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Epigenetic Therapy with Panobinostat Combined with Bicalutamide Rechallenge in Castration- Resistant Prostate Cancer Anna C

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Epigenetic Therapy with Panobinostat Combined with Bicalutamide Rechallenge in Castration- Resistant Prostate Cancer Anna C Published OnlineFirst January 3, 2019; DOI: 10.1158/1078-0432.CCR-18-1589 Clinical Trials: Targeted Therapy Clinical Cancer Research Epigenetic Therapy with Panobinostat Combined with Bicalutamide Rechallenge in Castration- Resistant Prostate Cancer Anna C. Ferrari1, Joshi J. Alumkal2, Mark N. Stein3, Mary-Ellen Taplin4, James Babb5, Ethan S. Barnett6, Alejandro Gomez-Pinillos5, Xiaomei Liu5, Dirk Moore6, Robert DiPaola7, and Tomasz M. Beer2 Abstract Purpose: This study assesses the action of panobino- Results: In the model, panobinostat/bicalutamide demon- stat, a histone deacetylase inhibitor (HDACI), in restor- strated synergistic antitumor effect while reducing AR activity. ing sensitivity to bicalutamide in a castration-resistant The dose-limiting toxicity was not reached. The probabilities of prostate cancer (CRPC) model and the efficacy and safety remaining rPF were 47.5% in the A arm and 38.5% in the B arm, of the panobinostat/bicalutamide combination in CRPC exceeding the protocol-specified threshold of 35%. The A arm patients resistant to second-line antiandrogen therapy but not the B arm exceeded expectations for times (medians) to (2ndLAARx). rP (33.9 and 10 weeks), and from PSA progression to rP (24 and Patients and Methods: The CWR22PC xenograft and 5.9 weeks). A arm/B arm events included: adverse events (AE), isogenic cell line were tested for drug interactions on 62%/19%; treatment stopped for AEs, 27.5%/11.5%; dose tumor cell growth and on the androgen receptor (AR), reduction required, 41%/4%. The principal A-arm grade 3 AR-splice variant7, and AR targets. A phase I trial had a AEs were thrombocytopenia (31%) and fatigue (14%). 3 Â 3 panobinostat dose-escalation design. The phase II Conclusions: The 40 mg panobinostat/bicalutamide study randomized 55 patients to panobinostat 40 mg regimen increased rPF survival in CRPC patients resist- (A arm) or 20 mg (B arm) triweekly Â2 weeks with ant to 2ndLAARx. Panobinostat toxicity was tolerable bicalutamide 50 mg/day in 3-week cycles. The primary with dose reductions. Epigenetic HDACI therapy reduces endpoint was to determine the percentage of radiographic AR-mediated resistance to bicalutamide in CRPC models progression-free (rPF) patients at 36 weeks versus historic with clinical benefit in patients. The combination merits high-dose bicalutamide. validation using a second-generation antiandrogen. Introduction (bicalutamide, flutamide, and nilutamide) or the adrenal androgen synthesis blocker ketoconazole, and the median The lineage dependence of prostate cancer on the androgen time to secondary progression was 6 to 8 months (4, 5). receptor (AR) pathway (1, 2) accounts for the therapeutic "Re-challenge" treatment with the same or an alternative anti- efficacy of castration (3) and for the response to antiandrogen androgen after progression on the first second-line antiandro- therapy after the development of castration resistance. How- gen treatment (2ndLAARx) yielded fewer responses and pro- ever, only a fraction of castration-resistant prostate cancer gressively shorter times to succeeding progression (5, 6). (CRPC) patients responded to first-generation antiandrogens Although, second-generation antiandrogens (enzalutamide and apalutamide) or the adrenal androgen synthesis blocker 1Icahn School of Medicine Mount Sinai, New York, New York. 2OHSU Knight abiraterone acetate (7–10) significantly delays progression and 3 Cancer Institute, Portland, Oregon. Columbia University Medical Center, increases overall survival, resistance inevitably follows, and the New York, New York. 4Dana-Farber Cancer Institute, Boston, Massachusetts. response to taxanes is short (11). Therefore, preventing or 5Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York. 6Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. reversing resistance to AR-directed agents may potentially block 7University of Kentucky College of Medicine, Lexington, Kentucky. lethal pathways of progression and prolong survival. Note: Supplementary data for this article are available at Clinical Cancer The development of resistance to AR-targeted agents Research Online (http://clincancerres.aacrjournals.org/). involves a host of genomic alterations that directly affect AR gene structure and function (12–16) as well as cross-talk with Prior Presentation: Presented at the 51st Annual Meeting American Society of – Clinical Oncology (ASCO), Chicago, IL, May 29–June 2, 2015. growth factor signaling pathways (17 19). The most prevalent AR alteration is overexpression (12–14), which is necessary Corrected online