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Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate
EUF-314; No. of Pages 6 E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Prostate Cancer
Statin Use and Survival in Patients with Metastatic Castrationresistant Prostate Cancer Treated with Abiraterone Acetate Giuseppe Di Lorenzo a,*, Guru Sonpavde b, Gregory Pond c, Giuseppe Lucarelli d, Sabrina Rossetti e, Gaetano Facchini e, Sarah Scagliarini f, Giacomo Cartenı` f, Piera Federico g, Bruno Daniele h, Franco Morelli i, Teresa Bellelli j, Matteo Ferro a, Sabino De Placido a,y, Carlo Buonerba a,j,y a
Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy;
Birmingham Comprehensive Cancer Center, Birmingham, AL, USA;
c
b
Department of Medicine, University of Alabama at
McMaster University, Hamilton, Ontario, Canada;
d
Department of Emergency and
e
Organ Transplantation, Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy; Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori “Fondazione G. Pascale”, Naples, Italy; f Unità Operativa Sperimentazioni Cliniche Oncologia, Azienda Ospedaliera di Rilievo Nazionale “Antonio Cardarelli”, Naples, Italy; h
g
Medical Oncology Department, G. Rummo Hospital, Benevento, Italy;
Department of Medical Oncology, Casa Sollievo della Sofferenza Hospital, Medical Oncology, San Giovanni Rotondo, Italy; i Medical Oncology, Hospital
San Luca, Vallo della Lucania, Salerno, Italy; j Istituto Zooprofilattico Sperimentale del Mezzogiorno, Portici, Italy
Article info
Abstract
Article history: Accepted March 21, 2017
Background: Although statin use has been associated with favorable effects in various solid malignancies, no conclusive evidence is available at present. Statins are safe and inexpensive, and may synergize with novel antiandrogen agents abiraterone via pharmacokinetic interactions and decrease substrate availability for de novo androgen biosynthesis. Objective: To determine whether statin use affects survival in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone. Design, setting, and participants: Medical records of patients with documented mCRPC between September 2011 and August 2016 were reviewed at multiple participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. A total of 187 patients receiving abiraterone for mCRPC between September 2011 and August 2016 were eligible for inclusion in this retrospective study. Outcome measurements and statistical analysis: Patients were assessed for overall survival (OS), statin use at the time of treatment initiation, prostate-specific antigen (PSA) variations, and other variables of interest. Univariable and multivariable analysis was used to explore the association of variables of interest with OS and PSA declines. Results and limitations: Statin use was a significant prognostic factor for longer OS in univariable (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.37–0.72; p < 0.001) and multivariable analysis (HR 0.40, 95% CI 0.27–0.59; p < 0.001) and was significantly associated with PSA declines (>50% decline at 12 wk: 72.1% in statin users vs 38.5% in non-users; p < 0.001). Conclusions: Our study suggests a prognostic impact of statin use in patients receiving abiraterone for mCRPC. The mechanism of this interaction warrants elucidation, but may include enhancement of the antitumor activity of abiraterone as well as cardioprotective effects. Patient summary: We assessed the effects of statin use in patients with advanced prostate cancer receiving abiraterone. Patients treated with a statin plus abiraterone appeared to live longer than those treated with abiraterone only. Since no negative drug-drug interaction is known and statins are widely used and inexpensive, further studies assessing the use of abiraterone plus statins are warranted. © 2017 Published by Elsevier B.V. on behalf of European Association of Urology.
Associate Editor: James Catto Keywords: Prostate cancer Statins Abiraterone
y These authors share senior authorship. * Corresponding author. Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Pansini, 5, Naples, Italy. Tel. +39 081 7463660. E-mail address: [email protected] (G. Di Lorenzo).
http://dx.doi.org/10.1016/j.euf.2017.03.015 2405-4569/© 2017 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Di Lorenzo G, et al. Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.03.015
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1.
Introduction
factors, previous local and systemic treatments and treatment with abiraterone, statin use, and early prostate-specific antigen (PSA) declines
Prostate cancer is the most prevalent malignancy in men, with an estimated 1 111 700 incident cases diagnosed in 2012 worldwide [1]. After benefitting from androgen ablation treatment, virtually all patients with recurrent/advanced disease develop castration-resistant prostate cancer (CRPC), which progresses despite androgen deprivation treatment [2]. In most patients with CRPC, the androgen receptor (AR) pathway continues to drive tumor growth [3], which is consistent with the effectiveness of the novel antiandrogen treatments abiraterone and enzalutamide [4–7]. While abiraterone acetate inhibits residual adrenal and intratumoral androgen synthesis by blocking CYP17A activity [8], enzalutamide directly inhibits the AR with no agonist activity [9]. Statins are commonly prescribed cholesterol-lowering drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, preventing the conversion of HMGCoA into mevalonate [10]. In vitro studies have shown that besides their direct pro-apoptotic effects, statins may also reduce cellular proliferation by inhibiting Ras proteins and other cellular pathways [11]. From a clinical perspective, statin use has been associated with survival benefits in large cohorts of patients with solid malignancies [12], including breast [13], colorectal [14], and prostate cancer [15,16], and multiple putative biological mechanisms have been proposed [17–19]. In the particular case of prostate cancer, previous studies have examined the impact of statins in broad heterogeneous populations with mostly localized hormone-naïve disease. For an androgen-addicted tumor such as prostate cancer, we hypothesized that statins may synergize with the novel antihormonal agent abiraterone in metastatic CRPC, considering that cholesterol is a substrate for adrenal and intratumoral androgen biosynthesis and accumulates in prostate cancer cells [20,21]. In this retrospective study, we assessed the prognostic role of statin use in patients starting abiraterone after controlling for known prognostic factors in a real-world clinical scenario.
2.
Patients and methods
2.1.
Inclusion criteria
The medical records of patients with documented mCRPC treated with abiraterone between September 2011 and August 2016 were reviewed at ten participating centers. Prostate cancer had to be histologically or cytologically confirmed. Ongoing androgen deprivation treatment or orchiectomy was required for inclusion in this study, in accordance with
>30% and >50% at 4, 8, 12, and 16 wk.
