Abiraterone (Zytiga, Johnson & Johnson), in a recent small study, showed promise in eliminating prostate tumors in some men with high risk prostate cancer. Zytiga, which won approval last year for treatment of metastatic prostate cancer after taxotere chemotherapy failure , has a novel mechanism of action. Abiraterone acetate (AA, above molecule) inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1), an enzyme important in the intracellular metabolism of testosterone and DHEA. Several common genetic polymorphisms in the general population exist with this enzyme, which may have impact on individual enzymatic regulation and activity to AA. Castration-resistant prostate cancer cells, starved of extracellular testosterone and adrenal androgens by antiandrogens and LHRH agonists, may be able to generate intracellular testosterone to evade treatment, and this mechanism is what abiraterone targets. Early clinical work with showed reductions in PSA in >50% of patients treated as well as radiographic responses.
The study by Dr Taplin et al (abstract 4521 publiched in the Journal of Clinical Oncology (30)) which will be reviewed at the upcoming 2012 ASCO meeting, demonstrated a significant anti-tumor effect of the “aggressive”combination with neoadjuvant AA +Lupron + prednisone(5mg) for men with localized high-risk prostate cancer. The men in the 6-month treatment arm did better that the 3-month group, with over 30% of men in the former group having minimal prostate cancer left in their prostate cancer specimens after surgery. Ten percent (10%) had a pathologic pT0 response, where no tumor was seen, which is important. This to me is the most interesting facet of the combination therapy, as more than 25% of high risk patients with presumed localized disease will develop metastatic disease in a 10 year time frame – these patients need more help than traditional multimodal therapy (surgery then radiation then hormone therapy). Grade 3 side effects relevant were hyperkalemia (5%) and elevated LFT’s (9%). My review of the abstract does not show the 3 month biopsy results to look at intracellular DHT. This omission may be relevant, as demonstration that abiraterone hits its intracellular “target” is important from a basic science standpoint, and that it truly is additive versus LHRH agonist only.
This neoadjuvant paradigm is commonly used in other diseases, including colorectal and gynecological malignancies, with improved survival and resectability noted. Prior studies using hormone therapy before surgical treatment in advanced localized prostate cancer showed reduced positive margins, but no improvement in biochemical-free survival. The addition of Zytiga to traditional hormone therapy , ie, “aggressive hormonal therapy” may hold relevance in treating men with advanced localized disease (neoadjuvant), early on in the biochemical recurrence if it gives pT0 responses, or in combination with radiation therapy. Expedited development of this approach in high risk prostate cancer is warranted if review and scrutiny of this small study is favorable.
I look forward to reviewing the data and hearing what the thought leaders have to say.
This abstract is available for review at the ASCO.org website: http://abstract.asco.org/AbstView_114_98106.html