A treatment paradox has recently come to light in prostate cancer: Blocking testosterone production halts tumor growth in early disease, while elevating the hormone can delay disease progression in patients whose disease has advanced.
The inability to understand how different levels of the same hormone can drive different effects in prostate tumors has been an impediment to the development of new therapeutics that exploit this biology.
Now, a Duke Cancer Institute-led study, performed in the laboratory of Donald McDonnell, Ph.D. and appearing this week in Nature Communications, provides the needed answers to this puzzle.
The researchers found that prostate cancer cells are hardwired with a system that allows them to proliferate when the levels of testosterone are very low. But when hormone levels are elevated to resemble those present in the normal prostate, the cancer cells differentiate.
“For decades, the goal of endocrine therapy in prostate cancer has been to achieve absolute inhibition of androgen receptor function, the protein that senses testosterone levels,” said lead investigator Rachid Safi, Ph.D., research assistant professor in the Department of Pharmacology and Cancer Biology, at Duke University School of Medicine.
“It’s been a highly effective strategy, leading to substantial improvements in overall survival,” he said. “Unfortunately, most patients with advanced, metastatic disease who are treated with drugs to inhibit androgen signaling will progress to an aggressive form of the disease for which there are limited therapeutic options.”
Using a combination of genetic, biochemical, and chemical approaches, the research team defined the mechanisms that enable prostate cancer cells to recognize and respond differently to varying levels of testosterone, the most common androgenic hormone.
It turned out to be rather simple. When androgen levels are low, the androgen receptor is encouraged to “go solo” in the cell. In doing so, it activates the pathways that cause cancer cells to grow and spread. However, as androgens rise, the androgen receptors are forced to “hang out as a couple,” creating a form of the receptor that halts tumor growth.
“Nature has designed a system where low doses of hormones stimulate cancer cell proliferation and high doses cause differentiation and suppress growth, enabling the same hormone to perform diverse functions,” McDonnell said.
In recent years, clinicians have begun treating patients with late-stage, therapy resistant prostate cancers using a monthly, high-dose injection of testosterone in a technique called bi-polar androgen therapy, or BAT. The inability to understand how this intervention works has hindered its widespread adoption as a mainstream therapeutic approach for prostate cancer patients.
“Our study describes how BAT and like approaches work and could help physicians select patients who are most likely to respond to this intervention,” McDonnell said. “We have already developed new drugs that exploit this new mechanism and are bringing these to the clinic for evaluation as prostate cancer therapeutics.”
In addition to McDonnell and Safi, study authors include Suzanne E. Wardell, Paige Watkinson, Xiaodi Qin, Marissa Lee, Sunghee Park, Taylor Krebs, Emma L. Dolan, Adam Blattler, Toshiya Tsuji, Surendra Nayak, Marwa Khater, Celia Fontanillo, Madeline A. Newlin, Megan L. Kirkland, Yingtian Xie, Henry Long, Emma Fink, Sean W. Fanning, Scott Runyon, Myles Brown, Shuichan Xu, Kouros Owzar, and John D. Norris.
The study received funding support from the National Cancer Institute (R01-CA271168, P30CA014236) and the North Carolina Biotechnology Center.
I did read this study some months ago in Nature Comms and gave a commentary on it here. The experiments were in vitro and in animal models and of a very high standard. As the comment above says at lower levels of T, the T receptor remains in the cytoplasm where it promotes proliferation and at higher levels the T receptor dimerises, enters the nucleus where it drives differentiation.
It is not clear whether this mechanism works in the context of different tumour genetic mutations. If not then this might explain why BAT does not work for all in late stage disease.
A key question is whether using a BAT approach at an early stage of PCa would be beneficial.
A parallel question is the role of estradiol (E2) which is synthesised from T in males and to which PCa cells also respond. Both T and E2 are involved in development of the prostate gland during maturation. So, speculating, maybe the ratio of E2 and T may be important (this has been raised in the literature by others.).
To confuse matters further a huge genetic multinational study from Oxford looking at risk factors for PCa showed that although T above a certain level was a predictor there was no dose relationship to level of risk. GLP-1 (glucagon like peptide) was also a predictor with a clear dose relationship ie higher levels = higher risk. The lowest levels of T were associated with increased risk of neuroendocrine tumours which mirrors what we see in patients with late stage PCa with heavily suppressed T.