2.3.
Data analysis
Summary statistics were used to describe the patient population and outcomes. Univariable Cox proportional hazards regression was used to evaluate variables as potentially prognostic for overall survival (OS). Multivariable modeling was conducted using the full model method, that is, including all potential factors in a multivariable model, regardless of whether they were statistically significant or not. The effect of statin use on survival was then assessed after adjusting for factors included in the multivariable model. Logarithmic transformation of factors was performed for statistical normalization purposes as necessary. Supportive analyses were performed by excluding patients who received enzalutamide before abiraterone (given the similar mechanism of action of these treatments). Differences in characteristics between patients treated with abiraterone plus statins and those who received abiraterone alone were assessed by using Fisher’s exact test for dichotomous variables, a x2 test for categorical variables (reason for discontinuation), the Wilcoxon rank-sum test for continuous variables, and a log-rank test for OS. The association between statin use at baseline and PSA declines at different time points was tested using Fisher’s exact test. All tests were two-sided and p 0.05 was considered statistically significant. No statistical adjustments were made for multiple testing. OS was defined as the time between treatment initiation and either the date of death or of last follow-up for surviving patients.
3.
Results
3.1.
Patient characteristics
A total of 187 patients starting abiraterone therapy between September, 2011 and January, 2016 were included. Summary statistics for patients treated with and without statins are shown in Table 1. No significant differences between the two groups were identified, except for a different distribution of the Gleason score, with approximately 25% vs. 50% of patients in the abiraterone plus statin vs. abiraterone only group having a Gleason score of 8-10, and a statistically (yet not clinically) meaningful difference in baseline hemoglobin levels. Patients were a mean age of 66.8, while 33 (17.7%) had visceral disease when treated with abiraterone, and 75 (40.7%) presented a Gleason score of 8 or higher. Median duration on abiraterone was 31.3 weeks and 11 patients remained on abiraterone at the time of analysis. Seventyone (38.4%) were being treated with statins. By weeks 4, 8, 12 and 16, median decline in PSA was 12.2%, 37.5%, 50.0% and 63.0% respectively. Median OS was 18 months. 3.2.
Association of statin use with survival and PSA declines
regulatory requirements for abiraterone prescription, with a serum testosterone level of <50 ng/dl. The castration-resistant state was ascertained locally according to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria [22]. Patients who received at least one 28-d cycle of abiraterone were regarded as eligible for this retrospective study.
2.2.
Data retrieved
Demographic data for eligible patients were retrieved, along with information regarding known and previously recognized baseline prognostic
Table 2 summarizes the results for Cox proportional hazards regression analyses. Excluding two patients with unknown statin use, the median and 1-yr survival among the 71 patients treated with statins were 22.2 mo (95% CI 19.4–25.0) and 87.1% (95% CI 76.6–93.1%), compared to 15.3 mo (95% CI 12.9–17.1) and 62.2% (95% CI 52.5–70.5%) for the 114 patients not on statins (Fig. 1). Statin use was a significant prognostic factor for longer OS in univariable analysis (hazard ratio [HR] 0.51, 95% CI 0.37–0.72;
Please cite this article in press as: Di Lorenzo G, et al. Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.03.015
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Table 1 – Baseline characteristics of the study cohort. Statins (n = 71)
Mean age at diagnosis, yr (SD) PSA at Dx (ng/ml) Gleason score 7 8–10 Time from first HDx of PC to ADT (mo) Time from first HDx of PC to mPC (mo) Time from first RDx of mPC to CRPC (mo) Prior prostatectomy, n (%) Prior radiotherapy, n (%) Prior docetaxel, n (%) Prior cabazitaxel, n (%) Prior enzalutamide, n (%) Time from Dx to AA (mo) Time on AA (wk) Visceral disease, n (%) Opiates, n (%) Alkaline phosphatase at AA start Hemoglobin at AA start Lactate dehydrogenase at AA start Neutrophils at AA start Lymphocytes at AA start Neutrophil/lymphocyte ratio PSA at start of AA PSA change from Dx to AA start (%) Change in PSA at 4 wk (%) Change in PSA at 8 wk (%) Change in PSA at 12 wk (%) Change in PSA at 16 wk (%) Reason for AA discontinuation, n (%) Radiological PSA/clinical progression PSA only progression Clinical progression Toxicity Not stated Still on treatment Time to death Deaths, n (%) Median survival, mo (95% CI) 1-yr survival, % (95% CI) 2-yr survival, % (95% CI)
No statins (n = 114)
n
Result
n
71 67
65.9 (6.3) 12 (1.97–180)
114 106
67.5 (6.2) 13 (4–1770)
71
53 (74.6) 18 (25.4) 19.8 (1.3 to 121.1) 26.7 (1.3 to 128.3) 26.7 (1.3 to 128.3) 31 (43.7) 36 (50.7) 43 (60.6) 17 (23.9) 7 (9.9) 63.4 (10.1–191.8) 49.1 (11.3–121.7) 9 (12.7) 43 (60.6) 170 (56–430) 11.8 (9.0–14.5) 260 (135–600) 4000 (2400–9200) 1715 (1100–3200) 2.20 (1.31–5.33) 85 (4.9–700) +471 (83.6 to 8650) 23.1 (86.3 to 107) 56.9 (93.8 to 50) 76.3 (98.3 to 200) 83.6 (98.8 to 276)
111
55 (49.5) 56 (50.5) 22.3 (10.9 to 178.3) 25.6 (3.3 to 207.9) 13.7 (1.3 to 167.9) 51 (45.1) 53 (46.9) 75 (65.8) 44 (38.6) 10 (8.8) 57.9 (6.2–212.5) 23.5 (4.1–118.1) 23 (20.2) 64 (56.1) 184 (48–1659) 11.5 (8.6–14.5) 290 (120–2297) 3900 (1900–7280) 1700 (500–3210) 2.18 (1.42–10.4) 90 (4.95–2000) 453 (98.7 to 28471) 11.0 (97.9 to 1894) 21.9 (99.0 to 2344) 35.6 (99.5 to 613) 13.3 (99.7 to 728)
70 68 68 71 71 71 71 71 71 64 71 71 63 69 59 58 56 56 71 67 69 68 68 67 71
a
114 110 108 113 113 114 114 114 114 110 a 114 114 80 83 75 72 72 72 114 106 108 105 104 96 114
54 (76.1) 4 (5.6) 5 (7.0) 0 (0.0) 1 (1.4) 7 (9.9)
p value
Result 0.12 0.30
0.001 0.75 0.77 0.14 0.88 0.65 0.53 0.053 0.80 0.38 <0.001 0.23 0.65 0.26 0.031 0.11 0.17 0.85 0.99 0.93 0.34 0.030 <0.001 <0.001 <0.001 0.10
76 (66.7) 9 (7.9) 17 (14.9) 5 (4.4) 3 (2.6) 4 (3.5)
71
<0.001
114 57 (80.3) 22.2 (19.4–25.0) 87.1 (76.6–93.1) 45.4 (32.8–57.2)
96 (84.2) 15.3 (12.9–17.1) 62.2 (52.5–70.5) 16.6 (9.8–24.9)
AA = abiraterone acetate; ADT = androgen deprivation therapy; CI = confidence interval; Dx = diagnosis; HDx = histological Dx; RDx = radiological Dx; PC = prostate cancer; mPC = metastatic PC; CRPC = castration-resistant PC; PSA = prostate-specific antigen. Results are reported as median (range) for continuous variables unless stated otherwise. a Excludes 11 patients still on abiraterone.
