Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 5  |  Page : 990-1001

CYP17 inhibitors improve the prognosis of metastatic castration-resistant prostate cancer patients: A meta-analysis of published trials


1 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
2 Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
3 Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
4 Department of Nursing, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Date of Submission05-May-2018
Date of Decision09-Jul-2019
Date of Acceptance22-Apr-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Ke Chen
Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022
China
Xiaoping Zhang
Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_295_18

Rights and Permissions
 > Abstract 


Background and Aims: CYP17 inhibitors can block androgen production both intratumorally and systemically, thus attenuating the progression of prostate cancer (PCa). Many randomized controlled trials (RCTs) showed promising results that men with metastatic castration-resistant PCa (mCRPC) might benefit from treatment with CYP17 inhibitors such as abiraterone acetate and orteronel. The goal of this study was to evaluate the efficacy of CYP17 inhibitors for the prognosis in patients with mCRPC.
Materials and Methods: Studies were identified in PubMed/MEDLINE, the Cochrane Library, and the Web of Science. The RCTs with mCRPC patients focusing on the efficacy of CYP17 inhibitors were involved. Then, we analyzed the patients' prognosis such as overall survival (OS) and radiographic progression-free survival (RPFS).
Results: A meta-analysis of the pooled data from seven randomized Phase III clinical trials was performed to compare 5516 mCRPC patients with CYP17 inhibitors versus that with placebo. Compared to placebo, the CYP17 inhibitors significantly increased the OS (pooled hazard ratios [HR]: 0.816, 95% confidence interval [CI]: 0.750–0.887), RPFS (pooled HR: 0.647, 95% CI: 0.557–0.752), and time to prostate-specific antigen (PSA) progression (pooled HR: 0.599, 95% CI: 0.517–0.693). Additional endpoints such as PSA response rate, objective response assessed by Response Evaluation Criteria in Solid Tumors, and time to initiation of chemotherapy were included in this study and were found having significant improvement with CYP17 inhibitors compared to placebo.
Conclusion: This research showed that CYP17 inhibitors had a significant improvement on prognosis of patients with mCRPC within a relative safety profile both in pre- and post-chemotherapy trials. These expected results provide evidence for the use of CYP17 inhibitors to treat mCRPCs.

Keywords: CYP17, meta-analysis, metastatic castration-resistant prostate cancer, prognosis


How to cite this article:
Cao Q, Bai P, Shi D, Liao J, Shi H, Xing Y, Chen K, Zhang X. CYP17 inhibitors improve the prognosis of metastatic castration-resistant prostate cancer patients: A meta-analysis of published trials. J Can Res Ther 2020;16:990

How to cite this URL:
Cao Q, Bai P, Shi D, Liao J, Shi H, Xing Y, Chen K, Zhang X. CYP17 inhibitors improve the prognosis of metastatic castration-resistant prostate cancer patients: A meta-analysis of published trials. J Can Res Ther [serial online] 2020 [cited 2020 Oct 22];16:990. Available from: https://www.cancerjournal.net/text.asp?2020/16/5/990/296432




 > Introduction Top


Prostate cancer (PCa) is the most common malignancy in men in the United States and ranks second in the cause of cancer death in men worldwide.[1] It was the main cause of cancer deaths in 24 countries, ranking sixth in developed countries, 12th in developing countries, and eighth globally.[2] Metastatic PCa often has lymphatic, blood, or local spreads, resulting in various sorts of clinical manifestations. The most common metastatic sites are bones and lymph nodes.[3]

Traditionally, androgen deprivation therapy (ADT) using luteinizing hormone-releasing hormone agonists or antagonists is widely used. Together with surgical castration through bilateral orchidectomy, they are regarded as first-line treatments for locally advanced and metastatic PCa.[4] However, adrenal or intratumoral androgen production is not affected by the ADT, which may cause the disease to recur.[5] Thus, some patients may suffer from the so-called castration-resistant PCa (CRPC).[6] In patients with metastatic CRPC (mCRPC), docetaxel plus prednisone chemotherapy was the first systemic treatment, and these patients benefited from it significantly.[7] Nevertheless, the clinical benefit of this approach is far from satisfactory.[8] The median survival of mCRPC patients treated with docetaxel is usually <2 years,[8],[9] which may require another effective treatment.

In recent years, some new therapeutic drugs have been beneficial to men with mCRPC.[10] Recent research in the treatment of PCa has focused on impairing androgen receptor (AR) signaling by blocking AR and inhibiting the activity of CYP17, a key enzyme involved in steroid hormone biosynthesis, particularly androgens.[11],[12] CYP17 has 17,20-lyase and 17α-hydroxylase activities.[11],[12],[13] It has been shown that the prostate can synthesize its own biologically active androgens at a level comparable to those directly derived from the testes.[14] Therefore, it would be an essentially effective therapeutic approach to the treatment of PCa through the inhibition of androgens from both testicular and adrenal sources. This has led to a number of inhibitors of the enzyme system CYP17 springing up.

