In the treatment of prostate cancer, much effort goes into suppressing testosterone, for instance by the use of androgen-deprivation therapy (ADT), but a new pilot study suggests that — paradoxically — testosterone may be useful.
In the small study, pharmacological doses of testosterone were given to asymptomatic men with castration-resistant prostate cancer (CRPC) on continuous ADT in what the researchers describe as bipolar androgen therapy (BAT), which exposed the prostate cancer cells alternately to very high and very low levels of testosterone over 4 weeks — with some clinical benefit.
Challenging current notions, the pilot study in 16 patients from the Johns Hopkins School of Medicine has provided provocative evidence that this approach can suppress levels of prostate-specific antigen (PSA) and also tumor growth in some asymptomatic men CRPC.
The observations were reported in the January 7 issue of Science Translational Medicine.
The results were promising enough for the researchers to plan further, larger studies.
"There has been a groundswell of interest in the idea of reversing resistance to androgen-deprivation therapy. It is important to get BAT into the mainstream as a therapeutic idea," Samuel R. Denmeade, MD, from the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, and a senior author on the study, told Medscape Medical News.
However, when approached for comment on the study, Marc B. Garnick, MD, Gorman Brothers Clinical Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, provided a counterpoise. "This study, as with any preliminary investigations that include cancer patients, raises many thought-provoking biological issues in the overall management of prostate cancer and the proper evaluation of safety of drugs, even older ones," he told Medscape Medical News.
Paradox of Testosterone Effects
The paradox at the heart of the study has been known for a while in human prostate cancer cell lines. While low levels of testosterone make prostate cells grow better, in some cells testosterone is associated with cell death, Dr Denmeade commented. It became important to see if this could be replicated in humans, he added.
In two studies that preceded this report, a similar approach showed only a small effect, Dr Denmeade explained. He said that it was important to test supraphysiologic doses or FDA-approved levels of testosterone, which, given over a 4-week cycle, allows prostate cancer cells to experience polar extremes of testosterone levels — initially high levels and later low levels, which they labeled BAT.
The Pilot Study
For their study, Dr Denmeade and his colleagues recruited 16 men with asymptomatic CRPC who had been taking ADT with a luteinizing hormone-releasing hormone (e.g., goserelin, leuprolide, and triptolerin) for a median of 45.5 months. Fourteen of the 16 men had received at least one second-line hormone therapy.
All men received an intramuscular injection of testosterone cypionate 400 mg on day 1 of a 28-day cycle. On days 1 to 14, they also received oral etoposide 100 mg.
The primary end point of the study was a decline of PSA after three cycles of testosterone and etoposide. If PSA levels declined or showed a trend toward declining (no more than 50% above baseline levels), men were continued on BAT alone.
Response to BAT
Median follow-up time was 124.5 days. Of 16 men enrolled, 2 experienced toxicity; one died from pneumonia and sepsis from etoposide and the second experienced prolonged erection.
Seven of the 14 men completed three cycles of therapy and showed declines in PSA and continued to receive BAT without etoposide. Four men showed PSA decline of at least 50% of baseline; two other patients experienced PSA reduction of 48% and 47%.
The other seven men showed no decrease in PSA levels.
Some men who showed PSA progression were considered to benefit from the therapy based on lack of radiographic progression and increased subjective quality of life, according to the researchers.
But Dr Garnick cautioned that "a substantial number of patients had increases in PSA values, which should carry concern in any man receiving exogenous androgens."
At baseline, 10 men had soft tissue metastases based on RECIST (Response Evaluation Criteria in Solid Tumors). Of these patients, after a follow-up of 91 days, two had progressive disease, three had stable disease, four showed a partial response, and one showed a complete response (50% response rate).
Ten patients receiving second-line therapy with abiraterone or antiandrogen therapy (e.g., enzalutamide, bicalutamide, nilutamide) had PSA declines that ranged from 30.8% to 99.5%.
The surprise was that all the men who were initially resistant to therapy with one or more drugs could be rechallenged after BAT and responded, some to the same drug they came off, Dr Denmeade told Medscape Medical News.
He was referring to the observation that two men were rechallenged with antiandrogen therapy and one with enzalutamide, the agents they had progressed on, while one man was rechallenged with enzalutamide having initially progressed on abiraterone. All these men showed declines in PSA.
BAT, therefore, has the potential to reverse the resistance that develops to testosterone-blocking drugs such as enzalutamide, the researchers concluded.
The observed high rate of PSA decline with androgen-ablative therapies after BAT raises the possibility that BAT may reverse resistance and resensitize the CRPC cells to therapies inhibiting androgen receptor signaling, the researchers comment in their discussion.
Although these findings need to be further validated in a larger study, this observation could have a major impact on the current treatment paradigm, they add.