p < 0.001) and after adjusting for factors in the multivariable model (HR 0.40, 95% CI 0.27–0.59; p < 0.001). Results were similar in a supportive analysis excluding 17 patients who had received prior enzalutamide: statin use remained a significant prognostic factor for OS in univariable (HR 0.48, 95% CI 0.34–0.68; p < 0.001) and multivariable analysis (HR 0.42, 95% CI 0.28–0.62; p < 0.001). The positive effect of statins on survival remained after adjusting for baseline PSA and percentage change in PSA over time (Table 3). Statin use at baseline was also associated with significantly better 30% and 50% PSA decline rates at 8, 12, and 16 wk (Table 4). 4.
Discussion
Accumulating evidence supports a beneficial effect of statin use in cancer patients. In a recently published meta-analysis [12] conducted in patients affected by various solid
malignancies, including breast, prostate, and colorectal cancer, clinically and statistically meaningful overall and cancer-specific survival advantages were associated with prediagnosis and postdiagnosis statin use in two cohorts of 947 410 and 104 811 participants, respectively. In particular, postdiagnosis use of statins was associated with a HR of 0.81 (95% CI 0.72–0.91) for all-cause mortality and a HR of 0.77 (95% CI 0.66–0.88) for cancer-specific mortality, while statin use before cancer diagnosis was associated with a HR of 0.79 (95% CI 0.74–0.85) for all-cause mortality and a HR of 0.69 (95% CI 0.60–0.79) for cancer-specific mortality. Notably in this large patient cohort, incremental benefits were associated with higher exposure to statins. When looking at single studies, heterogeneous, sometimes discordant, results were obtained in different prostate cancer patient populations, which included men with nonmetastatic disease only [23,24], men treated with prostatectomy or external-beam
Please cite this article in press as: Di Lorenzo G, et al. Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.03.015
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Table 2 – Prognostic factors for overall survival. Factor Age at diagnosis (per year) Prostate-specific antigen at TBL (LTF) Alkaline phosphatase at TBL (LTF) Hemoglobin at TBL (per unit) Lactate dehydrogenase at TBL (LTF) Neutrophils at TBL (LTF) Lymphocytes at TBL (per unit) Neutrophil/lymphocyte ratio (LTF) Gleason score (8 vs 7) Prior prostatectomy (yes vs no) Prior radiotherapy (yes vs no) Visceral disease (yes vs no) Opiates (yes vs no) Prior docetaxel (yes vs no) Prior cabazitaxel (yes vs no) Prior enzalutamide (yes vs no) Statins (yes vs no) Multivariable model Age at diagnosis (per year) Prostate-specific antigen at TBL (LTF) Alkaline phosphatase at TBL (LTF) Hemoglobin at TBL (per unit) Lactate dehydrogenase at TBL (LTF) Neutrophil/lymphocyte ratio at TBL (LTF) Gleason score (8 vs 7) Visceral disease at TBL (yes vs no) Opiates at TBL (yes vs no) Prior docetaxel (yes vs no) Prior cabazitaxel (yes vs no) Prior enzalutamide (yes vs no) Statins at TBL (yes vs no)
n
HR (95% CI)
p value
187 187 143 152 134 130 128 128 184 186 186 187 187 187 187 187 185
1.02 (1.00–1.05) 1.43 (1.22–1.67) 1.75 (1.11–2.76) 0.69 (0.57–0.83) 3.07 (1.79–5.25) 0.27 (0.12–0.62) 1.00 (1.00–1.00) 0.69 (0.31–1.56) 1.14 (0.81–1.59) 1.44 (1.04–1.98) 0.84 (0.61–1.15) 1.67 (1.07–2.59) 2.71 (1.91–3.86) 1.90 (1.34–2.70) 3.86 (2.70–5.52) 3.15 (1.75–5.68) 0.51 (0.37–0.72)
0.11 <0.001 0.016 <0.001 <0.001 0.002 0.48 0.37 0.46 0.028 0.27 0.023 <0.001 <0.001 <0.001 <0.001 <0.001
128 128 128 128 128 128 128 128 128 128 128 128 128
1.05 (1.01–1.10) 1.82 (1.32–2.51) 1.13 (0.58–2.23) 1.04 (0.78–1.38) 2.74 (1.21–6.20) 0.87 (0.36–2.16) 1.47 (0.93–2.32) 0.25 (0.11–0.56) 1.36 (0.81–2.28) 1.08 (0.64–1.84) 7.52 (4.06–13.93) 25.13 (7.72–81.81) 0.40 (0.27–0.59)
0.013 <0.001 0.72 0.79 0.016 0.77 0.10 <0.001 0.25 0.77 <0.001 <0.001 <0.001
HR = hazard ratio; CI = confidence interval; LTF = log transformed; TBL = treatment baseline.