CYP17 is a key enzyme for androgen synthesis and has been identified as being significantly associated with the pathogenesis of PCa.[15] By this enzyme system, 17α-hydroxypregnenolone is converted into dehydroepiandrosterone (DHEA),[16] which is a precursor of steroid hormones and eventually converts to testosterone and dihydroxytestosterone (DHT), the most effective androgen.

Abiraterone acetate (AA) is an orally effective selective androgen biosynthesis inhibitor that specifically inhibits the activity of CYP17 enzyme. In addition, oral AA could be converted by an enzyme to another congener D4A, which can interact with AR and other steroidogenic enzymes, providing an additional potent antitumor activity for abiraterone therapy.[17] The US Food and Drug Administration (FDA) approved the use of AA in combination with prednisone in patients who had received chemotherapy in April 2011 and approved it for use in chemotherapy-naive patients in December 2012.[18] In the global trials of COU-AA-301 and 302, abiraterone showed favorable survival benefits in post- and pre-docetaxel groups.

Orteronel is a novel androgen biosynthesis inhibitor. It is nonsteroidal and has a stronger inhibitory effect on 17,20-lyase than 17α-hydroxylase and can reversibly inhibit CYP17.[13] The extragonadal synthesis of androgens from the adrenal or PCa cells can be selectively inhibited by orteronel, which makes it promising to be a new therapeutic option for men with CRPC. Some Phase II clinical trials indicate that orteronel inhibits testosterone and DHEA production and suppresses prostate-specific antigen (PSA) levels in mCRPCs.[19],[20]

Currently, several new CYP17 inhibitors are being developed. And, the representing ones include VT-464 (Viamet Pharmaceuticals, Inc, Durham, NC, USA) and TOK-001 (Tokai Pharmaceuticals, Inc, Cambridge, MA, USA). Early results showed promising benefits, and Phase III trials are being conducted.

Based on some pivotal global trials, we performed a meta-analysis. The present meta-analysis aimed to analyze the published trials on CYP17 inhibitor therapy for patients in North America, European Union, Australia, as well as in Asia affected by mCRPC, in order to evaluate the efficacy of these therapies compared with placebo and provide a reliable basis for clinical therapy strategies.


 > Materials and Methods Top


Search strategies

We sought data from articles written in English, and only Phase III randomized controlled trials (RCTs) with mCRPC patients were involved. Studies were identified by a comprehensive search in PubMed/MEDLINE, the Cochrane Library, and the Web of Science. The search for relevant publications was conducted adopting the following Medical Subject Heading terms and free words: “metastatic castration-resistant prostate cancer, metastatic CRPC or mCRPC” AND “abiraterone, orteronel, CYP17, or CYP17 inhibitor.” The database was searched for articles published until March 1, 2018. The search was limited to human studies. When the results of research from the same population source were published in multiple journals, only the latest and updated versions were included.

Eligibility criteria

Trials that met the following criteria would be included: (i) population: histologically or cytologically diagnosed mCRPC cases; (ii) type of interventions: various CYP17 inhibitors for mCRPC versus placebo for mCRPC, despite post- or pre-chemotherapy; (iii) endpoints: comparable outcomes about efficacy and prognosis between CYP17 inhibitor and placebo such as overall survival (OS), radiographic progression-free survival (RPFS), time to PSA progression (TTPP),[21] PSA response rate, objective response rate by the Response Evaluation Criteria in Solid Tumors (RECIST), and time to pain progression; and (iv) study design: limited to RCTs and Phase III trials.

Studies that met the following criteria were excluded: (i) insufficient data or no accessible results; (ii) animal studies or simple molecular biology researches; (iii) prospective nonrandomized or retrospective study; (iv) one-arm study; and (v) nonoriginal research, such as review and editorials.

Data extraction

Two researchers independently extracted relevant data. The two reviewers would conduct discussions in case of disagreements. The following factors were extracted from each article: features of the included patients, such as number, race, and type of treatment; hazard ratio (HR) values and 95% confidence intervals (CIs); and results of research endpoints, such as the OS, RPFS, and TTPP.

Quality control

The quality of each study was evaluated by three independent authors. The quality was evaluated in accordance to the Jadad scale. The quality score was between 0 and 5.[22] Disagreements were resolved through discussions with third-party researchers.

Statistical analysis

HRs and 95% CIs were assessed adopting a fixed-effect model.[23] A random-effect model was used for studies with high heterogeneity.[24] Statistical heterogeneity was evaluated by the I-squared (I2) parameter. Studies with an I2 > 50% and P ≤ 0.1 were considered significant for heterogeneity.[25] We adopted Begg's test and Egger's test to assess the risk of publication bias.[26],[27] Sensitivity analysis was carried out to evaluate the stability of results by leaving one study out in each turn. Subgroup analyses with respect to chemotherapy naive versus postchemotherapy trials, abiraterone versus orteronel trials, and Asian versus Western patients were performed to assess the influence on the activity of CYP17 inhibitors. Statistical analysis was carried out using STATA version 14 (Stata Corporation, TX, USA). For all statistical analyses, P < 0.05 was considered to have a statistically significant difference.


