Bipolar Androgen Therapy and the Immune SystemPart Three: The Potential of Combination TherapyFebruary 15, 2022 | By JANET FARRAR WORTHIN

[podsart]

Just saw this article —not sure if it has been posted already

[pjoshea13]

You beat me to it.

I just saw it in the latest Prostapedia & was intrigued since I haven't seen anything on the COMBAT trial [1].

Many will recall that Janet Farrar Worthington coauthored Patrick Walsh's books (another Johns Hopkins connection):

"Guide to Surviving Prostate Cancer"

"The Prostate: A Guide for Men and the Women Who Love Them"

There are two earlier parts to Worthington's BAT coverage: [2] & [3]

-Patrick

[1] clinicaltrials.gov/ct2/show...

[podsart in reply to pjoshea13]

Patrick - good to hear from you. Thanks for all the great info and support you continue to provide— my wife and I really appreciate it, as I know, many others do as well

[podsart]

Do you think there’s a benefit possibility to continuous Supra t plus continuous xtandi?

[pjoshea13 in reply to podsart]

For many years I did 3 months of 4mg Androderm patches followed by 3 months of a product that started out as Prostasol (thought to be spiked with DES).

There was a 50% increase in PSA during the final month of T during the final 6 cycles (a PSADT of 2 monrhs?) but I remained castrate-sensitive.

But I was concerned that the cancer would find a work-around. So I tried pure BAT. The 28-day cycle was no good for me. The castrate phase was too short. In fact, Morgentaler has said that one ends the cycle as "near castrate". So I tinkered with it & avoided CRPC so far.

I hate to think that I am somehow a special case. After 18 years & using T in some way for 17 of those, I'm convinced that PCa might be controled for most with some form of BAT if started at diagnosis. i,e, never reaching CRPC.

The sad thing about that is that the Huggins castration therapy, which has been around for as long as I have been alive, will continue for many decades.

-Patrick

[podsart in reply to pjoshea13]

18 years, that’s impressive. I hope the best for you. I was just musing about continuous Supra T simultaneously with some dosage of continuous Xtandi -whether there’s any useful synergy in that continuous combination? Just musing that’s all.

[podsart]

Thanks for the clarification

[kaptank]

I posted on the 3 articles that this is one of.

healthunlocked.com/advanced...

Unfortunately we are not able to link to the 3 articles. They came from the Prostate Cancer Foundation newsletter. If you go there and search BAT they should come up for those who want.

I have copied the text below. I hope that is OK. I think anyone thinking about BAT needs to do some research and these articles are a good start.

"Could More Testosterone Be the Hidden Key to Fighting Prostate Cancer?

Researchers Drive Prostate Cancer “BATty” - Part One: The Concept of BAT

January 24, 2022 | By JANET FARRAR WORTHINGTON

Androgen deprivation therapy (ADT) has been the bedrock of treatment for advanced prostate cancer for more than half a century. But investigators at Johns Hopkins are rethinking it – in a way that sounds counterintuitive – and driving new approaches to tackle treatment resistance. They’re discovering that shaking up prostate cancer with high-dose testosterone makes it more vulnerable to other treatments.

ADT slows prostate cancer’s progress by shutting off testosterone. Eventually, however, cancer adapts to this new environment and PSA levels start to rise; this stage is called castrate-resistant prostate cancer (CRPC). ADT is not a curative treatment, and long-term ADT causes significant side effects, including fatigue, hot flashes, weight gain, and loss of sexual function.

Several years ago, medical oncologist Samuel Denmeade, M.D., Co-Director of the Johns Hopkins Prostate Cancer Program, and colleagues came up with a remarkable concept for attacking prostate cancer: alternating ADT with high-dose testosterone. “It had been known for a long time that something weird happened when you gave testosterone to prostate cancer cells,” says Denmeade. “Yes, with low doses you could get the cancer cells to grow – but plenty of reports said that paradoxically, at high doses the cancer cells don’t grow as well, or they die. Even Charles Huggins, who won the Nobel Prize for discovering hormonal therapy, said in his Nobel acceptance speech that another way to kill cancer would be to give too much hormone. I was always interested in that idea.”