Dr Garnick was, however, more critical of taking this to the next level. He pointed out that two patients withdrew for toxicity and another two had grade 3 pulmonary emboli.
In light of the recent cardiovascular adverse events surrounding exogenous testosterone administration in noncancer populations and the wide ranges of serum testosterone (some that were supraphysiologic) that were measured in the study, more concern needs to be paid to these issues well before wider use of this approach can be supported, Dr Garnick told Medscape Medical News.
Explaining How BAT Works
Dr Denmeade explained the importance of supraphysiologic dose of testosterone based on preclinical studies in cell culture.
In human prostate cancer under conditions of androgen-ablation therapies, such as abiraterone and enzalutamide, there is an overexpression of androgen receptor. These cells are resistant to growth inhibition by antiandrogens such as bicalutamide.
In addition, these cells are also paradoxically inhibited with supraphysiologic levels of androgen through stabilization of ligand-bound androgen receptor in the cell nucleus, inhibiting "DNA relicensing" and resulting in cell death. Cell death also occurs because of double-stranded DNA breaks caused by androgen exposure and aggravated by etoposide, Dr Denmeade explained.
When given to asymptomatic men with CRPC, supraphysiologic dose of testosterone once every 4 weeks allows polar extremes of testosterone levels — high levels when given initially at 400 mg intramuscularly to near castration levels over the 4-week cycle.
CRPC cells that survive initial high testosterone dose become susceptible to death when the dose returns to low levels at the end of the 4-week cycle, Dr Denmeade explained.
These investigators have provided a possible pathophysiologic role for manipulating the overexpressed androgen receptor and its biology in men with CRPC, Dr Garnick said in an email to Medscape Medical News. They further exploit, physiologically or cleverly, the addition of etoposide as a means to inhibit DNA repair and potentiate DNA double-strand breaks induced by androgens, he added.
Emphasizing Important Aspects of the Study
Dr Denmeade and his colleagues stress that it was important to highlight two aspects of the study.
First, men enrolled had to show progressive CRPC on continuous ADT. "On the basis of the proposed mechanisms of action, the use of testosterone in men who have not yet received ADT would be ill advised without definitive clinical evidence of benefit," Dr Denmeade and his colleagues write in their discussion.
Second, it was important to enroll asymptomatic men. In symptomatic men, testosterone could produce acute pain — within hours to days — potentially requiring hospitalization.
The Future of BAT
This approach of using BAT needs further study, the researchers point out, with different end points such as radiographic response or survival. Indeed, in a university press release Dr Denmeade cautioned that "men should not try to self-medicate their cancers with testosterone supplements available over the counter." The timing of testosterone treatment is critical and difficult to determine, he explained.
The results from this pilot study support future work toward establishing BAT as an effective therapy that can improve survival, overcome resistance to androgen-ablative therapies, and meaningfully improve quality of life, functional activity, and sexual function in men with CRPC, the researchers conclude.
Toward that end, Dr Denmeade told Medscape Medical News that in future studies that are being planned, BAT will be used without etoposide. These studies will also address Dr Garnick's comment to Medscape Medical News that the use of etoposide, intended for a biochemical modulation of double-strand breaks, is a confounding factor in interpreting efficacy results.
One study is currently open at Johns Hopkins and will enroll 60 men who progressed on abiraterone or enzalutamide. Following BAT and progression on BAT, men would be rechallenged with the abiraterone or enzalutamide — the same drug they came off. The primary end points of this study are PSA response to BAT and also PSA response to rechallenge with abiraterone or enzalutamide.
The second study will be a randomized multi-institutional head-to-head clinical trial comparing BAT with enzalutamide in men with CRPC who are progressing on abiraterone. Following abiraterone progression, men would be given BAT or enzalutamide. Radiographic progression-free survival will be the end point of this study.
"The pilot study was supported by small funds from a family foundation. Now we have support from the National Institutes of Health and the Department of Defense Prostate Cancer Research Program, " Dr Denmeade said.
However, Dr Garnick shared some concerns of rapid and large-scale advancement of these observations into further studies.
"Advances of androgen-receptor biology have come at a very fast pace and this study further exemplifies creative interventions of this biology. Yet, additional understanding about the safety of exogenous testosterone in this population, along with a better understanding of the contribution of its pharmacokinetics and safety in combination with etoposide, would be welcome before larger-scale trials are embraced, " Dr Garnick told Medscape Medical News.
The study was funded by the One-in-Six Foundation. Dr Denmeade is a consultant for Sophiris, GenSpera, and Medicenna. Dr Garnick was a member of the FDA advisory panel that evaluated the cardiovascular safety of testosterone replacement therapy.
Science Translational Med. 2015;7(269):269ra2. Abstract
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Cite this: Testosterone to Treat Castration-Resistant Prostate Cancer? - Medscape - Jan 15, 2015.