 > Results Top


Literature search

The flowchart of the search and study selection is shown in [Figure 1]. Three hundred and twenty three publications were identified using our search strategy. Among 104 potentially relevant articles selected on the basis of title and abstract content, 97 of these articles were excluded after carefully reading the full text, and 7 articles fulfilled the inclusion criteria for the present meta-analysis.[28],[29],[30],[31],[32],[33],[34]
Figure 1: Flowchart of the study selection

Click here to view


Study characteristics and quality assessment

Seven studies enrolling 3181 cases in the CYP17 inhibitor group and 2335 cases in the control group were included in this study according to the inclusion and exclusion criteria [Figure 1]. These studies were published between 2012 and 2017. Among these trials, four trials enrolled postchemotherapy patients and three involved chemotherapy-naive men. Four trials reported the efficacy of abiraterone, while three studies concerned about orteronel. Typically, among these trials, there were two studies that enrolled Asian population, which allowed us to compare the efficacy of CYP17 inhibitors with Western people. This may give us more attractive information about the inhibitors. The main characteristics of the researches included in this meta-analysis are listed in [Table 1]. All trials had good quality with a Jadad score of 5 [Table 1].
Table 1: Characteristics of the analyzed trials

Click here to view


Primary outcomes

Five RCTs reported the OS of CYP17 inhibitor plus prednisone versus placebo plus prednisone in a total of 5156 men with mCRPC [Table 2]. A significant improvement was found with CYP17 inhibitor plus prednisone compared to placebo plus prednisone (pooled HR: 0.816, 95% CI: 0.750–0.887) [Figure 2]. There was no statistically significant heterogeneity in the entire studies (χ2 = 6.59, df = 4, P = 0.159; I2 = 39.3%). Sensitivity analysis further confirmed the stability of our findings [Figure 3]. In order to further explore the efficacy, subanalyses were performed with regard to type of CYP17 inhibitor (abiraterone or orteronel), region of included patients, and relationship with chemotherapy usage (prechemotherapy or postchemotherapy). The result of subgroup analysis showed that OS was significantly improved with abiraterone compared to placebo (pooled HR: 0.736, 95% CI: 0.654–0.887), and heterogeneity was not detected across studies (χ2 = 0.57, df = 2, P = 0.751; I2 = 0.0%). However, OS was not improved with orteronel compared to placebo (pooled HR: 0.905, 95% CI: 0.804–1.019). There was no heterogeneity across studies (χ2 = 0.10, df = 1, P = 0.758; I2 = 0.0%). The Asian subgroup only contained one trial (Sun Y, et al.) which did not cross the efficacy boundary (pooled HR: 0.604; 95% CI: 0.356–1.026; P = 0.0597). The Western subgroup showed improved OS with CYP17 inhibitors compared to placebo (pooled HR: 0.822, 95% CI: 0.755–0.895), and no heterogeneity existed (χ2 = 0.10, df = 1, P = 0.150; I2 = 43.6%). As for the chemotherapy usage, there was no significant difference found in the improvement for OS between the subgroups of pre- and post-chemotherapy (pooled HR: 0.840, 95% CI: 0.743–0.949; pooled HR: 0.803, 95% CI: 0.674–0.958) [Figure 2] and [Table 2]. Publication bias did not exist evaluated by the use of Begg's test (P = 0.806) and Egger's test (P = 0.478) [Figure 4].
Table 2: Results of subgroup analysis of pooled hazard ratios of various endpoints of CYP17 inhibitor versus placebo in patients with metastatic castration-resistant prostate cancer

Click here to view
Figure 2: Meta-analysis of the pooled HRs of OS of CYP17 inhibitor versus placebo in patients with mCRPC. (a) Subgroup analysis of HRs of OS by factor of type of CYP17 inhibitor. (b) Subgroup analysis of HRs of OS by factor of region of included patients. (c) Subgroup analysis of HRs of OS by factor of relationship with chemotherapy usage. HR = Hazard ratio, OS = Overall survival, mCRPC = Metastatic castration-resistant prostate cancer, PSA = Prostate-specific antigen

Click here to view
Figure 3: Sensitivity analysis of the independent role of CYP17 inhibitor for (a) OS, (b) RPFS, and (c) TTPP. OS = Overall survival, RPFS = Radiographic progression-free survival, TTPP = Time to PSA progression, CI = Confidence interval, PSA = Prostate-specific antigen

Click here to view
Figure 4: Funnel plot, (a) Begg's test graph, and (b) Egger's test graph for the analysis of OS, (c) Begg's test graph, and (d) Egger's test graph for the analysis of RPFS, (e) Begg's test graph, and (f) Egger's test graph for the analysis of TTPP of CYP17 inhibitor versus placebo in patients with mCRPC. OS = Overall survival, RPFS = Radiographic progression-free survival, TTPP = Time to PSA progression, mCRPC = Metastatic castration-resistant prostate cancer, PSA = Prostate-specific antigen

