The panobinostat levels required to impair AR target gene transcription are not clinically tolerable, she noted. Whereas panobinostat alone is ineffective in patients with advanced prostate cancer, and at low doses (20 mg) in combination with bicalutamide, it exhibits antitumor activity in patients with CRPC when combined with bicalutamide at higher doses (40 mg panobinostat).1

That likely has implications for other epigenetic combination regimens, and for strategies for reversing enzalutamide resistance, Dr Ferrari postulated.


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“Enzalutamide is similar to bicalutamide, designed to bind the AR-LBD [ligand-binding domain] and block AR transcription in the setting of bicalutamide resistance,” she said. “Resistance also involves increases in flAR [full-length androgen receptor] mRNA and protein as well as ARSv7 and less frequently, a mutation in the LBD […] Panobinostat alone and in combination with enzalutamide deserves clinical testing.”

Toxicity was managed with dose reductions in 41% of 55 patients enrolled in the phase 2 study, and treatment was halted in 27.5% of patients because of adverse events, including grade 3 or higher thrombocytopenia or fatigue.1

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“Dose reductions were required in 41% [of patients], but these did not lead to the same frequency of interruptions because the grade 3 thrombocytopenia generally resolved within the 1-week off treatment in most cases and were subsequently avoided with dose reductions,” Dr Ferrari said.

“Surprisingly, the toxicity of [panobinostat] at the 40-mg dose level did not reach the maximum tolerated dose in phase 1 among CRPC patients, and in the phase 2 [study], the grade 1 and 2 [toxicities] were more prevalent and the grade 3 or 4 were controlled or avoided with dose reductions. This was essential for long-term tolerance of the treatment and for the clinical benefit of restoring sensitivity to bicalutamide to become apparent in resistant patients. Unfortunately, we did not always implement dose reduction early on to avoid drop-outs for low-grade and manageable toxicity.”

There are several deregulated gene pathways and proteins in CRPC that interact and activate AR function, Dr Ferrari noted. Targeted agents directly affected by HDACi might increase further the efficacy of AR down-regulation, she speculated.

“There are also demethylating agents which affect AR levels and activity,” she added. “In the future, these combined epigenetic approaches might be considered.”

Disclosure: Some of the authors disclosed conflicts from pharmaceutical companies. For a full list of disclosures, please refer to the original study.

Reference

  1. Ferrari AC, Alumkal JJ, Stein MN, et al. Epigenetic therapy with panobinostat combined with bicalutamide rechallenge in castration-resistant prostate cancer [published online September 17, 2018]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-18-1589