I think it will be a while before we have any definitive results from human studies of manipulating T levels in earlier disease. But hopefully the message is getting out that the simplistic view that “T is petrol on the fire” needs critical reexamination.
Haven't they studied BAT pretty well and determined it only works in about 30% of people and basically just allows cancer survival to equal about the same as SOC (but at a better quality of life)? Or is this BAT different in that it is recommended for people that have not progressed to metastatic PCa? Not sure I understand what the point here is.
Or maybe they are reinforcing the studies that PCa is more common in low testosterone settings. I know I used to take Androgel and quit and went back to 250-300 T and three years later, boom, i had prostate cancer.
There are highly respected oncologists at some COE who advocate TRT for certain patients who have undetectable PSA for a number of years, with castrate level testosterone following previous ADT therapy. TRT is no longer an absolute taboo with a history of prostate cancer, even limited metastatic disease. This is different from BAT. Enduring years of ADT therapy without testosterone carries significant risk and QOL issues. And there is the question of whether persistent low levels of T over years promotes eventual development of difficult to treat castrate resistant disease. Just a thought.
Regarding supplementation of testosterone there seems to be some hesitation by HCP. Although the evidence is limited, men who are managed expectantly for PCa, or who received radical local therapy, do not have worse outcomes when receiving testosterone supplementation [77]. We therefore advise to not hesitate to give testosterone substitution to symptomatic hypogonadal men with prostate cancer where ADT is not the treatment of choice"
I guess the issue is that I am trying to find a simple answer to a complex issue, but paradoxically, an issue that should have been studied a long time ago. I would have assumed that these are quite basic tenets of research. I am surprised that this too, hasn’t become part of the dogma puzzle.
When I was diagnosed in January 2014, they did not test my T. 1st time in my journey was January 2017 at Mayo prior to the start of triplet therapy after surgery and SRT failed. It was just under 300, low. Does that mean it was below 300 when I was diagnosed? I've read articles about low T and high risk PCa.
Both times I did ADT, my T recovered to levels higher than that, naturally. 600 after triplet therapy and currently over 400...
If the theory that T is pouring gas on the fire is an absolute the. Why after triplet therapy was it is almost five years after the last Lupron shot began to clear my system did my PSA begin to take off, requiring me to go back on treatment? The same this time, eight months after coming off treatment, T is 400+ and yet...
Do my results in the face of high risk PCa provide more data that the paradigm may not be valid for all?
I guess it goes back to my comments on statistics, Bell Curve, standard deviations, mean, mode, averages...
My T is not BAT so there's that.
I guess I would challenge any member of my medical team who had a "simplistic view that “T is petrol on the fire."
It's complex, that's for sure. I hesitate when anyone on my medical team talks in terms of maxims.
The question is not if T is petrol on the fire. The question is whether the absence of T is petrol on the fire on prostate tumors that have “learned” to create their own sources of T. The subsequent question, then, is if it makes sense, in some instances, to accelerate the introduction of testosterone to lower PSA levels. Paradoxically… just wondering if the absence of T doesn’t accelerate the tumors propensity to manufacture its own castrate resistant T
No one really knows. We're kind of on our own. Unfortunately, the medical community up to now has basically taken the position that you can do without testosterone just fine, so shaddap. I do think the tide is turning but of course as TA notes, you can do some damage if you have metastatic cancer and inject T.
I am very happy to have this post clarifying the bi-modal physiology of testosterone (T) and androgen receptors (AR) in prostate cancer. Standard BAT is a rather weak application of bi-modal adaptive testosterone therapies. It uses monthly injections of 400mg T-cypionate which has a seven day half-life. So you get a brief period of supra-physiologic T (>1000 ng/dL) lasting no longer than a week. Then a gradual decrease to low levels, but never reaching castrate (<50). So it is not surprising that the benefits is limited.
A better strategy that I and others are using is maintaining high levels of T (>1000) using weekly doses of T-cypionate (on the order of 250mg weekly) or of T-propionate 75 mg every other day (1 day half-life) or daily testosterone topical. If the cypionate is used it needs 5 weeks to wash-out and approach castrate levels. Then a cycle of ADT (typically one month) is used to "reset" the ARs and related cell signaling pathways and preventing mutational adaptation to high T levels. An "ARSI" drug such as darolutamide or enzalutamide can be added to the ADT to block any residual testosterone. Such regimens have been demonstrated in individuals with both mCRPC and in mHSPC (such as myself).