Click here to view


Secondary outcomes

Five RCTs presented the RPFS of CYP17 inhibitor versus placebo in a total of 4989 patients with mCRPC. All of these patients are Western population. A significant improvement was demonstrated with CYP17 inhibitor compared to placebo (pooled HR: 0.647, 95% CI: 0.557–0.752) [Figure 5]. Significant heterogeneity existed (c2 = 15.55, df = 4, P = 0.004; I2 = 74.3%). Sensitivity analysis revealed that the trial COU-AA-302[31] substantially affected pooled HR. After excluding this trial, the heterogeneity did not exist (χ2 = 3.65, df = 3, P = 0.30, I2 = 17.8%), and pooled HR was 0.702 (95% CI: 0.650–0.758) [Figure 3]. Subgroup analysis was performed same as above. We found that RPFS was significantly improved in the CYP17 inhibitor group versus the placebo group despite the type of CYP17 inhibitors and chemotherapy usage [Table 2]. Publication bias was not observed as assessed by the use of Begg's test (P = 0.462) and Egger's test (P = 0.528) [Figure 4].
Figure 5: Meta-analysis of the pooled HRs of RPFS of CYP17 inhibitor versus placebo in patients with mCRPC. (a) Subgroup analysis of HRs of RPFS by factor of type of CYP17 inhibitors. (b) Subgroup analysis of HRs of RPFS by factor of relationship with chemotherapy usage. HR = Hazard ratio, RPFS = Radiographic progression-free survival; mCRPC = Metastatic castration-resistant prostate cancer

Click here to view


A total of 5516 patients from seven RCTs were included in the meta-analysis to present the efficacy of TTPP. CYP17 inhibitors were found to significantly improve TTPP for patients with mCRPC (HR: 0.599, 95% CI: 0.517–0.693) [Figure 6]. Statistically significant heterogeneity was observed (c2 = 18.80, df = 6, P = 0.005; I2 = 68.1%). Then, sensitivity analysis revealed that the trial COU-AA-302 substantially influenced pooled HR. The heterogeneity did not exist after excluding this study (c2 = 7.33, df = 5, P = 0.197, I2 = 31.8%), and pooled HR was 0.671 (95% CI: 0.619–0.727) [Figure 3]. Moreover, the publication bias was not observed by the use of Begg's test (P = 0.133) and Egger's test (P = 0.238) [Figure 4]. No obvious difference was found in the subgroup analysis [Table 2]. Other endpoints such as PSA response rate and objective response assessed by the RECIST were included in this meta-analysis [Figure 7] and [Table 2], [Table 3]. Significant improvement for these endpoints was found with CYP17 inhibitor compared to placebo. In addition, an endpoint, time to pain progression, was found to be improved with CYP17 inhibitor versus placebo (pooled HR: 0.818, 95% CI: 0.722–0.926) with no significant heterogeneity existed (c2 = 6.38, df = 4, P = 0.173; I2 = 37.3%). However, only one of the five RCTs (Sun Y, et al.) contained showed improvement on the efficacy of time to pain progression [Figure 7] and [Table 2], and it was not improved with orteronel compared to placebo (pooled HR: 0.887, 95% CI: 0.745–1.057). More standardized information is needed to confirm this finding.
Figure 6: Meta-analysis of the pooled HRs of TTPP of CYP17 inhibitor versus placebo in patients with mCRPC. (a) Subgroup analysis of HRs of TTPP by factor of type of CYP17 inhibitor. (b) Subgroup analysis of HRs of TTPP by factor of region of included patients. (c) Subgroup analysis of HRs of TTPP by factor of relationship with chemotherapy usage. HR = Hazard ratio, TTPP = Time to PSA progression, mCRPC = Metastatic castration-resistant prostate cancer, PSA = Prostate-specific antigen

Click here to view
Figure 7: Meta-analysis of (a) PSA response rate, (b) objective response assessed by RECIST, (c) time to initiation of chemotherapy, and (d) time to pain progression of CYP17 inhibitor versus placebo for patients with mCRPC. MCRPC = Metastatic castration-resistant prostate cancer, RECIST = Response evaluation criteria in solid tumors, PSA = Prostate-specific antigen

Click here to view
Table 3: Results of subgroup analysis of pooled risk ratios of various endpoints of CYP17 inhibitor versus placebo in patients with metastatic castration-resistant prostate cancer

Click here to view



 > Discussion Top


Since 2004, docetaxel-based chemotherapy has become the first-line treatment for CRPC, with its significant survival benefit.[7],[35] However, many patients with mCRPC do not accept it due to its toxic effects.[36] Based on this background, in recent years, new drugs targeting different aspects start to come out, including androgen axis, immunotherapy, or bone-seeking radionuclides. Four new drugs (cabazitaxel, sipuleucel-T, denosumab, and AA) were approved by the FDA for therapy in men with mCRPC,[37],[38],[39] treated before or after common chemotherapy. Among these drugs, abiraterone is a representative of CYP17 inhibitors.

