Ketoconazole for the Treatment of Docetaxel-Naïve Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Systematic Review

Objective: This systematic review aimed to determine the efficacy of ketoconazole in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Materials and Methods: A literature search was performed on four databases of PubMed, Google Scholar, Cochrane Database of Systematic Reviews, and Directory of Open Access Journals (DOAJ). The initial search resulted in 602 articles, which were progressively eliminated based on duplication, irrelevancy, and unsuitable methodology. A total of seventeen articles were included in the final analysis, including four randomized controlled trials, nine retrospective cohorts, and four prospective cohorts, with a total population of 1,095 patients. A 200-400 mg, tid dose of ketoconazole was used in these studies along with corticoid replacement therapy with hydrocortisone, 20-30 mg in the morning and 10-20 mg in the evening, or prednisone, 5 mg, bid. Results: Based on our findings, 8 out of 17 studies reported PSA decrease of >50% in approximately half of the population, with a more significant PSA response at 400 mg ketoconazole dosage, and the average progression-free survival (PFS) of 2.6-14.5 months, or time to progression of 3.2-6.7 months. Conclusion: Ketoconazole with corticosteroid could be an effective alternative for the treatment of mCRPC with a satisfactory PSA response and disease progression.


Introduction
Sadikin Academic Medical Center reported that 39.3% of patients with prostate cancer treated in the hospital experienced metastatic progression. A report by the Indonesian Ministry of Health showed that approximately 10% of prostate cancer cases in Indonesia progressed to CRPC. Several new therapeutic agents for CRPC, such as sipuleucel-T, enzalutamide, radium-233, abiraterone, estramustine, and cabazitaxel, are currently not approved for use in Indonesia, thus they are not covered by the Indonesian national health insurance system. Therefore, a safe, efficient, and economical alternative is needed for mCRPC patients in Indonesia (Komite Penanggulangan Kanker Nasional., 2016).
Ketoconazole is a synthetic imidazole antifungal agent commonly used in the treatment of dermatophytosis or systemic fungal infections, including blastomycosis, histoplasmosis, paracoccydiomycosis, coccydiomycosis, and chromomycosis. Ketoconazole is a nonspecific cytochrome P450 inhibitor, which may inhibit gonadal and adrenal steroid synthesis (Sinawe et al., 2020). Furthermore, ketoconazole inhibits CYP17A1, a catalyst for two key reactions in the production of gonadal and extragonadal steroid hormones (androgen and testosterone), as shown in Figure 1 (Sinawe et al., 2020). Considering the limitations of chemotherapy in Indonesia, including the availability of drugs and facilities, the lack of oncological expertise, the high cost of chemotherapy, and the higher toxicity, our study was performed to determine the effectiveness of ketoconazole for the treatment of mCRPC.

Materials and Methods
This systematic review was done through searching PubMed, Cochrane Database of Systematic Reviews, Google Scholar, and Directory of Open Access Journals (DOAJ). The literature search was carried out with no time limitations using the keywords of ketoconazole, metastatic castrate-resistant prostate cancer, and mCRPC. A literature search was also performed on synonyms of mCRPC, including advanced prostate cancer, androgen-independent prostate cancer, hormone refractory prostate cancer, and rogressive androgen-independent prostate cancer. Studies that used ketoconazole after docetaxel chemotherapy were excluded from the analysis. This systematic review was performed according to the PRISMA guidelines (Moher et al., 2010).
All articles obtained from the initial search were analyzed in four steps. The first step was filtering the articles based on the searched keywords. The second step was analyzing the title and abstract based on the inclusion and exclusion criteria. In the third step, the generalized text was analysed based on the inclusion and exclusion criteria. In the fourth step, cross-referenced articles in other systematic reviews or studies. The number of eliminated articles is described in Figure 2.

Results
Out of seventeen included studies, four studies were randomized controlled trials (RCT), nine studies were retrospective cohorts, and four studies were prospective cohorts. All studies were done on a population of patients with prostate cancer resistant to metastatic castration and naïve to docetaxel. All of the studies used ketoconazole, 200 to 400 mg, tid as the primary intervention. Fifteen of the seventeen studies used hydrocortisone, prednisone, or prednisolone as an alternative therapy to prevent corticosteroid deficiency due to long-term use of ketoconazole.