My regimen is "long-cycle" BAT consisting of 8 weeks of T-cypionate (300mg weekly) then 4 weeks of T-propionate 75mg every other day. Then a 4 week period with Ogovyx and Nubeqa for ADT with AR blockade. This has worked now for over 3 years with complete response (ADT undetectable at <.015). This is not "SOC" and it is not in a clinical trial. I can't wait for that. And it is so easy and inexpensive to test it in oneself. If it should fail one can simply stop it. There is an informal cohort of us who have tried such regimens (or original BAT) in both hormone-sensitive and castrate resistant PCa. MB
That is such a success story. Congrats on persevering. With the caveat we all know, yes, it can come roaring back blah blah blah always the footnote. But that is just a great response for a well thought out regimen
Xavier- Can you explain what you meant by your “roaring back” comment. Did you mean that if BAT or a BAT- like treatment fails, the patient not only faces a rising PSA and cancer growth but an even more aggressive type than of other treatments were chosen instead. In other words, it sounds like there is a serious risk of making one’s status MUCH worse using BAT. Is that the case and is that what you meant?
Based on all my research I always had the theory that a novel approach like this may be potentially more effective than the SOC. I've found it extremely frustrating that the majority of investment in clinical studies of course is just involving new applications/combinations of high-cost/high-profit pharmaceuticals. This leaves PCa patients like yourself to do your own n=1 clinical study of a new treatment strategy.
The obvious facts are that ADT extends the lifespan of PCa patients but also starts a transformation to being castration resistant and onward you go. Factor that in with the significant hit to QOL with ADT and I think the current SOC has oversimplified the treatment strategy to make it easier on doctors to make recommendations while covering their asses, so to speak. It's not an unreasonable approach, making decisions based on SOC which is based on a large body of quality hard evidence.
I kind of thought of a BAT type strategy, even if inferior to SOC, when you factor in QOL effects of ADT, for many, having a higher average QOL over many years might be an even tradeoff for losing a little lifespan is you were to assume the worst in that novel strategies like yours are ultimately inferior to SOC as far as time to Prostate Cancer Specific Mortality. I can tell you one thing, if I was a lot older and closer to the average male lifespan, I'd be much less open to doing long-term ADT.
What are side effects of taking your T super high that constant for that long? I'm also curious what doctor or doctors at which center(s) agreed to go along with this?
I appreciate your post and will have a conversation with my MO regarding this type of treatment as I my ADT (Lupron and Abiraterone) seems to be losing its effectiveness.
When Dx at age 54 in 2012, my PSA was in the mid 40s with a Gleason score of 9 and 4-5 bone Mets. After about 10 yrs on the ADT indicated above (and surgical removal of my prostate along with more than 30 lymph nodes- one of which was “dirty”) my PSA started to become measurable and rose for many months before we added “whack-a-mole”.
We radiated my left hip over 2 yrs ago and will be radiating my L2 vertebrae next week. But, after 12+ yrs of ADT, it looks like I will need a new treatment in the coming months (or longer, if I am fortunate). Not sure what the recommendation will be from my MO but I will have to discuss your treatment with her.
Hi MateoBeach, I have been now on intermitent ADT first Lupron and lately Orgovyx and I am alive and can play tennis, but life is tougher, I has heart surgery on 2020 aortic valve replacement and my heart is starting to take a beating I think low T has something to do with it.
My brain is not superfast, I am 76 now and have these bloody hot spells day and night.
I am on degarelix ADT injections and I am also probably experiencing all of the above what you just said except I don't really recognise that I am experiencing bloody hot spells. Maybe that is just subjective and I simply don't experience it negative like you.
I am fine on ADT and have problems with my teeth. Otherwise I could comfortably live with all of these.
Actually I am not sure if I would be happy and ready to go through all of the emotional and physical roller coaster associated with frequent going up and down with my testosterone. Again I don't really know. Just guessing...
Bipolar Androgen Therapy (BAT) is an emerging treatment strategy for prostate cancer that alternates between very low and high testosterone levels. While it offers some exciting benefits compared to continuous Androgen Deprivation Therapy (ADT), it is not suitable for every patient. Here’s a detailed medical perspective tailored to your situation:
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Key Aspects of BAT
1. Mechanism:
BAT works by cycling testosterone between castration levels (low) and supraphysiological levels (high).
The rationale is twofold:
Cancer Control: Prostate cancer cells adapt to low testosterone over time, but sudden testosterone surges can disrupt their survival mechanisms.