CYP17 is an important enzyme in testosterone and estrogen synthesis. CYP17 inhibitors can block the synthesis of androgen steroids, leading to an androgen production decrease both intratumorally and systemically.[15] This provides therapeutic strategy for the treatment of CRPC, which is significantly relevant to the remaining androgens coming from the adrenal production of DHEA and androstenedione after androgen-deprivation therapy.[40],[41]

Our study is the first meta-analysis of RCTs to evaluate the outcome of CYP17 inhibitors in patients with mCRPC. We found that the OS of patients with CYP17 inhibitors was significantly improved compared with that of the control arm. Positive efficacy on RPFS and TTPP was also observed in patients who underwent CYP17 inhibition therapies. In all cases, HRs were statistically significant, demonstrating the survival benefit of these treatments in delaying the progression of PCa. There are already some meta-analyses discussing the efficacy of abiraterone in the treatment of CRPC and holding promising result.[42] Some other meta-analyses [43] have showed that agents targeting the androgen axis significantly prolonged OS in elderly men (≥75 years old) with CRPC, which is also consistent with our analysis result. Notably, in detail, from our subgroup analysis, we found that abiraterone improved OS of patients while orteronel did not, which may be owing to the fact that orteronel inhibits CYP17 reversibly, which also led to the termination of further clinical research of orteronel.[44] Direct clinical comparisons between orteronel and AA have not been made, and it is puzzling whether subtle differences in androgen synthesis inhibition mechanisms can be directly reflected in clinical performance, leading to possible differences in results.

The efficacy of the sequential use of CYP17 inhibitors and docetaxel in mCRPC patients is a confusing and essential clinical issue, which still waits to be solved.[45] Although there is no direct prospective evidence available to evaluate whether a treatment with docetaxel followed by CYP17 inhibitor is clearly superior to the opposite sequence, maybe we can interpret this problem with caution through cross-comparison of clinical trials despite those differences in study design or patient populations. A small retrospective study indicates that the antitumor activity of docetaxel in patients previously treated with abiraterone seems to be reduced and abiraterone could be more active predocetaxel.[46] In addition, some other observational studies have similar results.[47],[48],[49] Even so, the use of docetaxel is still recommended in mCRPC patients with postabiraterone progression.[50] However, our study indicated that there was no significant difference in the improvement for OS between the subgroups of pre- and post-chemotherapy. It seems that the sequence usage does not affect the efficacy of these two kinds of drugs. However, we must take note of the baseline difference of the study populations in our analyzed trials. For example, most patients in COU-AA-302 (chemotherapy naive) were asymptomatic or minimally symptomatic and the patients in COU-AA-301 (postdocetaxel) were predominantly symptomatic and had progressed disease. Hence, selecting the appropriate treatment with mCRPC is complex. However, the order of treatments is still needed to be considered because some agents do affect responses to subsequent reagents. We expect a prospective trial comparing CYP17 inhibitor followed by docetaxel with docetaxel followed by CYP17 inhibitor could be done, although it is difficult to conduct for lack of suitable surrogates of response. And now, the most important thing is to identify novel indicators of response and factors predictive of drug resistance. Thus, we can have more precise therapies to different individual patient features.

Some novel CYP17 inhibitors with either more selectivity or higher inhibitory actions to AR signaling are currently being studied. VT-464 is a potent nonsteroidal CYP17 lyase inhibitor, and a Phase I/II trial (NCT02361086) started in June 2014 is undergoing. Latest updated results showed that 73% chemotherapy-naive CRPC patients who received once-daily VT-464 treatment had 30%–90% PSA decline, which was promising and led to in-depth research. Ketoconazole, an imidazole antifungal agent, is a CYP17 inhibitor inhibiting a variety of cytochrome P450 enzymes, including CYP3A4, CYP24A1, and CYP17. Thus, it suppresses the conversion of cholesterol to pregnenolone and shows high antiandrogenic activity in adrenal and tumors.[51],[52],[53] A single-center trial found that ketoconazole is shown to improve PSA response and delay disease progression in mCRPC patients and has favorable safety profiles with 22% toxicity incidence in mCRPC patients.[54] Another CYP17 inhibitor TOK-001 (Galeterone ®) has AR antagonism, thus reducing intratumoral AR levels. It suppresses AR signaling through the inhibition of CYP17 lyase, AR splice variant-7 (AR-V7) degradation, and AR nuclear translocation blockade.[55] A Phase III, randomized study (NCT02438007) is being conducted comparing galeterone to enzalutamide in men expressing AR-V7 in mCRPC since June 2015, and we are waiting for the hopeful results.

In the same time, the risk of adverse events related to CYP17 inhibitors in men with mCRPC should also be concerned. These patients had a relatively high risk of heart disease, hypokalemia, hypertension, and abnormal liver function,[56] mainly because of the elevated mineralocorticoid levels. The good news is that the incidence of these side effects is not high,[57] and these toxicities could be supposedly avoided by the intake of low-dose glucocorticoids such as prednisone. Nevertheless, close monitoring of these side effects is recommended.