radiotherapy [25], men with localized high-risk or metastatic disease [26], men treated with external-beam radiotherapy only [27], and patients with castration-resistant prostate cancer receiving systemic abiraterone treatment
[28]. The available data have been systematically assessed in meta-analyses [29–31]. While Scosyrev et al [31] did not identify any protective effect of statin use in patients receiving prostatectomy or radiotherapy, two recently published meta-analyses found similar survival advantages. In a sample of 100 536 participants, Meng et al [29] found that prediagnostic statin use was associated with a significantly lower risk of both all-cause mortality (HR 0.56, 95% CI 0.38–0.83) and prostate cancer-specific mortality (HR 0.53, 95% CI 0.36–0.77), while postdiagnostic statin use was associated with a HR of 0.77 (95% CI 0.69– 0.87) for all-cause mortality and 0.64 (95% CI 0.52–0.79) for prostate cancer–specific mortality. Similar results have been reported by Raval et al [30]. While the preponderance of clinical findings concern patients with localized and/or hormone-sensitive disease, limited data are available in Table 3 – Effect of statins on survival after adjusting for baseline PSA and percentage change in PSA over time. n
Fig. 1 – Survival of patients receiving abiraterone with or without statins. A total of 71 patients treated with statins had median overall survival of 22.2 mo, compared to 15.3 mo for the 114 patients not receiving statins.
Baseline 4 wk 8 wk 12 wk 16 wk
185 177 173 172 162
HR (95% CI) 0.49 0.49 0.49 0.58 0.59
(0.35–0.69) (0.35–0.70) (0.35–0.70) (0.40–0.83) (0.40–0.86)
p value <0.001 <0.001 <0.001 0.003 0.006
PSA = prostate-specific antigen; HR = hazard ratio; CI = confidence interval.
Please cite this article in press as: Di Lorenzo G, et al. Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.03.015
EUF-314; No. of Pages 6 E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X
Table 4 – Effect of statins on >30% and >50% PSA decline rates at different time points. Patients, n/N (%)
PSA >30% 4 wk 8 wk 12 wk 16 wk PSA >50% 4 wk 8 wk 12 wk 16 wk
p value
No statins
Statins
39/108 (36.1) 46/108 (43.8) 55/104 (52.9) 44/96 (45.8)
32/69 (46.4) 47/68 (69.1) 53/68 (77.9) 57/67 (85.1)
0.21 0.002 0.001 <0.001
23/108 (21.3) 34/105 (32.4) 40/104 (38.5) 40/96 (41.7)
20/69 39/68 49/68 50/67
0.28 0.002 <0.001 <0.001
(29.0) (57.4) (72.1) (74.6)
a
PSA = prostate-specific antigen. Fisher’s exact test.
a
the setting of patients with castration-resistant disease receiving abiraterone. We hypothesized that in castrate patients who are potentially still sensitive to androgens, statins may synergize with the antiandrogen agent abiraterone on the grounds of the proven effect of statins on androgen biosynthesis [32]. Furthermore, statins may decrease the formation of lipid rafts that contain a subpopulation of androgen receptors regulating intracellular signaling pathways [11]. For this retrospective study, we presented data on statin use at baseline in a cohort of patients starting abiraterone and found that statin use at baseline was independently associated with both improved OS and higher rates of PSA declines at several time points, after correcting for multiple potential confounders. The characteristics of patients treated with or without statins were well balanced. While a significantly higher proportion of patients in the no-statin group compared to the statin group had a Gleason score of 8–10, it must be noted that a higher Gleason score has been associated with longer duration of abiraterone treatment [33]. The prognostic value of statin use in abiraterone patients was maintained even after adjusting for baseline PSA levels and PSA declines over time, suggesting that PSA declines may not explain the potential additional benefit associated with statin use in abiraterone patients. Other authors have hypothesized that abiraterone efficacy, which is dependent on inhibition of intratumoral steroidogenesis, may be improved by statin-induced inhibition of the organic anionic transporter solute SLCO2B1 [34], which mediates the uptake of the adrenal androgen dehydroepiandrosterone (DHEAS), a precursor a testosterone. Moreover, it has been reported that statins cause selective degradation of mutant variants of p53, which is frequently mutated in prostate cancer [35], by impairing its interaction with Hsp40 family member DNAJA1 [36]. Nevertheless, in another retrospective study of 108 men with mCRPC treated with abiraterone either with (n = 21) or without (n = 87) concomitant statin treatment, PSA decline 50% (57% vs 53%; p = 0.73), median progression-free survival (9 vs 10 mo; p = 0.97), and OS (14 vs
5
18 mo; p = 0.77) did not differ significantly between the groups [28]. Although the hypothesis that abiraterone may synergize with statins is intriguing, the available evidence, including the data presented here, is not sufficient to be conclusive. Like others, our study has a number of limitations, including those typical of retrospective studies and a lack of data for previous exposure to statins, statin type and treatment duration, comorbidities, serum lipid levels, cardiovascular events, and prostate cancer–specific survival. Nevertheless, the study by Boegemann et al [28] included only 21 patients treated with abiraterone plus statins, which may provide inadequate power for detection of any differences, while our study included 71 patients on abiraterone plus statins. 5.
Conclusions
In conclusion, our study is the largest full report exploring the prognostic value of statin use at the time of abiraterone treatment initiation. We note that the magnitude of the effect on survival associated with statin use in our patient population is consistent with previously published data in prostate cancer patients [29,30] and that statin use was associated with better odds of having PSA declines. Despite the multiple limitations of our study, our data suggest a potential protective effect of statins in patients undergoing abiraterone treatment. Given the potential utility of continuing statin administration in selected cancer patients with advanced disease [37] as well as the inexpensiveness and safety of statins, we believe that our findings add to the existing evidence supporting a prospective interventional study comparing abiraterone plus statins versus abiraterone alone in selected mCRPC patients. Further studies are required not only to confirm such an association but also to assess whether statins may be beneficial in all mCRPC patients or only in those receiving abiraterone.
