'Bipolar' Therapy: New Twist in Advanced Prostate Cancer

Roxanne Nelson, BSN, RN

January 13, 2016

SAN FRANCISCO — Preliminary data suggest that a new twist on manipulating hormones in prostate cancer shows some benefit. The standard approach to treatment is androgen deprivation therapy (ADT), but the new approach intersperses this with bipolar androgen therapy (BAT) with intramuscular testosterone injections.

Results from a small phase 2 study in 29 men with advanced hormone-sensitive prostate cancer show that the primary endpoint was met, with nearly 60% of men achieving a prostate-specific antigen (PSA) level <4 ng/mL after undergoing two cycles of BAT.

The findings, which were presented at Genitourinary Cancers Symposium (GUCS) 2016, also suggest that BAT may have a positive impact on quality of life.

"The name 'bipolar' comes from the fact that this therapy is designed to produce fluctuations in testosterone levels, from very low lows in the androgen deprivation period to very high highs after they get intramuscular testosterone injections," said lead author Michael T. Schweizer, MD, of the University of Washington/Fred Hutchinson Cancer Center, Seattle.

This approach, in which prostate cancer cells are alternately exposed to very high and very low levels of testosterone over 4 weeks, has previously been shown to have some clinical benefit.

Dr Schweizer explained that the current clinical trial follows on the heels of a pilot study that was conducted in men with castration-resistant prostate cancer. In that trial, a paradoxical antitumor effect was seen in patients treated with intermittent, high-dose testosterone, as reported by Medscape Medical News.

"We found that this approach suppressed PSA levels and controlled tumor growth in some men with castration-resistant prostate cancer, so we adapted it to men who were hormone sensitive," he told Medscape Medical News.

Because the adaptive increase in androgen receptor expression that follows long-term ADT may underlie this effect, Dr Schweizer and colleagues conducted the latest study in men with hormone- sensitive disease to see whether they would also respond to BAT if administered after a 6-month ADT "lead-in."

Primary and Secondary Endpoints Met

Following ADT treatment for 6 months, patients with a PSA level <4 ng/mL or ≥50% below baseline at the end of the treatment period went on to receive two rounds of alternating BAT-ADT.

A total of 29 men were initiated into the BAT phase of the study.

Each round of BAT-ADT consisted of three cycles of BAT and 12 weeks of ADT alone. ADT was continued throughout the study, including during cycles of BAT, to suppress endogenous testosterone production.

During rounds of BAT, testosterone cypionate or enanthate was administered intramuscularly at a dose of 400 mg every 28 days.

The primary endpoint was the percentage of patients with a PSA level <4 ng/mL at the end of the study. Thirty evaluable patients were needed to yield 82% power to reject a null rate of 40% in favor of 60% of patients with a PSA level <4 ng/ml at the end of the study.

"Seventeen men, which was 59% of the group, had a PSA <4 ng/mL, so the study was successful from that point of view," said Dr Schweizer.

For three (10%) patients, the PSA level was undetectable (<0.2 ng/mL) at the end of the study, and for the 26 patients who completed the study, PSA levels were below pretreatment baseline levels.

Of 10 patients in the BAT-ADT phase who had RECIST-evaluable disease, eight (80%) had objective responses, with four complete responses and four partial responses. Three patients eventually progressed.

Quality of life, as measured on several surveys, improved following the first round of BAT (post-ADT lead-in vs post-round 1 BAT).

Side effects were mostly of grade 1 or 2, Dr Schweizer reported. "They were probably more related to the ADT than the testosterone," he said.

Although acknowledging that the study was small and had only a single arm, Dr Schweizer said "the results are provocative and might justify additional testing." He added: "I would like to see this move to a randomized study and put this against intermittent therapy and see if it can perform as well and, hopefully, better."

As far as which population of men are most likely to benefit, he noted that they have more robust data right now on castration-resistant men, and there are two trials moving forward in that population. "In hormone-sensitive men, it's tough to say," he added. "We did see a variable PSA response rate even in men who did meet our primary endpoint, so I think that there are some underlying molecular features that can help us identify the men who are most likely to benefit."

Data Could Shift Paradigm

Sumanta Pal, MD, assistant professor, Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California, agrees that the data are preliminary and need validation.

"Having said that, these data are very promising and may really shift the paradigm in terms of how we have treated the disease for decades now," he told Medscape Medical News. "It is almost implicit that patients who receive testosterone have an improvement in their quality of life, given what we see in testosterone supplements in healthy males.

"One of most challenging consequences of androgen deprivation therapy is the drop in testosterone, which manifests as hot flashes, drop in libido, and many patients often express interest in taking testosterone, which seems almost heretical based on how we feel that prostate cancer works and functions," he noted.

 
Taking testosterone...seems almost heretical based on how we feel that prostate cancer works and functions. Dr Sumanta Pal
 

"But perhaps resensitizing prostate cancer to hormone treatments may be a more sophisticated approach to this problem and potentially add to the quality of life," he said.

The study was funded by the Patrick C. Walsh Prostate Cancer Research Fund. Dr Schweizer has disclosed no relevant financial relationships. Several coauthors report relationships with industry, as noted in the abstract. Dr Pal has received honoraria from Astellas, Pharma, Medivation, Novartis; has played a consulting/advisory role with Aveo, Genentech, Myriad Pharmaceuticals, Novartis, and Pfizer; and has received research funding from Medivation.

Genitourinary Cancers Symposium (GUCS) 2016: Abstract 236. Presented January 7, 2016.

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