Successful use of the potent enzyme inducer enzalutamide in a treatment-experienced HIV-positive male with prostate cancer

Although rates of AIDS-defining cancers have dramatically decreased in patients living with HIV (PLWH) due to effective antiretroviral therapy (ART), longer life expectancy has led to an increased incidence and prevalence of non-AIDS-defining cancers (NADC) such as anal, liver, lung, and prostate cancer [1]. The Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) study, a prospective observational study of 11 cohorts across Europe, Australia, and the United States, reported a 6.5% incidence of prostate cancer in PLWH from 2004 to 2010, making it the sixth most common NADC [2]. Prostate and lung cancer are projected to become the most frequently diagnosed cancers in PLWH in the United States by 2030 [3]. All patients with cancer should be on ART based on well documented mortality and morbidity benefits [4]. However, the potential for drug interactions is high as most antiretrovirals are substrates and potent inhibitors or inducers of CYP450 isoenzymes and drug transporters. Coadministration may lead to increased toxicity or decreased efficacy of either chemotherapy or ART [5–7]. Enzalutamide, a pure androgen receptor signaling inhibitor commonly used in metastatic castration-resistant prostate cancer (mCRPC), has an elimination half-life of 5.8 days and is a potent CYP3A4 inducer and moderate CYP2C19 and 2C9 inducer [8], decreasing exposures of CYP450 substrates midazolam, omeprazole, and S-warfarin by 86, 70, and 56%, respectively. In-vitro data suggest that enzalutamide also induces CYP2B6 and UGT1A1/4 [8]. Therefore, it has the potential to significantly reduce antiretroviral concentrations with risk of virologic failure. We report the successful use of enzalutamide for mCRPC in a treatment-experienced PLWH using nonstandard ART dosing and therapeutic drug monitoring (TDM). The patient provided consent for publication. A 58-year-old white male was diagnosed with HIV in 1988, and received multiple ART regimens before achieving HIV viral suppression less than 50 copies/ml in 2007. His HIV genotype included high-level resistance to all nucleoside reverse transcriptase inhibitors, all first-generation nonnucleoside reverse transcriptase inhibitors, and all protease inhibitors except for darunavir (low-level resistance mutations G73S, I84V). Since 2013, he has been on tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg daily and twice daily darunavir 600 mg, ritonavir 100 mg, raltegravir 400 mg, and etravirine 200 mg with CD4+ cell counts above 350 cells/μl and continued viral suppression. In 2014, the patient was diagnosed with Gleason 4 + 5 prostate cancer with bone metastases and experienced progression despite bicalutamide and leuprolide, thus requiring enzalutamide. Due to the potential for enzalutamide to significantly reduce concentrations of darunavir, ritonavir, etravirine, and raltegravir, his ART was modified to darunavir 600 mg/ritonavir 200 mg twice daily, dolutegravir 50 mg twice daily, etravirine 200 mg twice daily, and tenofovir disoproxil/emtricitabine daily. TDM of darunavir and etravirine were conducted at baseline and at weeks 2, 4, and 8 after enzalutamide initiation, and dolutegravir TDM was obtained at baseline and at week 8. Results showed a 53% increase in darunavir concentrations at week 2 (associated with a more than five-fold increase in ritonavir concentrations), a 25% reduction at week 4 compared with week 2, and a further 8% decrease at week 8 compared with week 4, reflecting the long elimination half-life of enzalutamide. Etravirine concentrations decreased 6% by week 8 but still remained above target. A significant impact of enzalutamide initiation on dolutegravir concentrations was not observed (Table 1). After 7 months of concomitant therapy with enzalutamide, prostate-specific antigen (PSA) improved from 1.1 to 0.10 ng/ml. At more than 2.5 years follow-up, the patient remains virally suppressed on the same medications, and his PSA continues to be low at 0.09 ng/ml.Table 1: Therapeutic drug monitoring results for darunavir, etravirine, and dolutegravir at baseline and after initiation of enzalutamide.Doubling the ritonavir dose appeared to counteract the induction effect of enzalutamide on darunavir concentrations, and may have also helped to ameliorate the impact on etravirine exposures. Using dolutegravir twice daily may have compensated for the potential induction effect of enzalutamide, etravirine, and ritonavir on dolutegravir exposures. Although the darunavir weighted genotypic inhibitory quotient (wGIQ) at week 8 was below the target wGIQ of 0.6 mg/l/mutation [9], in a study of 14 patients receiving darunavir-based regimens including two or more active agents, subtherapeutic darunavir pharmacokinetic/pharmacodynamics parameters were not associated with virologic failure [12]. Our patient's viral load has remained suppressed for over 2 years on his adjusted dose ART. The use of TDM to manage drug interactions has been well documented in patients receiving antituberculous or transplant medications with ART [13–15]. We report successful long-term treatment of advanced prostate cancer with enzalutamide in a treatment-experienced PLWH using modified ART dosing supported by TDM. This strategy may be helpful in other situations where significant drug interactions involving unstudied combinations are a concern. Acknowledgements Conflicts of interest S.N., J.B., and D.T. declare that they have no conflicts of interest. N.L.S. has received speakers or consultant honoraria and research grants for other studies from Gilead, Janssen Canada, Bristol-Myers Squibb, Merck, and ViiV Healthcare Canada. S.W. has served on advisory boards and spoken at CME events for AbbVie, Bristol-Myers Squibb, Gilead, Merck, and ViiV. S.W. receives career support from the Ontario HIV treatment network. A.L.T. has received speaker and consultant honoraria from Abbvie, Gilead, Merck, and ViiV.

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