Intermittent androgen deprivation therapy in patients with prostate cancer: Connecting the dots

Abstract

Intermittent androgen deprivation therapy (IADT) is now being increasingly opted by the treating physicians and patients with prostate cancer. The most common reason driving this is the availability of an off-treatment period to the patients that provides some relief from treatment-related side-effects, and reduced treatment costs. IADT may also delay the progression to castration-resistant prostate cancer. However, the use of IADT in the setting of prostate cancer has not been strongly substantiated by data from clinical trials. Multiple factors seem to contribute towards this inadequacy of supportive data for the use of IADT in patients with prostate cancer, e.g., population characteristics (both demographic and clinical), study design, treatment regimen, on- and off-treatment criteria, duration of active treatment, endpoints, and analysis. The present review article focuses on seven clinical trials that evaluated the efficacy of IADT vs. continuous androgen deprivation therapy for the treatment of prostate cancer. The results from these clinical trials have been discussed in light of the factors that may impact the treatment outcomes, especially the disease (tumor) burden. Based on evidence, potential candidate population for IADT has been suggested along with recommendations for the use of IADT in patients with prostate cancer.

hASH1 nuclear localization persists in neuroendocrine transdifferentiated prostate cancer cells, even upon reintroduction of androgen

“…iADT is thought to be beneficial 6,38 , possibly delaying delay prostate adenocarcinoma progression to CRPC by restoring apoptotic potential and sensitivity to treatment 39 . Whether iADT causes NE-like cells in the tumour to revert to adenocarcinoma, is unknown.…”

Chromatin reprogramming as adaptation mechanism in advanced prostate cancer

“…In this context, in PC, the epigenetic "fluidity" and tendency of the chromatin to be in relaxed structure could be a liability if targeted intermittently to prolong the duration of the effect and delay the emergence of resistance. This epigenetic "fluidity" can potentially explain the positive results demonstrated by the use of bipolar androgen therapy (BAT) (Teply and Antonarakis 2016;Teply, et al 2018), intermittent androgen deprivation therapy (Abrahamsson 2017;Hussain, et al 2016), and, with due precautions, also supra-physiological androgen therapy (Mohammad, et al 2017).…”

Resistance to Antiandrogens in Prostate Cancer: Is It Inevitable, Intrinsic or Induced?

“…Therefore, does the strategy of generating new ADT agents and a focus on the sequencing of the various blockades of the AR signaling pathway offer patients the best chance of long-term treatment? The cycling of ADT [ 15 , 175 ], and/or the perhaps anti-intuitive approach of overstimulation of the AR pathway [ 176 , 177 ], offer a remission but, nevertheless, temporary survival advantages. Application of ADT does offer an opportunity for more curative combinations of treatment, however.…”

“…Combination treatments, and various total androgen blockades—both constant and intermittent [ 14 ]—have all been tested in clinical trials. However, the cancer returns despite apparent increased survival in intermittently treated populations [ 15 ], a therapeutic strategy that is probably underused. If the tumor cells are indeed dependent on androgens, even in CRPC [ 16 ], then why a cocktail of inhibitors of androgen signaling does not inevitably result in increased remission or even a cure is unclear.…”