February 5, 2019. and sufficienttoleadtoCRPCprogressionandresistanceto Corresponding Author: Anna C. Ferrari, Icahn School of Medicine at Mount Sinai, antiandrogens (20). AR mutation frequency is low, but treat- One Gustave L. Levy Place, Box 1079, New York, NY 10029. Phone: 212-659- ment with antiandrogens can select for distinct mutations in 5600; Fax: 212-659-5599; E-mail: [email protected] the ligand-binding domain (LBD) that confer resistance and doi: 10.1158/1078-0432.CCR-18-1589 drive AR activity but not cross-resistance to other antiandro- Ó2018 American Association for Cancer Research. gens (21–25). Ligand-independent AR splice variants (ARSv) 52 Clin Cancer Res; 25(1) January 1, 2019 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst January 3, 2019; DOI: 10.1158/1078-0432.CCR-18-1589 Epigenetic Therapy in Antiandrogen-Resistant Prostate Cancer pathways involved in disease progression and drug resistance, Translational Relevance including those not controlled by AR (30, 35, 40, 41). The development of resistance to androgen pathway– In prostate cancer cells, both HDAC1 and HDAC3 are required targeted agents is central to prostate cancer lethality. Pre- for optimal transcriptional modulation of nearly all AR target clinical studies indicate that this drug-resistant state can be genes (42), although HDAC1 alone can directly interact with AR attenuated or reversed by epigenetic modulation. We pro- protein, to produce transcriptional repression (39). By disrupting pose that to achieve this requires the real-time copresence of transcriptional activation, the HDACIs LBH589 (panobinostat) the epigenetic effector and resistance agent. The relevance of and suberoylanilide hydroxamic acid (SAHA, Vorinostat) this hypothesis in castrate-resistant prostate cancer (CRPC) decreased AR mRNA synthesis and repressed transcriptional acti- was tested in a phase I/II trial of the histone deacetylase vation of the AR target genes PSA and TMPRSS2 (42). In CRPC cell inhibitor panobinostat in combination with continuous bica- lines with AR overexpression, PSA expression was inhibited in a lutamide in patients who had secondarily progressed on dose-dependent manner: 30%, 50%, and 85%, respectively, by bicalutamide and/or other first-generation antiandrogen(s). 10, 20, and 40 nmol/L panobinostat (42). These findings sug- The results provide evidence that compared with historic gested that patients with AR-driven CRPC may require higher controls treated with bicalutamide alone, the combination of doses of panobinostat monotherapy for an antitumor response bicalutamide with high-dose panobinostat administered than the dose approved for use in myeloma (43). In a clinical intermittently delayed radiographic progression of the disease; setting, this could be achieved using an intermittent oral schedule toxicity was not limiting, although dose reductions were to decrease toxicity (42). In addition, given the effect of panobi- required to extend treatment. Our results provide initial nostat on AR transcriptional activity and, also, PSA expression in proof-of-concept support for the potential effectiveness of model systems, it was proposed to use PSA changes as a correlative epigenetic therapy to reverse/delay antiandrogen-resistant biomarker to monitor the effect of HDACI treatment on the AR CRPC and warrant confirmation with currently available, pathway and to guide dose selection in clinical trials (42). more potent antiandrogens to further increase their survival Using cell line prostate cancer models, we previously explored benefits. the hypothesis that resistance to bicalutamide can be overcome by concomitant administration of panobinostat (20). We demon- strated that the HDACIs trichostatin-A and panobinostat effec- tively reduced overexpressed AR mRNA and protein levels in an androgen-independent, bicalutamide-resistant LNCaP deriv- are also enhanced by antiandrogen treatment including bi- ative (44, 45). Further, although bicalutamide alone was in- calutamide, and they frequently sprout in response to second- effective, when combined with panobinostat, the combination generation antiandrogens (26–28). More importantly, the induced both synergistic growth arrest and apoptosis greater overexpression of ARv7 has been shown to accelerate CRPC than panobinostat alone (46). These results suggested that pano- progression via a distinct mitosis-dependent transcriptome binostat reverses resistance to bicalutamide and that both are program that imparts cross-resistance to antiandrogens necessary to achieve an antiproliferative effect. We now show (29–32). These observations of the importance of AR over- that this drug combination is also effective in an additional expression in antiandrogen resistance suggest that aberrant prostate cancer model, namely a paired isogenic in vitro/in vivo regulatory mechanisms could play an important
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