truly chronic.”
Combining Bone-Targeted Therapy with Hormone Therapy
Combining bone-targeted therapy with hormone therapy is a strategy that has undergone testing and has produced optimistic data. “Prostate cancer is a very bone-directed disease," Dr. Hussain stated, and can be associated with significant co-morbidities in the bone. Zoledronic acid was one of the first agents to be FDA approved on grounds of skeletal-related events, albeit, she added, in the “pre-effective systemic therapy era," when there weren’t good treatments for patients for castration-resistant disease. Even so, Dr. Hussain said, the concept of was very attractive to test in the context of hormone-naïve prostate cancer.
Of multiple trials conducted in this setting, one, from the Alliance CLGB Intergroup trial, looking at adding zoledronic acid to androgen deprivation therapy, found no significant advantage to adding zoledronic acid. These data, which were confirmed by results from the STAMPEDE trial, directly affected patient care at the time of their release. “This observation has had an impact on standard of care," Dr. Hussain remarked. “In my clinic, a fair number of patients had already been placed on monthly zoledronic acid or denusomab in this disease setting, and this data shows there is no reason for routine use of these agents.”
Chemo-hormonal Therapy
In terms of outcomes, “the most exciting strategy we have seen is the concept of chemo-hormonal therapy," said Dr. Hussain. The idea of multi-targeted treatment strategies is not a new concept in oncology, she noted, certainly not in prostate cancer. A number of trials in prostate cancer with older chemotherapies have attempted to improve outcomes in hormone-sensitive disease. However, these drugs proved not to be effective.
After docetaxel was approved in castration-resistant disease, the next step became obvious. A trial led by Chris Sweeney and the ECOG Intergroup tested six cycles of docetaxel at the standard dose along with hormone therapy, versus hormone therapy alone, in 790 patients with metastatic disease. Results showed a “remarkable, unprecedented in this this disease setting," 13-month improvement in median survival, with a hazard ratio of .61 and a P value of .0003.
These outcomes were based on an a priori stratification by disease volume—high-volume versus low-volume disease, with high volume disease patients numbering 514. The results, according to Dr. Hussain, demonstrated a 17-month difference in survival when docetaxel was added to hormone treatment, and with a very impressive hazard ratio and P-value. Investigators noted a trend in the context of low-volume disease patients, but with low numbers. However, the follow-up was not adequate. And, Dr. Hussain added that although the hazard ratio was there, the P value was non–significant. “It will be interesting to see whether with additional follow-up, this difference becomes significant.”
Between this trial and the STAMPEDE trial, Dr. Hussain noted that there is currently “...compelling evidence that adding docetaxel at this stage of disease is very important.” She added a caution however: “One thing I should point out is that while this trial was conducted in metastatic disease, the median age was 63 years, which is relatively young. Still, as testimony to the tolerance of the treatment, 86% of patients were able to receive all six cycles of docetaxel, the vast majority of patients without requiring dose-reductions. Nevertheless," Dr. Hussain added, "side effects do occur with this therapy, and proper patient selection is important."
STAMPEDE data, recently reported by Nick James, focused on the population of metastatic prostate cancer patients who received standard of care hormonal therapy versus standard of care hormone therapy plus docetaxel. This study produced another “very impressive, unprecedented” median survival improvement and 5-year survival of 50%. “I don’t think I have seen these kinds of figures with any other trials in this setting,” Dr. Hussain commented, adding, "I think the combination of these trials provides compelling data, with the caution to clinicians to be careful in patient selection. Patients must be sufficiently 'fit' to receive chemotherapy."
Oligometastases
For the management of “oligomets,” (oligometastases: in Greek, oligo means “few to little”), prospective trials are needed, said Dr. Hussain, referring to definitions that differ, from, for example, 1 to 3 or 1 to 5 metastases and a low level of evidence from a small case series that does not rise to the level of changing standard of care.
Questions remain to be answered. How many lesions should be counted as “oligo” and how does location appertain in clinical decision-making? Do a liver lesion and a spine lesion count as oligometastases? Because the definition of oligo is defined and directed primarily by imaging, the sensitivity and accuracy of imaging is very critical to a clinical approach. Yet to be determined via randomized trials are the objectives of therapy—whether overall survival or delay of androgen deprivation therapy. “From my perspective, it ought to be about improving overall survival while minimizing side effects of therapy.” Clearly, she added, prospective trials are going to be needed.
Current and future goals in the management of patients with hormone-naïve prostate cancer include maximizing anti-tumor effects. “We have seen some positive results, which opens the door for more testing, whether it’s maximizing AR targeting or multi-targeted strategies, building on chemo-hormonal therapy, or other pathways."