Author contributions: Giuseppe Di Lorenzo had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Buonerba, Di Lorenzo. Acquisition of data: All authors. Analysis and interpretation of data: Buonerba, Di Lorenzo, Pond, Sonpavde. Drafting of the manuscript: Buonerba. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Pond. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: De Placido. Other: None.Financial disclosures: Giuseppe Di Lorenzo certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Guru Sonpavde has received consultant fees from Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, AstraZeneca, Merck, Genentech, Argos, and Agensys; institutional research support from Bayer, Onyx, Celgene,
Please cite this article in press as: Di Lorenzo G, et al. Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.03.015
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Boehringer-Ingelheim, Merck, and Pfizer; author fees from Uptodate; and speaker fees from Clinical Care Options. The remaining authors have nothing to disclose.
blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway. J Exp Clin Cancer Res 2010;29:127. [20] Krycer JR, Brown AJ. Cholesterol accumulation in prostate cancer: a classic observation from a modern perspective. Biochim Biophys
Funding/Support and role of the sponsor: None.
Acta 2013;1835:219–29. [21] Mostaghel EA, Solomon KR, Pelton K, Freeman MR, Montgomery RB. Impact of circulating cholesterol levels on growth and intratumoral
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Please cite this article in press as: Di Lorenzo G, et al. Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.03.015
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Prostate Cancer
Statin Use and Survival in Patients with Metastatic Castrationresistant Prostate Cancer Treated with Abiraterone Acetate Giuseppe Di Lorenzo a,*, Guru Sonpavde b, Gregory Pond c, Giuseppe Lucarelli d, Sabrina Rossetti e, Gaetano Facchini e, Sarah Scagliarini f, Giacomo Cartenı` f, Piera Federico g, Bruno Daniele h, Franco Morelli i, Teresa Bellelli j, Matteo Ferro a, Sabino De Placido a,y, Carlo Buonerba a,j,y a
Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy;
Birmingham Comprehensive Cancer Center, Birmingham, AL, USA;
c
b
Department of Medicine, University of Alabama at
McMaster University, Hamilton, Ontario, Canada;
d
Department of Emergency and
e
Organ Transplantation, Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy; Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori “Fondazione G. Pascale”, Naples, Italy; f Unità Operativa Sperimentazioni Cliniche Oncologia, Azienda Ospedaliera di Rilievo Nazionale “Antonio Cardarelli”, Naples, Italy; h
g
Medical Oncology Department, G. Rummo Hospital, Benevento, Italy;
Department of Medical Oncology, Casa Sollievo della Sofferenza Hospital, Medical Oncology, San Giovanni Rotondo, Italy; i Medical Oncology, Hospital
San Luca, Vallo della Lucania, Salerno, Italy; j Istituto Zooprofilattico Sperimentale del Mezzogiorno, Portici, Italy
Article info
Abstract
Article history: Accepted March 21, 2017
Background: Although statin use has been associated with favorable effects in various solid malignancies, no conclusive evidence is available at present. Statins are safe and inexpensive, and may synergize with novel antiandrogen agents abiraterone via pharmacokinetic interactions and decrease substrate availability for de novo androgen biosynthesis. Objective: To determine whether statin use affects survival in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone. Design, setting, and participants: Medical records of patients with documented mCRPC between September 2011 and August 2016 were reviewed at multiple participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. A total of 187 patients receiving abiraterone for mCRPC between September 2011 and August 2016 were eligible for inclusion in this retrospective study. Outcome measurements and statistical analysis: Patients were assessed for overall survival (OS), statin use at the time of treatment initiation, prostate-specific antigen (PSA) variations, and other variables of interest. Univariable and multivariable analysis was used to explore the association of variables of interest with OS and PSA declines. Results and limitations: Statin use was a significant prognostic factor for longer OS in univariable (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.37–0.72; p < 0.001) and multivariable analysis (HR 0.40, 95% CI 0.27–0.59; p < 0.001) and was significantly associated with PSA declines (>50% decline at 12 wk: 72.1% in statin users vs 38.5% in non-users; p < 0.001). Conclusions: Our study suggests a prognostic impact of statin use in patients receiving abiraterone for mCRPC. The mechanism of this interaction warrants elucidation, but may include enhancement of the antitumor activity of abiraterone as well as cardioprotective effects. Patient summary: We assessed the effects of statin use in patients with advanced prostate cancer receiving abiraterone. Patients treated with a statin plus abiraterone appeared to live longer than those treated with abiraterone only. Since no negative drug-drug interaction is known and statins are widely used and inexpensive, further studies assessing the use of abiraterone plus statins are warranted. © 2017 Published by Elsevier B.V. on behalf of European Association of Urology.
Associate Editor: James Catto Keywords: Prostate cancer Statins Abiraterone
y These authors share senior authorship. * Corresponding author. Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Pansini, 5, Naples, Italy. Tel. +39 081 7463660. E-mail address: [email protected] (G. Di Lorenzo).
http://dx.doi.org/10.1016/j.euf.2017.03.015 2405-4569/© 2017 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Di Lorenzo G, et al. Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.03.015
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1.
Introduction
factors, previous local and systemic treatments and treatment with abiraterone, statin use, and early prostate-specific antigen (PSA) declines
Prostate cancer is the most prevalent malignancy in men, with an estimated 1 111 700 incident cases diagnosed in 2012 worldwide [1]. After benefitting from androgen ablation treatment, virtually all patients with recurrent/advanced disease develop castration-resistant prostate cancer (CRPC), which progresses despite androgen deprivation treatment [2]. In most patients with CRPC, the androgen receptor (AR) pathway continues to drive tumor growth [3], which is consistent with the effectiveness of the novel antiandrogen treatments abiraterone and enzalutamide [4–7]. While abiraterone acetate inhibits residual adrenal and intratumoral androgen synthesis by blocking CYP17A activity [8], enzalutamide directly inhibits the AR with no agonist activity [9]. Statins are commonly prescribed cholesterol-lowering drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, preventing the conversion of HMGCoA into mevalonate [10]. In vitro studies have shown that besides their direct pro-apoptotic effects, statins may also reduce cellular proliferation by inhibiting Ras proteins and other cellular pathways [11]. From a clinical perspective, statin use has been associated with survival benefits in large cohorts of patients with solid malignancies [12], including breast [13], colorectal [14], and prostate cancer [15,16], and multiple putative biological mechanisms have been proposed [17–19]. In the particular case of prostate cancer, previous studies have examined the impact of statins in broad heterogeneous populations with mostly localized hormone-naïve disease. For an androgen-addicted tumor such as prostate cancer, we hypothesized that statins may synergize with the novel antihormonal agent abiraterone in metastatic CRPC, considering that cholesterol is a substrate for adrenal and intratumoral androgen biosynthesis and accumulates in prostate cancer cells [20,21]. In this retrospective study, we assessed the prognostic role of statin use in patients starting abiraterone after controlling for known prognostic factors in a real-world clinical scenario.
