20 December 2024

Bipolar Androgen Therapy: The ‘counter-intuitive’ new prostate cancer treatment showing great promise

By Tim Baker

Living with prostate cancer and its treatment presents many daunting challenges to quality of life and mental and physical well-being.

Hormone therapy, also known as Androgen Deprivation Therapy (ADT), has been the frontline treatment for prostate cancer for decades, but comes with an alarming suite of debilitating side effects – from loss of libido and erectile function,  increased risks of cardiovascular disease, diabetes, depression, to loss of muscle mass and bone density. And ADT eventually becomes ineffective as the cancer mutates and develops resistance.

In the search for new and improved prostate cancer treatments, balancing efficacy with better side effect profiles, a “counter-intuitive” therapy is emerging with enormous potential.

Bipolar Androgen Therapy (BAT) has been studied for around ten years, but a growing number of research studies and clinical trials are investigating how to deliver this treatment with the best results.

As the name suggests, BAT involves traditional Androgen Deprivation Therapy (ADT) with periodic high doses of testosterone. Conventional thinking would’ve once suggested this risked fuelling cancer progression, by providing prostate cancer cells with their fuel - testosterone. But in up to 30% of cases it appears to have the potential to “shock” the cancer into remission, while alleviating many of the more debilitating side effects of ADT and extending its effective lifespan.

Ask any man on ADT managing its many side effects,  and the prospects of a hit of testosterone sounds like mana from heaven. As someone who’s lived with metastatic prostate cancer for nearly ten years, and the brutal impacts of ADT, my first response was, where do I sign up?

But, as with all new and experimental treatments, a note of caution needs to be sounded. Medical researcher Dr Mitchell Lawrence, from Monash University’s Biomedicine Discovery Institute, is attempting to find answers to many of the unresolved questions around BAT – who will respond best to it and how should it be delivered? In doing so, he’s joined a growing international collaboration to help usher in a new generation of prostate cancer treatments, that promise better outcomes and improved quality of life.

Much of the early work on BAT was performed at the Johns Hopkins University School of Medicine, in Baltimore, Maryland, under the guidance of Samuel Denmeade, Professor of oncology, urology, and pharmacology and molecular sciences. Denmeade and his collaborators released an influential paper in 2015 – Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: Results from a pilot clinical study – which sparked great interest in their research.

“They’re very collaborative, very generous with their ideas,” says Dr Lawrence.  “The concept grew from there ... They have a number of different trials designs and have seen response rates of up to 30% with improved quality of life. There’ve been a couple of exceptional responders with striking reductions in tumour volume. We are trying to learn how to identify which tumours are more likely to respond. We may be able to increase the response rate by combining the therapy with chemo or immunotherapy.”

One of the problems with traditional ADT, apart from the debilitating and emasculating side effects, is that prostate cancer cells eventually mutate and ADT becomes ineffective. “If you keep doing the same thing the prostate cancer cells adapt,” says Dr Lawrence. “It’s comparable to anti-biotic resistance. By changing strategies we’re hoping to extend efficacy.”

The current research focus combines international clinical trials and laboratory research at Monash, using their collection of live prostate cancer cells, known as the Melbourne Urology Research Alliance.  “The lab work is complementary because of the way we can really deeply understand the response. It’s like simulating a clinical trial but testing every tumour in every treatment group.”

Dr Lawrence concedes the approach seems “counter intuitive” and stresses there is still much work to be done to fully understand BAT’s potential. “It’s done on a background of ADT. After each cycle (of high dose testosterone), it’s returning to a very low level. The oscillation between these levels is thought to be important. There are quite a lot of unanswered questions.”

In other words, don’t try this at home. “It’s still experimental, and should only be done in a trial setting ... It’s important this work is done in a rigorous way.”

While some patients see impressive results and relief of side effects, with improved sexual function, in others their tumours have continued to progress. Understanding this variation in responses forms a large part of the research focus. “There’s some indication of particular tumour types that might be most appropriate, with genetic markers that seem to indicate response.”

The other good news is testosterone has several advantages as a potential drug therapy. “It’s an old drug, it’s off patent, it’s been around since the ‘50s and ‘60s. There’s a lot of information around safety.”  And the research to date has been so encouraging there is a growing international research community collaborating on trying to progress BAT from clinical trials to treatment.

“We haven’t done our work in a vacuum,” says Dr Lawrence. “Studies are getting increasingly complex. You can’t do anything without a big team. We have great colleagues in Adelaide, Brisbane, Sydney, the UK, the US, all over. We meet up at conferences, and we enjoy working together. We can’t do everything we would like to do, so we fill in pieces for each other.”

International trials are launching now and being networked in Australia, with recruitment underway. 

The WOMBAT trial combines BAT with the hormone therapy drug Daralutamide for castrate resistant prostate cancer, under study chairs Prof Anthony Joshua and Dr. Megan Crumbaker.

Visit the ANZUP website for more information: https://anzup.org.au/clinical-trial/wombat/

References:

T. Schweizer, E. S. Antonarakis, H. Wang, A. Seun Ajiboye, A. Spitz, H. Cao, J. Luo, M. C. Haffner, S. Yegnasubramanian, M. A. Carducci, M. A. Eisenberger, J. T. Isaacs, S. R. Denmeade, Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: Results from a pilot clinical study. Sci. Transl. Med.7, 269ra2 (2015). DOI: 10.1126/scitranslmed.301056

J. Rollin, M. G. Lawrence, A. M. Joshua, L. A. Selth, Friend or foe? Deciphering androgen receptor action to improve bipolar androgen therapy for prostate cancer. Endocr Relat Cancer (2024). DOI: 10.1530/ERC-24-0208