To maximize anti-tumor effect, a better understanding of mechanisms of progression in this disease is needed, Dr. Hussain continued. Already, investment and research in this area has led to the identification of several potential relevant pathways that have been validated by several prospective phase III trials. These initiatives open the door to even more strategies that could potentially be moved to treatment of patients with earlier, hormone-naïve disease.
Other trials are aimed at the goal of maximizing anti-tumor effects, including a resurrection of the concept of maximal androgen blockade. Many other concepts are in discussion, along with a large number of open phase III trials. “I don’t recall ever in my lifetime seeing as many open phase III trials in this disease space.”
Current Clinical Translational Research, Personalized Medicine
Personalizing therapy is a very critical, and very timely, issue in this cancer no less than in others. Also important is the development of strategies for enhancing survivorship as patients live longer as well as addressing cost and value issues.
Although the concept of personalizing care is the subject of frequent discussion, it is not an easy thing to plan and undertake, Dr. Hussain said. “Precision medicine is complicated, but central to it is a better understanding of the genomic landscape.” What is clear from data from Dan Robinson, with the East Coast “Stand Up to Cancer Dream Team,” said Dr. Hussain, “...is that there are very many targets in this disease state—many alterations, which raises the question of how to identify the most promising targets for study.”
As to where in disease progress to personalize therapy, Dr. Hussain argues that it is when the disease is metastatic, but hormone naive, “...before it actually becomes devilish and castration-resistant.” This is a promising window of research opportunity that awaits exploration.
As to where in disease progress to personalize therapy, Dr. Hussain argues that it is when the disease is metastatic, but hormone naïve.
One project Dr. Hussain and colleagues are undertaking involves co-targeting cell cycle and androgen signaling with the use of a cdk46 inhibitor, in patients with RB-intact prostate cancer. The initiative is based on pre-clinical data from Karen Knutsen’s group, suggesting that targeting this pathway can be of value.
The drug under study is palbociclib, an agent that has also undergone investigation in breast cancer in combination with letrozole. This seven-center prostate cancer study has been activated, and had a current enrollment of 40 patients. Patients will be randomized, based on RB tumor positivity, to either to androgen deprivation therapy or a combination of palbociclib and androgen deprivation. Forty patients have been screened, and 30 patients have been randomized to the study at this reporting.
“This seven-center trial demonstrates that it is possible to conduct trials such as this in this patient population,” Dr. Hussain said. Enhancing survivorship is essential, as is management of symptoms and side effects for patients, she pointed out; the burdens of treatment are real and problematic at multiple levels, including costs and value to patients.
“We have come a long way in this disease,” Dr. Hussain observed. The promise of better therapies is real in metastatic hormone-naïve prostate cancer. Androgen deprivation continues to be the backbone of treatment, with median survival in the PSA era of about 4 years, and the remarkable 10-year estimated survival of 17%.
We have come a long way in this disease. Androgen deprivation continues to be the backbone of treatment, with median survival in the PSA era of about 4 years, and the remarkable 10-year estimated survival of 17%.
“Androgen deprivation and docetaxel result in an unprecedented improvement in median survival. As such, six cycles of docetaxel and androgen deprivation therapy is the standard of care for men with newly diagnosed hormone-sensitive disease, who are otherwise medical candidates for docetaxel.”
The data suggest that this approach should be taken particularly in patients with high-volume disease. Routinely, there is no role for bone-targeted therapy. Several ongoing or planned phase III trials are focused on maximizing the anti-tumor effect.
"The charge moving forward must be placed on impact and value. This stage of disease is still deadly in the majority of patients," Dr. Hussain pointed out. Even today, clinicians must use a 'one-size-fits-all' approach, and there are currently no predictive biomarkers or validated personalized therapeutics. “The emerging data suggests that this stage of disease—the metastatic, hormone-naïve disease—provides a large window of opportunity to convert it from deadly to a truly chronic disease, as a first step toward a cure."
Vision for the Future: Future ParadigmsProstate cancer is a smart and adaptive cancer, Dr. Hussain asserted in her concluding remarks, adding that while AR-signaling is very critical, "...thus far targeting it alone may not enough." This may be an increment in the forward march of progress, she said, but the totality of the disease biology must be taken into account, using multi-targeted strategies. Aiming at a “cell kill” ought to be the focus of care. As patients live longer, survivorship and treatment-related physical and monetary costs demand more attention.
Hussain M. Changes in the treatment of hormone-naïve disease. In: Prostate Cancer: Year in Review and Keynote Lecture. Genitourinary Cancers Symposium; January 2016. San Francisco, CA.
Written by: Barbara Jones