2.
Patients and methods
2.1.
Inclusion criteria
The medical records of patients with documented mCRPC treated with abiraterone between September 2011 and August 2016 were reviewed at ten participating centers. Prostate cancer had to be histologically or cytologically confirmed. Ongoing androgen deprivation treatment or orchiectomy was required for inclusion in this study, in accordance with
>30% and >50% at 4, 8, 12, and 16 wk.
2.3.
Data analysis
Summary statistics were used to describe the patient population and outcomes. Univariable Cox proportional hazards regression was used to evaluate variables as potentially prognostic for overall survival (OS). Multivariable modeling was conducted using the full model method, that is, including all potential factors in a multivariable model, regardless of whether they were statistically significant or not. The effect of statin use on survival was then assessed after adjusting for factors included in the multivariable model. Logarithmic transformation of factors was performed for statistical normalization purposes as necessary. Supportive analyses were performed by excluding patients who received enzalutamide before abiraterone (given the similar mechanism of action of these treatments). Differences in characteristics between patients treated with abiraterone plus statins and those who received abiraterone alone were assessed by using Fisher’s exact test for dichotomous variables, a x2 test for categorical variables (reason for discontinuation), the Wilcoxon rank-sum test for continuous variables, and a log-rank test for OS. The association between statin use at baseline and PSA declines at different time points was tested using Fisher’s exact test. All tests were two-sided and p 0.05 was considered statistically significant. No statistical adjustments were made for multiple testing. OS was defined as the time between treatment initiation and either the date of death or of last follow-up for surviving patients.
3.
Results
3.1.
Patient characteristics
A total of 187 patients starting abiraterone therapy between September, 2011 and January, 2016 were included. Summary statistics for patients treated with and without statins are shown in Table 1. No significant differences between the two groups were identified, except for a different distribution of the Gleason score, with approximately 25% vs. 50% of patients in the abiraterone plus statin vs. abiraterone only group having a Gleason score of 8-10, and a statistically (yet not clinically) meaningful difference in baseline hemoglobin levels. Patients were a mean age of 66.8, while 33 (17.7%) had visceral disease when treated with abiraterone, and 75 (40.7%) presented a Gleason score of 8 or higher. Median duration on abiraterone was 31.3 weeks and 11 patients remained on abiraterone at the time of analysis. Seventyone (38.4%) were being treated with statins. By weeks 4, 8, 12 and 16, median decline in PSA was 12.2%, 37.5%, 50.0% and 63.0% respectively. Median OS was 18 months. 3.2.
Association of statin use with survival and PSA declines
regulatory requirements for abiraterone prescription, with a serum testosterone level of <50 ng/dl. The castration-resistant state was ascertained locally according to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria [22]. Patients who received at least one 28-d cycle of abiraterone were regarded as eligible for this retrospective study.
2.2.
Data retrieved
Demographic data for eligible patients were retrieved, along with information regarding known and previously recognized baseline prognostic
Table 2 summarizes the results for Cox proportional hazards regression analyses. Excluding two patients with unknown statin use, the median and 1-yr survival among the 71 patients treated with statins were 22.2 mo (95% CI 19.4–25.0) and 87.1% (95% CI 76.6–93.1%), compared to 15.3 mo (95% CI 12.9–17.1) and 62.2% (95% CI 52.5–70.5%) for the 114 patients not on statins (Fig. 1). Statin use was a significant prognostic factor for longer OS in univariable analysis (hazard ratio [HR] 0.51, 95% CI 0.37–0.72;
Please cite this article in press as: Di Lorenzo G, et al. Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.03.015
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Table 1 – Baseline characteristics of the study cohort. Statins (n = 71)
Mean age at diagnosis, yr (SD) PSA at Dx (ng/ml) Gleason score 7 8–10 Time from first HDx of PC to ADT (mo) Time from first HDx of PC to mPC (mo) Time from first RDx of mPC to CRPC (mo) Prior prostatectomy, n (%) Prior radiotherapy, n (%) Prior docetaxel, n (%) Prior cabazitaxel, n (%) Prior enzalutamide, n (%) Time from Dx to AA (mo) Time on AA (wk) Visceral disease, n (%) Opiates, n (%) Alkaline phosphatase at AA start Hemoglobin at AA start Lactate dehydrogenase at AA start Neutrophils at AA start Lymphocytes at AA start Neutrophil/lymphocyte ratio PSA at start of AA PSA change from Dx to AA start (%) Change in PSA at 4 wk (%) Change in PSA at 8 wk (%) Change in PSA at 12 wk (%) Change in PSA at 16 wk (%) Reason for AA discontinuation, n (%) Radiological PSA/clinical progression PSA only progression Clinical progression Toxicity Not stated Still on treatment Time to death Deaths, n (%) Median survival, mo (95% CI) 1-yr survival, % (95% CI) 2-yr survival, % (95% CI)
No statins (n = 114)
n
Result
n
71 67
65.9 (6.3) 12 (1.97–180)
114 106
67.5 (6.2) 13 (4–1770)
71