Although our study indicated that CYP17 inhibitors had a favorable benefit in mCRPC patients, what was noteworthy was that clinical responses might confirm the phenomenon of resistance to CYP17 inhibitors appearing. Some patients treated with abiraterone relapsed within a year, and AR was activated again as the relapsed tumors again expressed high levels of downstream AR genes, such as PSA. The mechanism of resistance to CYP17 inhibitors remains unclear, but great progress has been made in this area. Mouse xenograft studies suggest that relapsed tumors generated after a treatment with CYP17 inhibitor, which apparently reduces the levels of androgens, have great selective pressure for elevated CYP17 expression and intratumoral de novo steroid synthesis.[58] These studies indicate that de novo intratumoral steroid synthesis may contribute to the resistance to CYP17 inhibitors. In addition, the strong selective pressure has the potential to shift the pattern of mCRPC to neuroendocrine prostate cancers or double-negative PCa, which do not express the AR or markers of neuroendocrine differentiation.[59] This phenotype shift can bypass AR dependence, resulting in CYP17 inhibitor resistance. Combined inhibitors of Mitogen-activated protein kinase (MAPK) or Fibroblast growth factor receptor (FGFR) may be fruitful in these patients with AR-null phenotype.[60] What's more, some preclinical researches indeed demonstrate that CYP17 inhibitor resistance, especially abiraterone resistance, is caused by an upregulation of steroidogenic enzymes.[61] The steroidogenic enzymes can convert D4A with increased SRD5A enzyme activity to 5α-Abi, which promotes AR activity.[62] Thus, patients would benefit from abiraterone therapy with SRD5A inhibition.[62]

We are concerned about further investigation in clinical trials.

Nonetheless, in our study, some important limitations should be underlined. First, only seven trials of two drugs were included in the final analysis and the individual patient data are actually unknown. Second, the number of trials is further reduced in the subgroup analysis, and the results of primary endpoint (OS) varied in different drug subgroups. Some endpoint events, such as RPFS, were missing in some trials. Third, the prognosis results of the novel CYP17 inhibitors in large population are being or to be processed, and those data need to be included in future studies to further evaluate the effects of CYP17 inhibitors on the prognosis of mCRPC patients.


 > Conclusion Top


With our meta-analysis, we demonstrated that CYP17 inhibitors had a significant improvement on the prognosis of patients with mCRPC within a relative safety profile in spite of chemotherapy usage. Moreover, our analysis supports the use of CYP17 inhibitors in the treatment of mCRPC in Asian and Western population.

Financial support and sponsorship

This study was supported by Key Research and Development Plan in China (grant no. 2017YFB1303100) and the National Natural Science Foundation of China (grant nos. 81672524, 81672528, and 81874090).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30.  Back to cited text no. 1
    
2.
Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, et al. The global burden of cancer 2013. JAMA Oncol 2015;1:505-27.  Back to cited text no. 2
    
3.
Bubendorf L, Schöpfer A, Wagner U, Sauter G, Moch H, Willi N, et al. Metastatic patterns of prostate cancer: An autopsy study of 1,589 patients. Hum Pathol 2000;31:578-83.  Back to cited text no. 3
    
4.
Sharifi N, Gulley JL, Dahut WL. An update on androgen deprivation therapy for prostate cancer. Endocr Relat Cancer 2010;17:R305-15.  Back to cited text no. 4
    
5.
Joob B, Wiwanitkit V. Screening for prostate cancer starting at age 50-54 years. J Cancer Res Ther 2019;15:S177.  Back to cited text no. 5
    
6.
Droz JP, Fléchon A, Terret C. Prostate cancer: Management of advanced disease. Ann Oncol 2002;13 Suppl 4:89-94.  Back to cited text no. 6
    
7.
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12.  Back to cited text no. 7
    
8.
Huang X, Chau CH, Figg WD. Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: From recent successes and failures. J Hematol Oncol 2012;5:35.  Back to cited text no. 8
    
9.
Bracarda S, Logothetis C, Sternberg CN, Oudard S. Current and emerging treatment modalities for metastatic castration-resistant prostate cancer. BJU Int 2011;107 Suppl 2:13-20.  Back to cited text no. 9
    
10.
Lorente D, Mateo J, Perez-Lopez R, de Bono JS, Attard G. Sequencing of agents in castration-resistant prostate cancer. Lancet Oncol 2015;16:e279-92.  Back to cited text no. 10
    
11.
Ohlmann CH, Merseburger AS, Suttmann H, Schilling D, Trojan L, Kempkensteffen C, et al. Novel options for the treatment of castration-resistant prostate cancer. World J Urol 2012;30:495-503.  Back to cited text no. 11
    
12.
Yamaoka M, Hara T, Hitaka T, Kaku T, Takeuchi T, Takahashi J, et al. Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: Effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. J Steroid Biochem Mol Biol 2012;129:115-28.  Back to cited text no. 12
    
13.
Kaku T, Hitaka T, Ojida A, Matsunaga N, Adachi M, Tanaka T, et al. Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer. Bioorg Med Chem 2011;19:6383-99.  Back to cited text no. 13
    
14.
Labrie F, Bélanger A, Luu-The V, Labrie C, Simard J, Cusan L, et al. Gonadotropin-releasing hormone agonists in the treatment of prostate cancer. Endocr Rev 2005;26:361-79.  Back to cited text no. 14
    
15.
Vasaitis TS, Bruno RD, Njar VC. CYP17 inhibitors for prostate cancer therapy. J Steroid Biochem Mol Biol 2011;125:23-31.  Back to cited text no. 15
    
16.
DeVore NM, Scott EE. Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001. Nature 2012;482:116-9.  Back to cited text no. 16
    