Improved Quality of Life: Testosterone restoration may mitigate many side effects associated with continuous ADT.
2. Current Evidence:
Clinical trials (e.g., the RESTORE study) suggest BAT can:
Stabilize PSA levels in some patients with metastatic castration-resistant prostate cancer (mCRPC).
Resensitize cancer cells to subsequent ADT or novel anti-androgens (like enzalutamide).
BAT has been shown to improve certain quality-of-life metrics, such as mood, energy levels, muscle strength, and cognitive function.
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Benefits of BAT Compared to Continuous ADT
1. Cognitive Improvements:
Cognitive side effects like slower thinking, memory lapses, and difficulty concentrating are commonly linked to the testosterone suppression of ADT.
BAT may alleviate cognitive impairment by restoring normal or high testosterone levels during the "high" phases of therapy.
Testosterone is neuroprotective and influences neurotransmitter balance, which could improve brain function and mental clarity.
2. Mood and Psychological Well-being:
BAT may reduce symptoms of depression, anxiety, and emotional flatness, which are common on continuous ADT.
Patients on BAT often report feeling more energetic and engaged.
3. Physical Improvements:
Testosterone restoration can improve muscle mass, bone density, and overall strength, addressing some of the physical decline caused by ADT.
BAT may also reduce fatigue, a debilitating side effect of continuous ADT.
4. Cancer Sensitization:
In some cases, BAT has been shown to enhance the effectiveness of subsequent treatments by making cancer cells more vulnerable to therapies like enzalutamide or abiraterone.
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Potential Negative Side Effects of BAT
1. Cancer Progression Risk:
BAT is not suitable for all prostate cancer patients, particularly those with rapidly growing or poorly differentiated tumors. High testosterone levels during BAT cycles may potentially stimulate cancer growth in some cases.
Close monitoring of PSA levels and cancer activity through imaging is essential.
2. Emotional and Physical Roller Coaster:
As you mentioned, the cyclic nature of BAT could cause fluctuations in mood, energy, and physical health. Some patients find these changes disruptive.
3. Side Effects of High Testosterone:
Possible side effects during the "high" phases include:
Increased red blood cell counts (polycythemia), which can raise the risk of blood clots.
Acne or oily skin.
Mood swings, including irritability or aggression.
4. Heart Health Risks:
Although testosterone at normal levels is beneficial for cardiovascular health, supraphysiological levels during BAT cycles could pose risks for patients with pre-existing heart conditions (e.g., aortic valve replacement).
5. Uncertain Long-Term Benefits:
While BAT shows promise in clinical trials, its long-term efficacy and safety compared to continuous ADT are still under investigation. Continuous ADT remains the standard of care for many advanced prostate cancer patients.
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Your Specific Case: ADT with Cognitive Side Effects
Given your tolerance for ADT but concerns about cognitive decline, BAT may be worth considering if your oncologist determines you’re a suitable candidate. Here’s why:
1. Cognitive Improvement:
BAT could help address cognitive deficits caused by testosterone deprivation. Restoring testosterone during BAT’s high phases may improve memory, focus, and overall brain function.
2. Cancer Control:
If your prostate cancer is stable and well-managed with continuous ADT, your oncologist may recommend continuing with your current therapy.
However, if your cancer becomes resistant to ADT, BAT may be an option to re-sensitize cancer cells while potentially improving your quality of life.
3. Emotional Readiness:
Your hesitation about the "roller coaster" nature of BAT is valid. Transitioning to BAT requires careful monitoring and may cause temporary instability in mood or energy levels.
4. Heart Health Considerations:
Since you do not report significant cardiovascular issues beyond routine aging-related concerns, BAT could be explored cautiously. However, patients with a history of heart disease or valve replacement (like Rick Martin) require stricter monitoring during BAT.
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Summary: Is BAT Right for You?
Benefits: BAT may help improve cognitive function, mood, energy, and overall quality of life while potentially providing an alternative cancer control strategy if ADT loses effectiveness.
Risks: It introduces variability in testosterone levels, which could cause mood swings or cancer progression in some patients. Regular monitoring is essential.
Suitability: If you’re "fine" on ADT and your cancer remains stable, your current regimen might remain the best choice for now. If cognitive effects worsen or you seek improved quality of life, BAT could be worth exploring in consultation with your oncologist.
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Next Steps
1. Discuss with Your Oncologist:
Share your concerns about cognitive decline and inquire about BAT’s potential benefits and risks in your specific case.
