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Bipolar Androgen Therapy Prostate Cancer

Hormone Therapy For Prostate Cancer

Bipolar Androgen Therapy (BAT)- Sam Denmeade MD, Prostate cancer treatment with testosterone bursts

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Hormone therapy is also called androgen suppression therapy. The goal is to reduce levels of male hormones, called androgens, in the body, or to stop them from fueling prostate cancer cells.

Androgens stimulate prostate cancer cells to grow. The main androgens in the body are testosterone and dihydrotestosterone . Most androgen is made by the testicles, but the adrenal glands as well as the prostate cancer itself, can also make a fair amount. Lowering androgen levels or stopping them from getting into prostate cancer cells often makes prostate cancers shrink or grow more slowly for a time. But hormone therapy alone does not cure prostate cancer.

Bipolar Androgen Therapy For Men With Metastatic Castration

BJU International

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  • Resensitization Of Prostate Cancer With Bipolar Androgen Therapy

    Bipolar androgen therapy may be more effective at resensitizing metastatic castration-resistant prostate cancer to direct androgen receptor antagonists than abiraterone. This mode of therapy consists of driving testosterone levels to the supraphysiologic range, followed by a return to near-castrate levels of 28-day treatment cycles. In addition, the presence of AR-V7 seemed to predict a worse outcome with BAT and rechallenge with enzalutamide or abiraterone. These findings were presented during the ASCO20 Virtual Scientific Program by , of Johns Hopkins University, Baltimore .

    The study enrolled 59 patients with prostate cancer whose last therapy was either abiraterone or enzalutamide . Patients received at least one dose of 400mg BAT intramuscularly every 28 days. After clinical or radiographic progression on BAT, patients were re-challenged with the androgen receptor targeted therapy to which they were most recently resistant.

    Of the patients who were previously on abiraterone, 5 achieved a 50% decline in prostate specific antigen from baseline after BAT. In addition, 9 patients in the enzalutamide group achieved a 50% reduction in PSA. The objective response rate for the abiraterone group was 28.6% and was 50% in the enzalutamide group.

    Disclosure: For full authors disclosures, visit coi.asco.org.

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    Treatment To Lower Androgen Levels From The Adrenal Glands

    LHRH agonists and antagonists can stop the testicles from making androgens, but cells in other parts of the body, such as the adrenal glands, and prostate cancer cells themselves, can still make male hormones, which can fuel cancer growth. Drugs are available that block the formation of androgens made by these cells.

    Abiraterone blocks an enzyme called CYP17, which helps stop these cells from making androgens.

    Abiraterone can be used in men with advanced prostate cancer that is either:

    • High risk
    • Castrate-resistant

    This drug is taken as pills every day. It doesnt stop the testicles from making testosterone, so men who havent had an orchiectomy need to continue treatment with an LHRH agonist or antagonist. Because abiraterone also lowers the level of some other hormones in the body, prednisone needs to be taken during treatment as well to avoid certain side effects.

    Ketoconazole , first used for treating fungal infections, also blocks production of androgens made in the adrenal glands, much like abiraterone. It’s most often used to treat men just diagnosed with advanced prostate cancer who have a lot of cancer in the body, as it offers a quick way to lower testosterone levels. It can also be tried if other forms of hormone therapy are no longer working.

    Ketoconazole also can block the production of cortisol, an important steroid hormone in the body, so men treated with this drug often need to take a corticosteroid .