About 10 years ago, Denmeade conducted a small study to test the concept of using testosterone against prostate cancer. “At the time, it seemed like all the data and literature suggested that the dose was really important; it had to be a high dose.” The hypothesis: Prostate cancer cells adjust to a very low-testosterone environment (created by ADT) by making very high levels of the androgen receptor (AR). And here, as he says, “too much of a bad thing can be a good thing.” These high levels of the AR now make cancer vulnerable to very high levels of testosterone. Cancer cells that survive this respond to high-dose testosterone by turning the AR back down – and making the cancer once again susceptible to very low testosterone.

“The idea is to screw up the cancer cell’s ability to adapt.” Denmeade and colleagues coined the term, Bipolar Androgen Therapy (BAT), “to capture these polar extremes of very high and very low. Not just making the testosterone high, but cycling between high and low.” It’s this cycling that seems to be the key to keeping the cancer off-balance, slowing its ability to flourish. In BAT, men experience high testosterone levels that decrease over a 28-day period, then bounce back up with the next testosterone injection.

In that early study, of just a handful of patients, “we were very cautious, because we didn’t want to make the disease worse. We built in all these safety parameters. But we were surprised: it didn’t seem we made anybody worse. It seemed very safe. The patients did very well, and some of them stayed on the testosterone for a year or more. Most of them felt really good. A number of them did not want to come off of it when it seemed they were progressing: they were just so happy to have more energy, and some of them could have sex again.”

Armed with this initial clinical data to show that BAT was safe and to show some response, Denmeade received funding for additional proof-of-concept studies from PCF, among other sources. Larger studies at Johns Hopkins have followed, including RESTORE, TRANSFORMER, and COMBAT. Other trials testing this concept have been completed or are under way at the University of Washington, University of Colorado, and in Australia, Brazil, and the Netherlands.

A trial of BAT has recently opened in the VA system for Veterans with certain types of metastatic CRPC. Please click here for more information about the trial, and talk to your doctor if you think it might be right for you.

Contact information:

[e-mail]

Phone: [phone] x67190

Dr. Bruce Montgomery

[e-mail]

Part2: How BAT Works

Several years ago, medical oncologist Samuel Denmeade, M.D., Co-Director of the Johns Hopkins Prostate Cancer Program, and colleagues came up with a remarkable concept for attacking prostate cancer: alternating ADT with high-dose testosterone.

Patients have asked Denmeade if this treatment, called Bipolar Androgen Therapy (BAT), could be used as initial therapy for metastatic cancer instead of androgen deprivation therapy (ADT), or even as primary therapy instead of prostatectomy or radiation. “No and no,” says Denmeade. “BAT was designed to work against castration-resistant prostate cancer (CRPC).”

In CRPC, the cancer’s environment is significantly different than it is in earlier- stage cancer. As CRPC cells learn to adapt to the lack of testosterone with ADT, “they crank up the androgen receptor (AR) to high levels,” and make themselves comfortable in the new environment. But with high levels of AR, the cancer cells are sitting ducks, vulnerable to the shotgun blast of a hefty dose of testosterone. “Flooding the prostate cancer cell with testosterone gums up the works: suddenly, the cancer cells have to deal with too much androgen (male hormone) bound to the receptor. This disrupts their ability to divide. They either stop growing or die.”

It’s all about creating chaos in the environment, so the cancer cells can’t thrive, and timing is critical. “ADT initially works because prostate cancer cells are suddenly deprived of testosterone, and most of them can’t survive this shock.” Cancer cells die by the thousands, PSA plummets, imaging scans show cancer shrinking, and symptoms improve. But prostate cancer, like the Road Runner, is elusive. Over time, the hardy band of surviving cells regroups, adapts to living in the low-testosterone environment, and begins to grow again. “BAT is a similar type of hormone shock – just in the opposite direction,” says Denmeade. “A key feature of BAT is the rapid change from a very high- to low-testosterone level.” Men remain on ADT, and receive monthly shots of high-dose testosterone, which gradually fades, then bumps back up again with the next monthly shot. That’s the bipolar part of Bipolar Androgen Therapy (see Figure). “The repeated shocks of BAT cycling don’t give the cancer cells time to adapt, “because the underlying environment is always changing.”

