A recent post in HU-APC discussed a COMBAT-CRPC interview of Dr. Antonarakis by Prostate Cancer Foundation president, Dr. Charles Ryan. I feel this deserves more attention to highlight their important research findings which can help guide clinical use of BAT and to understanding why it is effective.
The State of Bipolar Androgen Therapy in Prostate Cancer - Emmanuel Antonarakis May 2022 ASCO-GU
urotoday.com/video-lectures...
Dr. Antonarakis is discussing the COMBAT-CRPC Trial, in which they gave BAT (Bipolar Androgen Therapy) to men with highly pretreated (advanced) mCRPC during a 3 months intake. Then added immune checkpoint inhibitor nivolumab. Since BAT causes DNA damage and genomic rearrangements, they wanted to see if the nivolumab, as an immune therapy (PD-1 inhibitor) might add to the efficacy of BAT.
Note that this study, like most other BAT trials, used the original 28 day cycles of 400 mg IM Testosterone Cypionate. And continued ADT treatment throughout. Even though the T-cyp will not be eliminated in just 28 days so they never actually become castrate (<50 or <20 ng/dL total T) at any point, even at the end of the cycles.
The TRANSFORMER study (Denmeade et al) previously showed that overall beneficial responses (substantial PSA declines and no progression occurred in about 30% of patients. 50% had neutral response, no great benefit measurable, but no progression. Only 10% showed PSA progression during the first 3 months of cycles and were dropped from continuing it.
In COMBAT the initial PSA responders were even higher, at 40%. In only a few there was evidence of additional benefit when nivolumab was added at 3 months, albeit with additional side effects. Their impression is that the addition of PD-1 inhibitor nivolumab did not make a significant additional benefit.
Perhaps more important is that they were able to further illuminate some of the specific mechanisms related to BAT efficacy. This was through meticu;ous genetic and cellular research on the subjects done in the first 3 months, before nivolumab was added.
1) That it does not appear to reverse ARV-7 (Androgen Receptor Splice Variant 7). And the presence or absence of ARV-7 did not predict responsiveness nor non-responsiveness to BAT. In TRANSFORMER it was shown that the presence of ARV-7 was a marker for worse outcomes with both BAT or with enzalutamide.
2) That BAT reduces the amount of AR in both cytoplasm and nucleus. It apparently reverses the AR amplification that occurs from prior ADT therapy.
3) That it powerfully lowers the oncogene (cancer promoting) MYC mRNA transcript and MYC protein, and that this correlates with a good BAT response. "This oncogene, MYC, is amplified or overexpressed in many castration-resistant prostate cancers, and bipolar androgen therapy really decreases MYC protein and MYC transcript in a big way. The patients who had MYC protein and RNA transcript reductions actually had longer progression-free survival. There seems to be an MYC effect with bipolar androgen therapy."
4) That PC proliferation (replication and growth) goes down as indicated by the marker Ki-67 and this also correlates with a good response." So, three interesting findings from that study: one that AR itself goes down, more so in the responders; that MYC, that the protein and RNA level goes down; and that Ki-67 goes down. And that correlates with the objective responses and the PFS."
5) Those men with HRR mutations BRCA2 and ATM did better with BAT, presumably because they cannot repair the double stranded DNA breaks that BAT can cause. Those with Homologous Recombination Repair deficiencies showed "preferential" improved responses to BAT.
6) And men with p53 mutations also appear to do better with BAT." The BAT paradox. It was that patients with p53 mutations that always portend a worse prognosis to basically all therapies that we have, including chemotherapies as well, actually those men with p53 somatic mutations are more sensitive to BAT. They do better with BAT." The idea is that they don't have effective DNA repair mechanisms to repair the genetic damage to PC cells caused by BAT.
BAT: Bipolar Androgen Therapy: A Paradoxical Approach for the Treatment of CRPC.
BAT: transformer trial