53 (74.6) 18 (25.4) 19.8 (1.3 to 121.1) 26.7 (1.3 to 128.3) 26.7 (1.3 to 128.3) 31 (43.7) 36 (50.7) 43 (60.6) 17 (23.9) 7 (9.9) 63.4 (10.1–191.8) 49.1 (11.3–121.7) 9 (12.7) 43 (60.6) 170 (56–430) 11.8 (9.0–14.5) 260 (135–600) 4000 (2400–9200) 1715 (1100–3200) 2.20 (1.31–5.33) 85 (4.9–700) +471 (83.6 to 8650) 23.1 (86.3 to 107) 56.9 (93.8 to 50) 76.3 (98.3 to 200) 83.6 (98.8 to 276)
111
55 (49.5) 56 (50.5) 22.3 (10.9 to 178.3) 25.6 (3.3 to 207.9) 13.7 (1.3 to 167.9) 51 (45.1) 53 (46.9) 75 (65.8) 44 (38.6) 10 (8.8) 57.9 (6.2–212.5) 23.5 (4.1–118.1) 23 (20.2) 64 (56.1) 184 (48–1659) 11.5 (8.6–14.5) 290 (120–2297) 3900 (1900–7280) 1700 (500–3210) 2.18 (1.42–10.4) 90 (4.95–2000) 453 (98.7 to 28471) 11.0 (97.9 to 1894) 21.9 (99.0 to 2344) 35.6 (99.5 to 613) 13.3 (99.7 to 728)
70 68 68 71 71 71 71 71 71 64 71 71 63 69 59 58 56 56 71 67 69 68 68 67 71
a
114 110 108 113 113 114 114 114 114 110 a 114 114 80 83 75 72 72 72 114 106 108 105 104 96 114
54 (76.1) 4 (5.6) 5 (7.0) 0 (0.0) 1 (1.4) 7 (9.9)
p value
Result 0.12 0.30
0.001 0.75 0.77 0.14 0.88 0.65 0.53 0.053 0.80 0.38 <0.001 0.23 0.65 0.26 0.031 0.11 0.17 0.85 0.99 0.93 0.34 0.030 <0.001 <0.001 <0.001 0.10
76 (66.7) 9 (7.9) 17 (14.9) 5 (4.4) 3 (2.6) 4 (3.5)
71
<0.001
114 57 (80.3) 22.2 (19.4–25.0) 87.1 (76.6–93.1) 45.4 (32.8–57.2)
96 (84.2) 15.3 (12.9–17.1) 62.2 (52.5–70.5) 16.6 (9.8–24.9)
AA = abiraterone acetate; ADT = androgen deprivation therapy; CI = confidence interval; Dx = diagnosis; HDx = histological Dx; RDx = radiological Dx; PC = prostate cancer; mPC = metastatic PC; CRPC = castration-resistant PC; PSA = prostate-specific antigen. Results are reported as median (range) for continuous variables unless stated otherwise. a Excludes 11 patients still on abiraterone.
p < 0.001) and after adjusting for factors in the multivariable model (HR 0.40, 95% CI 0.27–0.59; p < 0.001). Results were similar in a supportive analysis excluding 17 patients who had received prior enzalutamide: statin use remained a significant prognostic factor for OS in univariable (HR 0.48, 95% CI 0.34–0.68; p < 0.001) and multivariable analysis (HR 0.42, 95% CI 0.28–0.62; p < 0.001). The positive effect of statins on survival remained after adjusting for baseline PSA and percentage change in PSA over time (Table 3). Statin use at baseline was also associated with significantly better 30% and 50% PSA decline rates at 8, 12, and 16 wk (Table 4). 4.
Discussion
Accumulating evidence supports a beneficial effect of statin use in cancer patients. In a recently published meta-analysis [12] conducted in patients affected by various solid
malignancies, including breast, prostate, and colorectal cancer, clinically and statistically meaningful overall and cancer-specific survival advantages were associated with prediagnosis and postdiagnosis statin use in two cohorts of 947 410 and 104 811 participants, respectively. In particular, postdiagnosis use of statins was associated with a HR of 0.81 (95% CI 0.72–0.91) for all-cause mortality and a HR of 0.77 (95% CI 0.66–0.88) for cancer-specific mortality, while statin use before cancer diagnosis was associated with a HR of 0.79 (95% CI 0.74–0.85) for all-cause mortality and a HR of 0.69 (95% CI 0.60–0.79) for cancer-specific mortality. Notably in this large patient cohort, incremental benefits were associated with higher exposure to statins. When looking at single studies, heterogeneous, sometimes discordant, results were obtained in different prostate cancer patient populations, which included men with nonmetastatic disease only [23,24], men treated with prostatectomy or external-beam
Please cite this article in press as: Di Lorenzo G, et al. Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.03.015
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Table 2 – Prognostic factors for overall survival. Factor Age at diagnosis (per year) Prostate-specific antigen at TBL (LTF) Alkaline phosphatase at TBL (LTF) Hemoglobin at TBL (per unit) Lactate dehydrogenase at TBL (LTF) Neutrophils at TBL (LTF) Lymphocytes at TBL (per unit) Neutrophil/lymphocyte ratio (LTF) Gleason score (8 vs 7) Prior prostatectomy (yes vs no) Prior radiotherapy (yes vs no) Visceral disease (yes vs no) Opiates (yes vs no) Prior docetaxel (yes vs no) Prior cabazitaxel (yes vs no) Prior enzalutamide (yes vs no) Statins (yes vs no) Multivariable model Age at diagnosis (per year) Prostate-specific antigen at TBL (LTF) Alkaline phosphatase at TBL (LTF) Hemoglobin at TBL (per unit) Lactate dehydrogenase at TBL (LTF) Neutrophil/lymphocyte ratio at TBL (LTF) Gleason score (8 vs 7) Visceral disease at TBL (yes vs no) Opiates at TBL (yes vs no) Prior docetaxel (yes vs no) Prior cabazitaxel (yes vs no) Prior enzalutamide (yes vs no) Statins at TBL (yes vs no)
n
HR (95% CI)
p value
187 187 143 152 134 130 128 128 184 186 186 187 187 187 187 187 185
1.02 (1.00–1.05) 1.43 (1.22–1.67) 1.75 (1.11–2.76) 0.69 (0.57–0.83) 3.07 (1.79–5.25) 0.27 (0.12–0.62) 1.00 (1.00–1.00) 0.69 (0.31–1.56) 1.14 (0.81–1.59) 1.44 (1.04–1.98) 0.84 (0.61–1.15) 1.67 (1.07–2.59) 2.71 (1.91–3.86) 1.90 (1.34–2.70) 3.86 (2.70–5.52) 3.15 (1.75–5.68) 0.51 (0.37–0.72)
0.11 <0.001 0.016 <0.001 <0.001 0.002 0.48 0.37 0.46 0.028 0.27 0.023 <0.001 <0.001 <0.001 <0.001 <0.001
128 128 128 128 128 128 128 128 128 128 128 128 128
1.05 (1.01–1.10) 1.82 (1.32–2.51) 1.13 (0.58–2.23) 1.04 (0.78–1.38) 2.74 (1.21–6.20) 0.87 (0.36–2.16) 1.47 (0.93–2.32) 0.25 (0.11–0.56) 1.36 (0.81–2.28) 1.08 (0.64–1.84) 7.52 (4.06–13.93) 25.13 (7.72–81.81) 0.40 (0.27–0.59)
0.013 <0.001 0.72 0.79 0.016 0.77 0.10 <0.001 0.25 0.77 <0.001 <0.001 <0.001
HR = hazard ratio; CI = confidence interval; LTF = log transformed; TBL = treatment baseline.
