Concomitant antihypertensive medication and outcome of patients with metastatic castration‐resistant prostate cancer receiving enzalutamide or abiraterone acetate

Abstract Background The introduction of novel hormonal therapies represented by enzalutamide (ENZ) and abiraterone acetate (ABI) has reached a great progress in the treatment of metastatic castration‐resistant prostate cancer (mCRPC). The majority of mCRPC patients are elderly suffering from chronic co‐morbidities requiring use of various concomitant medications. In the present study, we focused on impact of concomitant antihypertensive medication on the outcomes of mCRPC patients treated with ENZ or ABI. Methods In total, 300 patients were included and their clinical data were retrospectively analyzed. Results Angiotensin‐converting enzyme inhibitors (ACEIs) represented the only concomitant medication significantly associated with survival. The median radiographic progression‐free survival (rPFS) and overall survival (OS) for patients using ACEIs were 15.5 and 32.3 months compared to 10.7 and 24.0 months for those not using ACEIs (p = 0.0053 and p = 0.0238, respectively). Cox multivariable analysis revealed the use of ACEIs a significant predictive factor for both rPFS (HR = 0.704, p = 0.0364) and OS (HR = 0.592, p = 0.0185). Conclusion The findings of this study suggest an association between the concomitant use of ACEIs and longer survival of mCRPC patients receiving ENZ or ABI therapy.


| BACKGROUND
Prostate cancer (PC) represents most frequently diagnosed malignancy in men worldwide. 1,2There is a substantial proportion of metastatic PC patients, who develop metastatic castration-resistant PC (mCRPC), which was defined as castrate testosterone levels and a radiographic progression and/or biochemical progression of prostatespecific antigen (PSA) levels on androgene deprivation therapy (ADT). 3In the last decade, a great progress has been reached in the systemic therapy for mCRPC patients.5][6][7][8][9] Despite this indisputable therapeutic revolution, the prognosis of mCRPC remains poor and further treatment optimization seems to be desirable.
The majority of mCRPC patients are elderly suffering from various chronic co-morbidities requiring use of several concomitant medications.Cardiovascular diseases in particular represent the most common group of chronic co-morbidities in the PC patient population. 10,11The emerging issue that should be elucidated is whether the concomitant administration of cardiovascular medication may affect the efficacy of anticancer therapy in these patients.3][14][15][16][17][18][19][20][21][22][23][24] Notably, the data on mCRPC are very limited and this field remains unexplored.
In our retrospective study we focused on the possible impact of concomitant exposure to common antihypertensive medication on the outcomes of mCRPC patients receiving ENZ or ABI.

| Study design
Data from mCRPC patients receiving ENZ or ABI were analyzed.We retrospectively assessed the association between radiographic progression-free survival (rPFS) and overall survival (OS) and the use of antihypertensive medications including beta-blockers (BBs), angiotensinconverting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs) and diuretics.Clinical data were extracted from the hospital information system.The use of concomitant antihypertensive medication was assessed at the beginning of ENZ or ABI therapy.All the assessed concomitant medications were administered individually.
The protocol of the study and the form of Informed consent for participants were approved by the Ethical Committee of the Faculty of Medicine and University Hospital in Pilsen on June 7, 2021 (No. 245/2021) and complied with the International Ethical Guidelines for Biomedical Research, the Declaration of Helsinki, and local laws.The Informed consent was obtained from all the participants.

| Patients and treatment
Patients with histologically confirmed mCRPC fulfilling the criteria for castration resistance were treated with ENZ or ABI between 2007 and 2022 at the Department of Oncology and Radiotherapeutics, University Hospital in Pilsen, Pilsen, Czech Republic.ENZ (Xtandi, Astellas Pharma Inc., Tokyo, Japan) was administered orally in the standard approved dose (160 mg daily).ABI (Zytiga, Janssen Pharmaceuticals Co., Beerse, Belgium) was administered orally in the standard approved schedule (1000 mg daily) in combination with prednisone (10 mg daily).The therapy with ENZ or ABI was continued until disease progression, unacceptable toxicity, or patient refusal.
The routine clinical checks including physical examination and biochemical laboratory tests with PSA were performed each moth, and radiographic controls using computed tomography (CT) or positron emission tomography-CT (PET/CT) or PET-magnetic resonance (PET/ MR) were performed every 3 to 6 months.The objective response to therapy was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). 25

Conclusion:
The findings of this study suggest an association between the concomitant use of ACEIs and longer survival of mCRPC patients receiving ENZ or ABI therapy.