17.
Li Z, Bishop AC, Alyamani M, Garcia JA, Dreicer R, Bunch D, et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature 2015;523:347-51.  Back to cited text no. 17
    
18.
Kluetz PG, Ning YM, Maher VE, Zhang L, Tang S, Ghosh D, et al. Abiraterone acetate in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer: U.S. Food and Drug Administration drug approval summary. Clin Cancer Res 2013;19:6650-6.  Back to cited text no. 18
    
19.
Dreicer R, MacLean D, Suri A, Stadler WM, Shevrin D, Hart L, et al. Phase I/II trial of orteronel (TAK-700)--an investigational 17,20-lyase inhibitor—in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res 2014;20:1335-44.  Back to cited text no. 19
    
20.
Hussain M, Corn PG, Michaelson MD, Hammers HJ, Alumkal JJ, Ryan CJ, et al. Phase II study of single-agent orteronel (TAK-700) in patients with nonmetastatic castration-resistant prostate cancer and rising prostate-specific antigen. Clin Cancer Res 2014;20:4218-27.  Back to cited text no. 20
    
21.
Singh OP, Yogi V, Redhu P, Ghori HU, Pareek A, Lal N. Role of serum prostate-specific antigen as predictor for bone metastases in newly diagnosed prostate cancer. J Cancer Res Ther 2019;15:S39-41.  Back to cited text no. 21
    
22.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials 1996;17:1-2.  Back to cited text no. 22
    
23.
Cochran WG. The combination of estimates from different experiments. Biometrics 1954;10:101-29.  Back to cited text no. 23
    
24.
Dersimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin Trials 1986;7:177-88.  Back to cited text no. 24
    
25.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.  Back to cited text no. 25
    
26.
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088-101.  Back to cited text no. 26
    
27.
Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34.  Back to cited text no. 27
    
28.
Cathomas R, Crabb SJ, Mark M, Winterhalder R, Rothermundt C, Elliott T, et al. Orteronel switch maintenance therapy in metastatic castration resistant prostate cancer after first-line docetaxel: A Multicenter, randomized, double-blind, placebo-controlled trial (SAKK 08/11). Prostate 2016;76:1519-27.  Back to cited text no. 28
    
29.
Fizazi K, Jones R, Oudard S, Efstathiou E, Saad F, de Wit R, et al. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J Clin Oncol 2015;33:723-31.  Back to cited text no. 29
    
30.
Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: Final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012;13:983-92.  Back to cited text no. 30
    
31.
Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): Final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015;16:152-60.  Back to cited text no. 31
    
32.
Saad F, Fizazi K, Jinga V, Efstathiou E, Fong PC, Hart LL, et al. Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): A double-blind, multicentre, phase 3, randomised, placebo-controlled trial. Lancet Oncol 2015;16:338-48.  Back to cited text no. 32
    
33.
Sun Y, Zou Q, Sun Z, Li C, Du C, Chen Z, et al. Abiraterone acetate for metastatic castration-resistant prostate cancer after docetaxel failure: A randomized, double-blind, placebo-controlled phase 3 bridging study. Int J Urol 2016;23:404-11.  Back to cited text no. 33
    
34.
Ye D, Huang Y, Zhou F, Xie K, Matveev V, Li C, et al. A phase 3, double-blind, randomized placebo-controlled efficacy and safety study of abiraterone acetate in chemotherapy-naïve patients with mCRPC in China, Malaysia, Thailand and Russia. Asian J Urol 2017;4:75-85.  Back to cited text no. 34
    
35.
Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr., Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513-20.  Back to cited text no. 35
    
36.
Lissbrant IF, Garmo H, Widmark A, Stattin P. Population-based study on use of chemotherapy in men with castration resistant prostate cancer. Acta Oncol 2013;52:1593-601.  Back to cited text no. 36
    
37.
Beltran H, Beer TM, Carducci MA, de Bono J, Gleave M, Hussain M, et al. New therapies for castration-resistant prostate cancer: Efficacy and safety. Eur Urol 2011;60:279-90.  Back to cited text no. 37
    
38.
Cersosimo RJ. New agents for the management of castration-resistant prostate cancer. Ann Pharmacother 2012;46:1518-28.  Back to cited text no. 38
    
39.
Di Lorenzo G, Ferro M, Buonerba C. Sipuleucel-T (Provenge®) for castration-resistant prostate cancer. BJU Int 2012;110(2 Pt 2):E99-104.  Back to cited text no. 39
    
40.
Attard G, Reid AH, A'Hern R, Parker C, Oommen NB, Folkerd E, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol 2009;27:3742-8.  Back to cited text no. 40
    
41.
Tolcher AW, Cooper J. Castration-resistant prostate cancer–hormone therapy redux. J Clin Oncol 2010;28:1447-9.  Back to cited text no. 41
    
42.
Zhou ZR, Liu SX, Zhang TS, Xia J, Li B. Abiraterone for treatment of metastatic castration-resistant prostate cancer: A systematic review and meta-analysis. Asian Pac J Cancer Prev 2014;15:1313-20.  Back to cited text no. 42
    