    Suo 201: Bipolar Androgen Therapy For Men With Castration Resistant Prostate Cancer

    Bipolar Androgen Therapy for Prostate Cancer Shows Promise

    Washington, DC As part of the SUO 2019 advanced prostate cancer session, Dr. Samuel Denmeade discussed his work with bipolar androgen therapy for men with castration resistant prostate cancer . Dr. Denmeade reminds us that metastatic prostate cancer remains an incurable disease, with a median overall survival in the CRPC state of three years. The mainstay of treatment is androgen deprivation therapy , however it is associated with many side effects:

    • Depression
    • Fatigue
    • Lack of focus

    One of the main challenges of treating advanced prostate cancer is the development of resistance with each subsequent line of therapy. For example, enzalutamide in PREVAIL had a PSA progression-free survival of only 11.2 months. According to Dr. Denmeade, there are three phases of androgen inhibition: shock, adaptation, and resistance. The shock phase is when there is androgen receptor activity inhibition, which is followed by adaptation, namely androgen receptor overexpression, gene amplification, and development of ligand-independent androgen receptor variants.

    The hypothesis for BAT is that men with CRPC could respond to rapid cycling between polar extremes of supraphysiologic and castrate testosterone levels, whereby rapid cycling disrupts adaptive autoregulation of the androgen receptor. Adaptive downregulation of the androgen receptor expression may re-sensitize CRPC to androgen ablative therapies. Schematically, BAT is as follows:

    Dr. Denmeade concluded with several take home points:

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    Intermittent Versus Continuous Hormone Therapy

    Most prostate cancers treated with hormone therapy become resistant to this treatment over a period of months or years. Some doctors believe that constant androgen suppression might not be needed, so they advise intermittent treatment. The hope is that giving men a break from androgen suppression will also give them a break from side effects like decreased energy, sexual problems, and hot flashes.

    In one form of intermittent hormone therapy, treatment is stopped once the PSA drops to a very low level. If the PSA level begins to rise, the drugs are started again. Another form of intermittent therapy uses hormone therapy for fixed periods of time for example, 6 months on followed by 6 months off.

    At this time, it isnt clear how this approach compares to continuous hormone therapy. Some studies have found that continuous therapy might help men live longer, but other studies have not found such a difference.

    Improving Quality Of Life

    Hormone-suppressing therapies for prostate cancer carry a host of unpleasant and sometimes dangerous side effects. But the bipolar testosterone treatment had positive effects, especially given that the men in the trial had been on castrating therapies for years, Schweizer said.

    The researchers didnât conduct formal surveys on the menâs quality of life, but anecdotally, âthe men who get these therapies really feel wonderful,â Schweizer said. âThey were able to have sex again with their wives in some instances, energy levels went up they lost weight, gained some muscle back.â

    The participantsâ temporary relief from the long-term effects of their past treatment was a boon for Schweizer too. He normally doesnât get to test drugs with such pleasant associations.

    âA lot of the drugs that we test in oncology have a lot of adverse effects ⦠but this was definitely not one of those studies,â he said. âRight now we donât think we can cure metastatic prostate cancer, so if youâre talking about trying to alleviate suffering, I think maximizing the quality of someoneâs life is really important.â

    Solid tumors, such as those of the prostate, are the focus of Solid Tumor Translational Research, a network comprised of Fred Hutchinson Cancer Research Center, UW Medicine and Seattle Cancer Care Alliance. STTR is bridging laboratory sciences and patient care to provide the most precise treatment options for patients with solid tumor cancers.

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    Bipolar Androgen Therapy Effective In Metastatic Castration

    Bipolar androgen therapy resulted in similar progression-free survival and reduction in prostate-specific antigen compared with enzalutamide among men with metastatic castration-resistant prostate cancer , according to the results of a phase 2 trial published in the Journal of Clinical Oncology.1

    The TRANSFORMER trial is unique in that it compares two treatments with diametrically opposite effects on the androgen receptor therapeutic target, the authors wrote.

    Androgen deprivation therapy is the standard of care for prostate cancer but can result in treatment resistance due to adaptive upregulation of the androgen receptor. BAT aims to address this by rapidly cycling the patient from high to low serum testosterone.

    The phase 2 TRANSFORMER study randomly assigned 195 patients with asymptomatic metastatic CRPC to receive monthly BAT as testosterone cypionate or enzalutamide. The primary endpoint was PFS and secondary endpoints included overall survival , PSA, and safety. Crossover was allowed at progression.