Ketoconazole Toxicity
Ketoconazole generally shows a good safety profile, although its toxicity should be considered in managing mCRPC patients. Administration of systemic ketoconazole most commonly causes gastrointestinal side effects, including nausea, vomiting, constipation, abdominal pain, dry mouth, and discoloration of the tongue. Inhibition of steroid synthesis may result in adrenal insufficiency, which may consequently lead to orthostatic hypotension and side effects associated with sex hormones, including gynecomastia (Sinawe et al., 2020). Therefore, long-term administration of ketoconazole must be accompanied by replacement therapy using corticosteroids. The most severe symptoms of toxicity are generally associated with hepatotoxicity, which can cause jaundice, severe hepatitis, and liver failure (National Institute of Health, 2017).
Almost all studies used the National Cancer Institute Common Toxicity Criteria monitoring system to evaluate and analyze ketoconazole toxicity. The symptoms of grade 3-4 toxicity indicate poor tolerance by the patient and require cessation of the regimen as soon as possible. If the symptoms of toxicity have improved to degrees 1 or 2, the regimen can be restarted with a reduced dose. The summary of the analyzed studies is described in Table 1.

Discussion
Secondary hormonal manipulation is a suitable therapeutic option to reduce the burden of disease and improve patients' quality of life with CRPC. Ketoconazole is a nonspecific cytochrome P450 inhibitor, which inhibits CYP17A1, a catalyst for two key reactions in the production of gonadal and extragonadal steroid hormones, namelyandrogen and testosterone (Almassi et al., 2018;Moher et al., 2010). A n o t h e r m e c h a n i s m t h a t m a y i n f l u e n c e the pathogenesis of CRPC involves the effect of ketoconazole on T cell proliferation. In this case, cytochrome P450 regulates the influx of Ca 2 + ions in T cells and causes inhibition of interleukin (IL) -2 synthesis and T24 cell proliferation (Jensen et al., 1999).
The adrenal cortex produces 10-30% of serum androgens, including androstenedione, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS). Free and serum testosterone suppression is obtained within 2 hours of oral ketoconazole consumption, with maximum suppression after 8 hours. The testosterone suppression effect of ketoconazole is rapid and reversible, and normal testosterone levels are restored within 24 hours. Inhibition of CYP17A1 in the androgen synthesis pathway plays a significant role in ketoconazole's action against castration resistance. Androgen depletion therapy generally inhibits gonadal androgen synthesis, while ketoconazole inhibits both gonadal and adrenal androgen synthesis simultaneously (Patel et al., 2018). Furthermore, another source of androgen in prostate cancer is the de novo androgen synthesis in prostate cancer cells, mediated by CYPA1 and 3β-dehydroxysteroid dehydrogenase isoenzyme 1 (3βHSD1 or HSD3B1). HSD3B1 activity increases extragonadal androgen precursor conversion to intratumoral androgen, making ketoconazole's extragonadal activity even more potent against intratumor androgen levels in patients with high HSD3B1 activity (Almassi et al., 2018;Moher et al., 2010).
Ketoconazole for the treatment of mCRPC can be administered with three approaches: (1) a low dose regimen of 200 mg, tid, increased to 400 mg, tid if PSA response is not achieved within 3 months; (2) a high-dose regimen of 400 mg, tid, lowered to 200 mg if the patient exhibited gastrointestinal intolerance or toxicity symptoms; or (3) an intermediate-dose of 300 mg, tid. The patients received ketoconazole on an empty stomach, either one hour before or two hours after eating, unless this resulted in nausea or gastrointestinal upset, in whom the ketoconazole was taken at mealtime (Harris et al., 2002;Milikan et al., 2001). Corticosteroids used for replacement therapy include hydrocortisone, 30 mg in the morning and 10 mg in the evening, or prednisone, 5 mg, bid (Millikan et al., 2001;Harris et al., 2002). In our study, in 17 extracted studies, it was concluded that ketoconazole significantly reduced more than fifty percent PSA value with or without corticosteroids or other adjuvants. It may be chosen for alternative ADT for metastatic CRPC patients especially in developing countries that cant afford abiraterone acetate or enzalutamide.
Inhibition of adrenal steroids by agents such as ketoconazole is the standard therapy for mCRPC, although the serological and radiographic benefits are not significant, and progression-free survival generally does not exceed 8-10 months. PSA evaluation can be conducted monthly, as done by Barata et al., (2018). In addition, an early decrease of PSA was detected within the first four weeks in Yun et al., (2011)' study. All of the analyzed studies reported a significant decrease in serum PSA ( >50%) in mCRPC patients receiving ketoconazole. Eight studies reported PSA response in >50% of patients, while Scholz et al., reported an even greater decrease of PSA (>75%) in 44% of patients. Chiang et al., (2012) reported a greater decrease in PSA in the group receiving mg ketoconazole at dose of 400, compared to the group receiving ketoconazole at dose of 200 mg.
Signs of toxicity must be closely monitored, and the treatment with ketoconazole should be ceased immediately if grade 3 or 4 toxicity occurred. In grades < 3 toxicity, the patients should be monitored for the signs, and this management should be continued until disease progression.
In conclusion, ketoconazole with corticosteroid replacement can be used as an anti-androgenic treatment option for docetaxel-naïve mCRPC, with satisfactory PSA response and progression-free survival.