| Statistical analysis
Standard descriptive statistics and frequencies were used to characterize the sample data set.Baseline clinical characteristics of antihypertensive users and nonusers were compared using the t-test (normally distributed continuous variables), the Mann-Whitney U-test (non-normally distributed continuous variables), Fisher's exact test and the chi-squared test (categorical variables).Overall survival (OS) was defined as a time from the date of treatment initiation until the date of death.Radiographic progression-free survival (rPFS) was defined as a time from the date of treatment initiation until the date of first documented radiographic progression or death.Patients in whom the terminal event had not occurred were censored at the date of the last follow-up.OS and rPFS were estimated using the Kaplan-Meier method and point estimates were accompanied by two-sided 95% confidence intervals.The Gehan-Wilcoxon test was used for the assessment of statistical significance of the differences in survival between users and nonusers of individual comedication types.Multivariable Cox proportional hazards model was then used to verify the prognostic independence of antihypertensive usage of other common clinical factors.The median follow-up time was estimated using the inverse the Kaplan-Meier method.The level of statistical significance was set at α = 0.05 and all reported p-values are two-tailed.The statistical analysis was performed using STATISTICA (Version 12; StatSoft, Inc., TuIsa, OK, USA).

| Patient characteristics
In total, 300 mCRPC patients were included in our study and their characteristics are summarized in Table 1.
The Kaplan-Meier analysis with Gehan-Wilcoxon test assessing the impact of concomitant antihypertensive medication on patients' survival found that ACEIs were the only individual medication type with significant impact on rPFS and OS, increasing the observed median survival times by 45% (p = 0.0053) and 35% (p = 0.0238), respectively (Table 2).
The results of the Cox multivariable analysis show that the use of ACEIs remains a significant factor associated with both rPFS (HR = 0.704 [95% CI 0.506-0.978],p = 0.0364) and OS (HR = 0.592 [95% CI 0.383-0.916],p = 0.0185) (Table 4).Other independent favorable factors for superior rPFS were pre-chemotherapy setting of ENZ or ABI treatment and metachronous metastatic disease, while other independent favorable factors for superior OS included Gleason score of 7 or lower, metachronous metastatic disease, and the absence of visceral metastases.