Ask if there are clinical trials or newer therapies that might offer similar cognitive benefits with less risk.
2. Address Cognitive Decline:
Incorporate cognitive exercises, a healthy diet (rich in omega-3s and antioxidants), and regular physical activity.
Consider discussing medications or therapies that might support brain health with your doctor.
3. Monitor Quality of Life:
Keep track of how ADT is affecting your mental, emotional, and physical well-being. A detailed record could help guide future treatment decisions.
4. Stay Informed:
Follow emerging research on BAT and other innovative therapies. As studies progress, new insights may further refine its role in prostate cancer care.
BAT is a promising approach, but its suitability depends on your cancer profile, overall health, and personal preferences. A thoughtful discussion with your oncologist will help determine the best course of action.
You're absolutely correct to question whether Bipolar Androgen Therapy (BAT) might "overpromise" given that it does not consistently extend life in clinical trials. Let’s analyze this concern in detail, considering your current stability on ADT:
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Does BAT Extend Life?
1. Current Evidence on Survival Benefits:
BAT has not demonstrated a clear ability to extend overall survival compared to standard continuous ADT in advanced prostate cancer.
Clinical trials like the RESTORE trial and others have shown BAT may:
Stabilize or delay cancer progression in certain cases.
Enhance the effectiveness of subsequent therapies like enzalutamide or abiraterone.
However, its primary benefits lie in improving quality of life, rather than directly extending lifespan.
2. Survival vs. Quality of Life:
For patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease is progressing on continuous ADT, BAT might be considered as a quality-of-life intervention.
If you are currently stable on ADT and experiencing manageable side effects, there may be no clear survival advantage to switching to BAT.
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Would BAT "Overpromise"?
1. Potential Overpromising:
Quality of Life Benefits: BAT is often marketed as a way to improve energy, cognition, mood, and physical well-being. While this is true for some patients, the improvements can vary significantly.
Some patients report significant relief from ADT side effects.
Others find the "roller coaster" of testosterone fluctuations disruptive and destabilizing.
Cancer Control: While BAT can "shock" resistant cancer cells and delay progression, it is not a guaranteed benefit. For someone whose cancer is already well-managed with ADT, BAT might not offer additional advantages.
2. Your Case: Stability on ADT:
If you're currently "relatively fine" on ADT:
Switching to BAT might not offer enough additional quality-of-life improvements to justify the potential risks and uncertainties.
The cyclical nature of BAT may introduce unnecessary emotional and physical fluctuations for a patient who is already stable and tolerating ADT.
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BAT vs. Staying on ADT: Key Considerations
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Should You Stick With ADT?
Since you’re tolerating ADT well and are stable:
1. BAT May Be Premature:
If your cancer remains well-controlled and your quality of life is acceptable, the added complexity and uncertainty of BAT may not outweigh its potential benefits.
BAT might be more appropriate if:
You develop castration-resistant prostate cancer (CRPC) and your disease progresses on ADT.
Your cognitive or physical symptoms from ADT become unmanageable.
2. Focus on Symptom Management:
For cognitive effects, you might consider:
Cognitive rehabilitation: Brain training exercises, memory aids.
Medications: Certain drugs like modafinil or donepezil have been studied for ADT-related cognitive impairment.
Lifestyle adjustments: Exercise, sleep optimization, and a brain-healthy diet.
These interventions may improve your quality of life without switching to BAT.
3. Reassess Only if Needed:
Revisit BAT if your cancer progresses, or if ADT side effects (like cognitive impairment) worsen significantly and affect your daily life.
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Conclusion
For someone like you who is stable and relatively fine on ADT, BAT may not provide enough added value at this stage to justify the risks or potential disruptions. Its quality-of-life benefits, while promising, are not guaranteed and may feel destabilizing compared to the steady effects of continuous ADT. Unless your cancer becomes resistant or ADT side effects become intolerable, sticking with ADT and focusing on managing its cognitive impacts might be the best course of action for now.
Consulting your oncologist to explore supportive therapies for ADT-related cognitive decline could further improve your quality of life while maintaining your current treatment stability.
I think this paradox has been acknowledged quite a while back and was the justification for some here to try BAT? Although maybe this is just additional confirmative evidence that may fuel a more aggressive BAT strategy or even make it SOC for some?
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Abstract from U of Maryland by Costello & Ferguson