    At baseline, the median age was 71 87% of patients were White, 7% were Black or African American, 3% were Asian, 1% were American Indian, and 3% were of other race. The majority of patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. Most patients had a Gleason score of 7, 8, or 9-10. The mean baseline PSA was 47.45.

    In subgroup analyses, both PFS and OS favored BAT among men with a short response to abiraterone.

    Reference

    ‘bipolar’ Therapy: Treating Advanced Prostate Cancer With High

    Lutetium-177 and Bipolar Androgen Therapy: Future Game Changers In Prostate Cancer | PCRI

    Scientists have long understood that testosterone fuels prostate tumors, a discovery that prompted the development of hormone-blocking âcastrationâ treatments for prostate cancer that delay the cancerâs growth in many men.

    But a new study shows that a certain type of prostate cancer, after months or years of testosterone deprivation, can develop a lethal sensitivity to testosterone in a new treatment approach â âbipolar androgen therapyâ â which combines high-dose testosterone with androgen-blocking therapy.

    Drugs that suppress natural production of testosterone can extend survival for men with prostate cancer, but eventually they stop working as the cancer becomes resistant to treatment. Known as castration-resistant prostate cancer, this advanced disease is the most lethal form, said Dr. Michael Schweizer, a clinical researcher at Fred Hutchinson Cancer Research Center.

    Although men with early-stage prostate cancer can survive for many years with slow-growing tumors, if they live long enough, all men with prostate cancer will eventually develop this lethal form.

    âThereâs really a need for new drugs to treat these men,â Schweizer said.

    Fourteen of the 16 men completed the therapy, and many of those showed signs that their disease was waning. Some menâs tumors even appeared to become newly sensitized to those same castrating drugs that had previously stopped working.

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    Serial Bipolar Androgen Therapy Using Cyclic Supraphysiologic Testosterone To Treat Metastatic Castration

    John T. Isaacs1,2, W. Nathaniel Brennen1,2, Samuel R. Denmeade1,2

    1Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and The Brady Urologic Institute , The Johns Hopkins University School of Medicine , , USA

    Correspondence to:

    Provenance: This is an invited article commissioned by the Section Editor, Dr. Peng Zhang, MD, PhD .

    Submitted Sep 21, 2019. Accepted for publication Oct 04, 2019.

    doi: 10.21037/atm.2019.10.32

    Figure 1vsFigure 2

    Bipolar Androgen Therapy Vs Enzalutamide In Asymptomatic Patients With Metastatic Castration

    3/31/2021 3:32:08 PM

    In the phase II TRANSFORMER trial reported in the Journal of Clinical Oncology, Denmeade et al found no difference in progression-free survival with bipolar androgen therapydefined as rapid cycling between high and low serum testosteronevs enzalutamide in men with metastatic castration-resistant prostate cancer whose disease progressed after treatment with abiraterone. Results among patients crossing over to the alternative treatment indicated that bipolar androgen therapy may sensitize castration-resistant prostate cancer to subsequent antiandrogen therapy.

    In the U.S. multicenter trial, 195 men were randomly assigned between April 2015 and April 2018 to receive bipolar androgen therapy with testosterone cypionate at 400 mg intramuscularly once every 28 days or enzalutamide at 160 mg daily . Patients were permitted to cross over to the alternative treatment upon disease progression. The primary endpoint was clinical or radiographic progression-free survival.

    Progression-Free Survival

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    Bipolar Androgen Therapy For Patients Who Have Progressed On Abiraterone

    February 26, 2021 | Media Relations

    Led by Dr. Samuel R. Denmeade and his team at Johns Hopkins School of Medicine Sidney Kimmel Comprehensive Cancer Center, the PCCTCs TRANSFORMER Trial ) is the first randomized study to assess high-dose testosterone as a treatment for metastatic castration-resistant prostate cancer . Results published in the Journal of Clinical Oncology give evidence that bipolar androgen therapy rapid cycling between high and low serum testosteronesignificantly disrupts adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. Critically, the study produced potentially practice-changing outcome data suggesting BAT efficacy is at least as good as enzalutamide as the treatment of choice for men with mCRPC progressing on abiraterone, with lower toxicity and higher quality of life.

