“Bipolar Androgen Therapy for Prostate Cancer

Androgen Therapy for Prostate Cancer" (Emmanuel Antonarakis) [#56] androgen-directed therapies, genetically-targeted therapies, and immunotherapies for men with recurrent or advanced prostate cancer, and using germline and tumor genomics to inform precision oncology approaches for these patients.

He also has an interest in liquid biomarker development, including the clinical validation of the AR-V7 marker as well as DNA repair markers and their therapeutic implications. How is bipolar androgen therapy administered?

Bipolar androgen therapy (BAT) consists of cycling testosterone (a male hormone in the class of androgens, responsible for many normal functions, including growth and development of the genitals, muscles, and bones) levels from supraphysiological (greater than normally present in the body, >1500 ng/dl) to low (<150 ng/dl).

It can be accomplished by injecting 400 mg of testosterone cypionate once a month. There is no reason that testosterone propionate could not be used instead of testosterone cypionate. We do not know if administering testosterone once every four weeks is optimum. Six weeks might be better as it allows cypionate to decay to a lower value.

Some variations on BAT that have been considered include combining it with an immune checkpoint blockade.

In the COMBAT trial, BAT was combined with an immune checkpoint blockade (nivolumab) and the PSA50 response rate (a decrease > 50% compared to baseline) was 40%, and the RECIST (Response Evaluation Criteria in Solid Tumors, the percentage of patients whose cancer shrank or disappeared after treatment) rate was 24%.

The use of darolutamide interleaved with BAT might reduce the potential for future use of darolutamide monotherapy. The ExBAT clinical trial is using darolutamide interleaved with BAT. BAT has been used with etoposide. This combination should work well. However, it was found that etoposide therapy has many side effects and the benefit was deemed to be less than the harm.

How do people typically respond to bipolar androgen therapy? Responses are roughly divided into thirds: one third will see a marked improvement in their PSA and a reduction in cancer, one third will see a PSA plateau (no progression = a benefit), and one third will see an increase in PSA and in cancer growth. PSA is a rough marker.

Scans and genetic tests should be performed to monitor therapeutic action. Sometimes PSA will increase but cancer scans show no growth or even regression. Along those lines, sometimes increased bone metastasis activity appears to occur for about 2-3 months before drastic reductions in activity are seen. It is reasonable to have a liquid biopsy prior to starting BAT and once in a while during BAT.

However, PSA, scans, and clinical symptoms are preferred. If PSA increases for 1-2 cycles, do not panic. PSA often increases before it starts going down. Sometimes PSA decreases yet scans get worse for a few months.

opsy prior to starting BAT and once in a while during BAT. However, PSA, scans, and clinical symptoms are preferred. If PSA increases for 1-2 cycles, do not panic. PSA often increases before it starts going down. Sometimes PSA decreases yet scans get worse for a few months. What makes decisions difficult is sometimes PSA increases AND scans progress for a few months prior to receding.

“Bipolar Androgen Therapy for Prostate Cancer" (Emmanuel Antonarakis) [#56] AR panels (10, 20, 50 genes) in RNA signature analysis can be used to determine AR activity. Pain, especially bone pain, can occur, usually from inflammation. You can use 600-800 mg of Ibuprofen, Motrin, or another NSAID to control it. Besides reducing cancer, what are the other benefits of bipolar androgen therapy?

BAT can substantially down-regulate androgen receptors (ARs) and despite this can continue to work. Someone who has become castrate resistant (not responding to androgen deprivation drugs, like Lupron or abiraterone) can become hormone sensitive again (will respond). BAT can improve the effectiveness of some drugs.

For example, in the TRANSFORMER study, 78% of men had a response to Xtandi if BAT was performed first, triple the conventional rate. In addition to controlling the disease as well as many therapies, quality of life is usually markedly improved, particularly libido and energy. When should you consider getting bipolar androgen therapy?

The ideal time to get BAT is when you start to show that you are becoming castrate resistant, i.e., when your PSA (prostate specific antigen, a biomarker of prostate cancer activity) rises indicating you are not responding to your androgen deprivation therapy. How can you predict if you might get a good response from bipolar androgen therapy?

Paradoxically, the markers for BAT response are the same markers that usually signal an aggressive cancer. The following genetic mutations have been displayed by extreme BAT responders: ●BRCA2 ●TP53 ●TP53/BRCA2 ●TP53/ BARD1 ●BRCA2/ATM ●ARID1A ●ATM/RB1 ●CDK12 has some response. ●Men with HRR mutations had a 68% PSA response rate (any PSA reduction).

Men without an HRR mutation had a 37% PSA response rate. ●Men with tumor suppressor loss (TP53/PTEN, PTEN/RB1, TP53/RB1) exhibited a 54% PSA response rate. Contraindications (don’t consider BAT if you have): ●Symptomatic bone pain. You could make the pain worse.

“Bipolar Androgen Therapy for Prostate Cancer" (Emmanuel Antonarakis) [#56] ●Bone mets that are close to the spine or are threatening a fracture. You could wind up with spinal cord compression or a fracture. ●If the prostate gland is bulky or a pelvic lymph node is close to obstructing your urinary tract, you could develop a renal obstruction or possibly even kidney failure.

BAT does not seem to work well if you have AR-V7 splice variant but in general the higher the AR activity the better for BAT. Proteomics has not been explored in relation to BAT response prediction.

tructing your urinary tract, you could develop a renal obstruction or possibly even kidney failure. BAT does not seem to work well if you have AR-V7 splice variant but in general the higher the AR activity the better for BAT. Proteomics has not been explored in relation to BAT response prediction. However, it is possible that if you have higher AR activity or HR mutation (e.g.

BRCA2) you might have a higher likelihood of responding to BAT. What if you are still responding to androgen deprivation therapy? According to the standard of care, BAT is not recommended if you are still responding to androgen deprivation therapy. However, some men try BAT anyway.

Men with hormone- sensitive prostate cancer who have PSA/cancer regression from BAT therapy should publicize their results in conjunction with their medical oncologists.

The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action.

You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health.

“Bipolar Androgen Therapy for Prostate Cancer" (Emmanuel Antonarakis) [#56] Meeting Notes The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action.

You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health. SUMMARY KEYWORDS patients, psa, mutation, response, testosterone, study, question, cancer, bat, called, therapy, high, responding, proteomic, lupron, showed, ar, weeks, bipolar, heterogeneity SPEAKERS Dr.

Antonarakis (42:36), Russ Hollyer (5:14), Brian McCloskey (1:46), Robert Ellis (1:43), Ken Anderson (1:42), Amit Gattani (0:49), Robert Gurmankin (0:27), Mike Yancey (0:23), Brad Power (0:17) Session Outline 1.Dr. Antonarakis’s background. (0:00) 2.Dr. Sam Denmead’s background. (1:02) 3.Lhrh and PSA graph. (6:22) 4.What are the different types of responses and frequency of responses? (10:42) 5.

What do people prefer? BAT or Abiraterone? (17:03) 6.Technical slide on p53 mutations. (22:48) 7.Cypionate vs. Propionate for the treatment of prostate cancer. (29:17) 8.PSA and cancer. (34:19) 9.The ideal time to start treatment with CDK12. (39:40) 10.How to screen for heterogeneity? (43:56) 11.Germline genetic testing for testosterone. (49:06) Russ Hollyer 0:00 Dr.