43.
Roviello G, Cappelletti MR, Zanotti L, Gobbi A, Senti C, Bottini A, et al. Targeting the androgenic pathway in elderly patients with castration-resistant prostate cancer: A meta-analysis of randomized trials. Medicine (Baltimore) 2016;95:e4636.  Back to cited text no. 43
    
44.
Kim W, Ryan CJ. Quo vadis: Advanced prostate cancer-clinical care and clinical research in the era of multiple androgen receptor-directed therapies. Cancer 2015;121:361-71.  Back to cited text no. 44
    
45.
Lorente D, Fizazi K, Sweeney C, de Bono JS. Optimal treatment sequence for metastatic castration-resistant prostate cancer. Eur Urol Focus 2016;2:488-98.  Back to cited text no. 45
    
46.
Mezynski J, Pezaro C, Bianchini D, Zivi A, Sandhu S, Thompson E, et al. Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: Clinical evidence for cross-resistance? Ann Oncol 2012;23:2943-7.  Back to cited text no. 46
    
47.
Aggarwal R, Harris A, Formaker C, Small EJ, Molina A, Griffin TW, et al. Response to subsequent docetaxel in a patient cohort with metastatic castration-resistant prostate cancer after abiraterone acetate treatment. Clin Genitourin Cancer 2014;12:e167-72.  Back to cited text no. 47
    
48.
Azad AA, Leibowitz-Amit R, Eigl BJ, Lester R, Wells JC, Murray RN, et al. A retrospective, Canadian multi-center study examining the impact of prior response to abiraterone acetate on efficacy of docetaxel in metastatic castration-resistant prostate cancer. Prostate 2014;74:1544-50.  Back to cited text no. 48
    
49.
Schweizer MT, Zhou XC, Wang H, Bassi S, Carducci MA, Eisenberger MA, et al. The influence of prior abiraterone treatment on the clinical activity of docetaxel in men with metastatic castration-resistant prostate cancer. Eur Urol 2014;66:646-52.  Back to cited text no. 49
    
50.
Crawford ED, Higano CS, Shore ND, Hussain M, Petrylak DP. Treating patients with metastatic castration resistant prostate cancer: A Comprehensive review of available therapies. J Urol 2015;194:1537-47.  Back to cited text no. 50
    
51.
Ang JE, Olmos D, de Bono JS. CYP17 blockade by abiraterone: Further evidence for frequent continued hormone-dependence in castration-resistant prostate cancer. Br J Cancer 2009;100:671-5.  Back to cited text no. 51
    
52.
Dreicer R, Carducci M. E-1899: An eastern cooperative oncology group study comparing ketoconazole plus hydrocortisone with docetaxel plus estramustine for asymptomatic, Androgen-Independent, nonmetastatic prostate cancer patients with rising PSA levels. Rev Urol 2003;5 Suppl 2:S35-41.  Back to cited text no. 52
    
53.
Yap TA, Carden CP, Attard G, de Bono JS. Targeting CYP17: Established and novel approaches in prostate cancer. Curr Opin Pharmacol 2008;8:449-57.  Back to cited text no. 53
    
54.
Keizman D, Huang P, Carducci MA, Eisenberger MA. Contemporary experience with ketoconazole in patients with metastatic castration-resistant prostate cancer: Clinical factors associated with PSA response and disease progression. Prostate 2012;72:461-7.  Back to cited text no. 54
    
55.
Njar VC, Brodie AM. Discovery and development of Galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer. J Med Chem 2015;58:2077-87.  Back to cited text no. 55
    
56.
Roviello G, Sigala S, Danesi R, Re MD, Bonetta A, Cappelletti MR, et al. Incidence and relative risk of adverse events of special interest in patients with castration resistant prostate cancer treated with CYP-17 inhibitors: A meta-analysis of published trials. Crit Rev Oncol Hematol 2016;101:12-20.  Back to cited text no. 56
    
57.
Iacovelli R, Verri E, Cossu RM, Aurilio G, Cullurà D, De Cobelli O, et al. The incidence and relative risk of cardiovascular toxicity in patients treated with new hormonal agents for castration-resistant prostate cancer. Eur J Cancer 2015;51:1970-7.  Back to cited text no. 57
    
58.
Cai C, Chen S, Ng P, Bubley GJ, Nelson PS, Mostaghel EA, et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res 2011;71:6503-13.  Back to cited text no. 58
    
59.
Beltran H, Tomlins S, Aparicio A, Arora V, Rickman D, Ayala G, et al. Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res 2014;20:2846-50.  Back to cited text no. 59
    
60.
Bluemn EG, Coleman IM, Lucas JM, Coleman RT, Hernandez-Lopez S, Tharakan R, et al. Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling. Cancer Cell 2017;32:474-89.  Back to cited text no. 60
    
61.
Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk S, Matsumoto AM, et al. Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: Induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res 2011;17:5913-25.  Back to cited text no. 61
    
62.
Li Z, Alyamani M, Li J, Rogacki K, Abazeed M, Upadhyay SK, et al. Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. Nature 2016;533:547-51.  Back to cited text no. 62
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Materials and Me...>Results>Discussion>Conclusion>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed220    
    Printed4    
    Emailed0    
    PDF Downloaded16    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]