    While no advantage was observed between arms in the primary endpoint of clinical or radiographic PFSmedian PFS at crossover, 50% PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% to BAT and the PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT. Moreover, OS was 37.1 months for patients crossing from BAT to enzalutamide versus 30.2 months for the opposite sequence . Patient-reported QoL also consistently favored BAT.

    Early Versus Delayed Treatment

    Bipolar Androgen Therapy for Prostate Cancer Shows Promise

    For men who need hormone therapy, such as men whose PSA levels are rising after surgery or radiation or men with advanced prostate cancer who dont yet have symptoms, its not always clear when it is best to start hormone treatment. Some doctors think that hormone therapy works better if its started as soon as possible, even if a man feels well and is not having any symptoms. Some studies have shown that hormone treatment may slow the disease down and perhaps even help men live longer.

    But not all doctors agree with this approach. Some are waiting for more evidence of benefit. They feel that because of the side effects of hormone therapy and the chance that the cancer could become resistant to therapy sooner, treatment shouldnt be started until a man has symptoms from the cancer. This issue is being studied.

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    About Dr Dan Sperling

    Dan Sperling, MD, DABR, is a board certified radiologist who is globally recognized as a leader in multiparametric MRI for the detection and diagnosis of a range of disease conditions. As Medical Director of the Sperling Prostate Center, Sperling Medical Group and Sperling Neurosurgery Associates, he and his team are on the leading edge of significant change in medical practice. He is the co-author of the new patient book Redefining Prostate Cancer, and is a contributing author on over 25 published studies. For more information, contact the Sperling Prostate Center.

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    Bipolar Androgen Therapy In Prostate Cancer

    Critical Reviews in Oncology/Hematology

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  • Don’t Miss: What’s The Survival Rate For Prostate Cancer

    Dont Keep The Doctors Guessing

    However, the last thing we want is to also keep the doctors guessing. How can they know if this new treatment is working or not, and for which patients? The medical researchers who are testing BAT need to find out as soon as possible if mPCa is progressing so they can shift gears to another therapy. A multidisciplinary group out of Johns Hopkins and Brazils Hospital Moinhos de Vento explored the utility of an imaging isotope used as a radiotracer in PET/CT scans to identify early progression. This kind of imaging highlights cancer cells even in very small concentrations because it targets a cellular molecule called PSMA that is highly expressed by PCa. Specifically, they put 18F-DCFPyL PET/CT to the test to detect clinical response in six mPCa patients on BAT:

    Three of 6 patients had progression on 18F-DCFPyL PET/CT. Radiographic progression on CT or bone scanning was observed within 3 mo of progression on 18F-DCFPyL PET/CT. For the 3 patients who did not have progression on 18F-DCFPyL PET/CT, radiographic progression was not observed for at least 6 mo.

    Although the study was small, its very promising, since conventional imaging missed progression in the three men who were revealed to have progression by 18F-DCFPyL PET/CT. A news story summed up the significance of this discovery, The finding may fill a need for a new imaging strategy to determine whether patients will respond to bipolar androgen therapy, according to the authors, who pioneered the strategy.

    When Is Hormone Therapy Used

    The TRANSFORMER Study: Bipolar Androgen Therapy vs. Enzalutamide in Asymptomatic Men With mCRPC

    Hormone therapy may be used:

    • If the cancer has spread too far to be cured by surgery or radiation, or if you cant have these treatments for some other reason
    • If the cancer remains or comes back after treatment with surgery or radiation therapy
    • Along with radiation therapy as the initial treatment, if you are at higher risk of the cancer coming back after treatment
    • Before radiation to try to shrink the cancer to make treatment more effective

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