Testosterone Levels During BAT

So far, in four clinical trials at Hopkins, Denmeade and colleagues have given BAT to about 350 men with CRPC, most of whom have also received enzalutamide (Xtandi), abiraterone (Zytiga), or both. For men with CRPC whose disease is worsening on ADT or on AR-blocking drugs like enzalutamide or abiraterone, BAT is highly promising. In the recent TRANSFORMER study, “we compared BAT head-to-head with enzalutamide” in patients with CRPC who had progressed on ADT and abiraterone. “It was kind of a weird study, comparing a drug to its exact opposite: an androgen vs. an anti-androgen. I don’t know if anybody’s ever done a study like that. To our amazement, BAT and enzalutamide were nearly identical in terms of their effect.” PSA levels dropped in about 25 percent of men on either treatment, and for both treatments, the response lasted about six months.

However, the real difference between the treatment arms was seen after cross-over – when men on BAT were switched to enzalutamide or vice versa. “If we gave BAT first and then enzalutamide, almost 80 percent responded, and the response lasted almost a year. That’s quite an improvement in the rate of response and duration.” Among patients who received enzalutamide first, followed by BAT, the response rate to enzalutamide was only 23 percent.

This begs the question: Why stop after one round of BAT then enzalutamide? Why not just keep going? “We should be able to cycle back and forth over and over again,” says Denmeade. The STEP-UP trial, of 150 patients at Johns Hopkins and eight other centers nationwide, is looking at just this, “sequencing androgen and anti-androgen. There are two BAT treatment arms: in one, the patients just switch every two months – two months of testosterone, two months of enzalutamide. In the other, the men stay on testosterone until their PSA goes up, and then switch to enzalutamide, and stay on that until their PSA goes up,” then repeat. Cancer response is also monitored by regular CT and bone scans. Patients stop treatment if scans show cancer progression.

The BAT studies thus far have been small, Denmeade says. “We need a big phase 3 study; we’ve just been nipping at the edges.” For now, BAT remains investigational; positive results from larger randomized trials are needed for it to be considered standard of care. While not a cure for advanced prostate cancer, BAT may become an option for extending life and, importantly, improving quality of life.

Note: BAT is not recommended for men with symptomatic bone pain from metastatic prostate cancer, because it can make that pain worse. “This pain increase occurs within hours of testosterone injection, and resolves as testosterone levels in the blood decline over the first cycle of BAT,” says Denmeade. “The worsening pain is not due to rapid growth of prostate cancer, but more likely to testosterone-stimulated release of inflammatory factors.”

Part 3: BAT and immune system, combination treatments

Some men are exceptional responders to Bipolar Androgen Therapy (BAT). Its pioneer, medical oncologist Samuel Denmeade, M.D., Co-Director of the Johns Hopkins Prostate Cancer Program, has a few patients who have remained on BAT alone for several years. But for many men, the response is temporary; just a few months. Why? Could it have something to do with mutated genes? What about the immune system?

“One of the things observed in the lab by our colleague Dr. Sushant Kachhap is that when we give testosterone, the prostate cancer cells get stressed and turn on all these immune factors,” says Denmeade. “Testosterone activates immune pathways.” When three men who had participated in BAT trials later had “dramatic” responses to immunotherapy – 100-percent decreases in PSA, and one man remains in long-term remission – “we thought that might be the secret: androgen plus immunotherapy.”

COMBAT, a small, phase 2 study supported by PCF, co-led by Hopkins investigators Mark Markowski, M.D., Ph.D., and Emmanuel Antonarakis, M.D., (now Director of Genitourinary Oncology at the University of Minnesota) tested the combination of BAT and immunotherapy in 45 men with metastatic castration-resistant prostate cancer (mCRPC). The men were treated with BAT in combination with nivolumab (an immunotherapy agent). “We saw an impressive clinical response rate of 40 percent,” says Markowski. “We also observed a durable benefit, lasting over a year, in a few patients who had received extensive prior therapies.” The results suggested that BAT alone has significant efficacy, while nivolumab improves responses in some patients. The combination of BAT with nivolumab was safe and well tolerated by the participants. Markowski and Antonarakis are designing a randomized Phase 3 study to compare combined BAT plus nivolumab versus standard treatments for patients with mCRPC.

In the COMBAT trial, “we treated a group of incredible men who agreed to have tumor biopsies before and after three cycles of BAT,” says Denmeade. “We are studying the heck out of these biopsies,” looking for specific biomarkers or gene mutations that might help predict who will have the deepest and longest-lasting responses. The team is also performing additional studies of the interactions between BAT and the immune system to discover how this treatment can be improved. "

[podsart in reply to kaptank]

Thanks

[Mount_Rainier in reply to kaptank]

Thank you!

[Okay4now]

Thanks - very encouraging !!