| DISCUSSION
The advent of NHTs brought a great progress into the systemic treatment of mCRPC and recently, also into the treatment of metastatic hormone-sensitive PC (mHSPC).
The data from our retrospective study suggest that the concomitant use of ACEIs is significantly associated with better outcome in mCRPC patients receiving ENZ or ABI.Among all the investigated antihypertensive medications, only the use of ACEIs showed significant association with patients' outcome.Furthermore, the results of the multivariate Cox proportional hazards model revealed the concomitant use of ACEIs as an independent predictive factor for both rPFS and OS.The circulating renin-angiotensin system (RAS) is fundamentally known to regulate blood pressure and electrolyte homeostasis.In addition, local RAS acting at the cellular level is involved in various important biological processes including cell growth, metabolism and proliferation. 26It is expressed in many tissues including cancer cells and tumor microenvironment. 27,28The local RAS has been proposed to have an important role in development and pathophysiology of PC. 29 Two RAS signaling pathways can be distinguished, classical and alternative, both involved in cancer-related processes.The classical RAS signaling is mainly represented by the Angiotensin (Ang) II/AT1 and AT2 receptor (AT1R, AT2R) pathway.Besides its major role in the constitution of cardiovascular homeostasis, it can stimulate angiogenesis, inflammation and also cancer cell proliferation acting thru the activation of mitogen-activated protein kinase (MAPK) and signal transducer activator of transcription 3 (STAT3) signaling pathways. 30The alternative RAS signaling is mainly represented by the Ang (1-7)/MAS receptor signaling pathway.Its functions have been recently studied, mainly in cardiovascular regulation. 31Interestingly, it has been reported that Ang (1-7) also plays a role in cancer.However, the effect of alternative RAS signaling in cancer is not fully understood, it seems that it is different according to the specific cancer type. 29Anti-neoplastic properties of Ang (1-7) have been suggested in lung, colon, breast and PC, while cancer-promoting effects have been suggested in renal cell cancer. 29AS inhibitors (RASIs), represented by ACEIs and ARBs, are agents commonly used in the treatment of arterial hypertension, myocardial infarction, heart failure and chronic kidney disease.After being used for decades in various cardiovascular diseases, RASIs have recently received a considerable attention also in oncology.
3][34][35][36] Although, several anticancer effects of RASI have been suggested in experimental models, their impact on the clinical outcome of PC patients has not been fully elucidated.The impact of RASIs on favorable prognosis of patients with localized-stage PC has been suggested by Santala et al.Their study including 14,422 patients undergoing surgery showed that the use of ARBs was associated with decreased risk of cancer-specific death. 19Similar findings have been reported by Siltari et al.  who observed an association between the use of ARBs and improved cancer-specific survival in a heterogeneous cohort of 8253 PC patients treated with ADT (HR = 0.81, 95% CI 0.67-0.99). 20Interestingly, in both studies, the positive effect seemed to be apparent particularly for ARBs, not for ACEIs, which is contradictory to our results showing longer survival in ACEIs users, and not in those using ARBs.Although the reason for such contradictory results is not clear, different patient population and treatment should be pointed out.The study by Santala et al. focused in early-stage HSPC patients treated surgically and the study by Siltari et al. focused on HSPC patients treated with ADT. 19,20Thus, both studies included patient cohorts different to our study focusing on mCRPC, which has substantially different biological properties compared to HSPC. 36Regarding the data on ACEIs, Ronquist et al. reported that the addition of captopril tend to lower recurrence rate after radical prostatectomy in a small sample prospective study. 22In the field of mCRPC, data on the impact of concomitant RASI use are very limited.Uemura et al. reported a promising effect of ARB, candesartan, in a cohort of heavily pretreated mCRPC patients in a Phase II pilot trial. 23The data from a retrospective study, recently reported by Wilk et al., including 93 mCRPC men treated with ABI in the post-chemotherapy setting show longer time to treatment failure in RASI users versus nonusers (HR = 0.61, 95% CI 0.4-0.94,p = 0.02), while the type of RASI was not specified. 24It is worth mentioning that their study was substantially limited by the small number of patients included (in total: 93, 37 [40%] used RASIs), which resulted in the absence of relevant assessments of OS and of the specific role of RASI subgroups (i.e., ARBs vs. ACEIs).Similarly, we found significantly better outcome for mCRPC patients using RASIs in general.Furthermore, among all RASIs included in our study, the impact on survival was significant only for ACEIs.As the different effects of ACEIs and ARBs cannot be clearly explained, this issue should be further examined.However, we can hypothesize that the beneficial effect of ACEIs could be predominantly based on their influence on the alternative RAS pathway, besides the inhibition of Ang II formation preventing downstream signaling mediated by AT1R.It has been proposed that ACEIs do not interfere with the conversion of Ang I to Ang (1-9) catalyzed by endopeptidases.After the conversion, Ang (1-9) is cleaved by ACE-2, which is not affected by ACEIs, to become Ang (1-7) binding to MAS receptors. 37,38The anticancer effects of Ang (1-7)/MAS signaling have been mentioned above.Noatably, it has been demonstrated that Ang (1-7) is able to effectively reduce prostate cancer metastasis in experimental models with androgen-independent prostate cancer cells. 39Aditionally, when the effect of ACEIs was analyzed for ENZ and ABI users separately, both groups showed longer rPFS and OS of ACEI users, while the statistical significance was reduced (showing a significant result only for rPFS in ENZ users) in comparison to the effect observed in the whole sample.This is, however, to be expected as the statistical sample got smaller with the separation of ENZ and ABI users.The fact that both groups showed similarly reduced significance could be an indication that both ENZ and ABI users contributed to the effect of ACEIs observed in the whole sample to a similar degree.
16][17][18][19][20][21]24 We did not find a significant impact of concomitant use of BBs on the survival of mCRPC patients in our study.Our results are in agreement with several studies assessing the role of concomitant medication in PC patients discussed above, including the study by Wilk et al. focused on mCRPC patients. 14,19,20,24ajor limitations of the present study represent the retrospective design and the limited number of patients, in particular those using a specific concomitant antihypertensive medication.The dosage and duration of the observed concomitant medication was not available.Furthermore, the present study did not include any control cohort of patients treated with other type systemic therapy (e.g., chemotherapy), thus it cannot be clearly interpreted that the concomitant use of ACEIs impacts specifically the efficacy of NHTs or whether it could improve the prognosis of mCRPC patients in general.Another potential limitation of our study is that there were included patients treated with two NHTs with different mechanism of action represented by ENZ and ABI and the specific molecular mechanism of the additive effect of ACEIs cannot be clearly explained.Nevertheless, according to our best knowledge, the present study is the largest one published so far focusing on the potential impact of the concomitant use of antihypertensive medication on survival of patients with mCRPC receiving NHTs.Moreover, the strength of this study is that all the patients were treated in a single clinical Center under similar conditions of common clinical practice.unrelated to this project.Jan Filipovsky has received honoraria from Servier a ProMED.CS, all unrelated to this project.MS has received research support and honoraria from Janssen, Bristol Myers Squibb, Ipsen, MSD, Astellas and Bayer, all unrelated to this project.SB received honoraria as speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, AstraZeneca, Merck, all unrelated to this project.PH, HK, MH, JK, OS, OT and VL declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

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Statistically significant values are in bold.F I G U R E 1Kaplan-Meier estimates of radiographic progression-free survival (rPFS) (A) and overall survival (OS) (B) according to the use of angiotensin-converting enzyme inhibitors (ACEIs).

Median survival months, (95% CI) p-Value Median survival months, (95% CI) p-Value
Baseline patient characteristics.The Kaplan-Meier analysis with Gehan-Wilcoxon test assessing the impact of the used concomitant medications on radiographic progression-free survival (rPFS) and overall survival (OS).