radiotherapy [25], men with localized high-risk or metastatic disease [26], men treated with external-beam radiotherapy only [27], and patients with castration-resistant prostate cancer receiving systemic abiraterone treatment
[28]. The available data have been systematically assessed in meta-analyses [29–31]. While Scosyrev et al [31] did not identify any protective effect of statin use in patients receiving prostatectomy or radiotherapy, two recently published meta-analyses found similar survival advantages. In a sample of 100 536 participants, Meng et al [29] found that prediagnostic statin use was associated with a significantly lower risk of both all-cause mortality (HR 0.56, 95% CI 0.38–0.83) and prostate cancer-specific mortality (HR 0.53, 95% CI 0.36–0.77), while postdiagnostic statin use was associated with a HR of 0.77 (95% CI 0.69– 0.87) for all-cause mortality and 0.64 (95% CI 0.52–0.79) for prostate cancer–specific mortality. Similar results have been reported by Raval et al [30]. While the preponderance of clinical findings concern patients with localized and/or hormone-sensitive disease, limited data are available in Table 3 – Effect of statins on survival after adjusting for baseline PSA and percentage change in PSA over time. n
Fig. 1 – Survival of patients receiving abiraterone with or without statins. A total of 71 patients treated with statins had median overall survival of 22.2 mo, compared to 15.3 mo for the 114 patients not receiving statins.
Baseline 4 wk 8 wk 12 wk 16 wk
185 177 173 172 162
HR (95% CI) 0.49 0.49 0.49 0.58 0.59
(0.35–0.69) (0.35–0.70) (0.35–0.70) (0.40–0.83) (0.40–0.86)
p value <0.001 <0.001 <0.001 0.003 0.006
PSA = prostate-specific antigen; HR = hazard ratio; CI = confidence interval.
Please cite this article in press as: Di Lorenzo G, et al. Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.03.015
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Table 4 – Effect of statins on >30% and >50% PSA decline rates at different time points. Patients, n/N (%)
PSA >30% 4 wk 8 wk 12 wk 16 wk PSA >50% 4 wk 8 wk 12 wk 16 wk
p value
No statins
Statins
39/108 (36.1) 46/108 (43.8) 55/104 (52.9) 44/96 (45.8)
32/69 (46.4) 47/68 (69.1) 53/68 (77.9) 57/67 (85.1)
0.21 0.002 0.001 <0.001
23/108 (21.3) 34/105 (32.4) 40/104 (38.5) 40/96 (41.7)
20/69 39/68 49/68 50/67
0.28 0.002 <0.001 <0.001
(29.0) (57.4) (72.1) (74.6)
a
PSA = prostate-specific antigen. Fisher’s exact test.
a
the setting of patients with castration-resistant disease receiving abiraterone. We hypothesized that in castrate patients who are potentially still sensitive to androgens, statins may synergize with the antiandrogen agent abiraterone on the grounds of the proven effect of statins on androgen biosynthesis [32]. Furthermore, statins may decrease the formation of lipid rafts that contain a subpopulation of androgen receptors regulating intracellular signaling pathways [11]. For this retrospective study, we presented data on statin use at baseline in a cohort of patients starting abiraterone and found that statin use at baseline was independently associated with both improved OS and higher rates of PSA declines at several time points, after correcting for multiple potential confounders. The characteristics of patients treated with or without statins were well balanced. While a significantly higher proportion of patients in the no-statin group compared to the statin group had a Gleason score of 8–10, it must be noted that a higher Gleason score has been associated with longer duration of abiraterone treatment [33]. The prognostic value of statin use in abiraterone patients was maintained even after adjusting for baseline PSA levels and PSA declines over time, suggesting that PSA declines may not explain the potential additional benefit associated with statin use in abiraterone patients. Other authors have hypothesized that abiraterone efficacy, which is dependent on inhibition of intratumoral steroidogenesis, may be improved by statin-induced inhibition of the organic anionic transporter solute SLCO2B1 [34], which mediates the uptake of the adrenal androgen dehydroepiandrosterone (DHEAS), a precursor a testosterone. Moreover, it has been reported that statins cause selective degradation of mutant variants of p53, which is frequently mutated in prostate cancer [35], by impairing its interaction with Hsp40 family member DNAJA1 [36]. Nevertheless, in another retrospective study of 108 men with mCRPC treated with abiraterone either with (n = 21) or without (n = 87) concomitant statin treatment, PSA decline 50% (57% vs 53%; p = 0.73), median progression-free survival (9 vs 10 mo; p = 0.97), and OS (14 vs
5
18 mo; p = 0.77) did not differ significantly between the groups [28]. Although the hypothesis that abiraterone may synergize with statins is intriguing, the available evidence, including the data presented here, is not sufficient to be conclusive. Like others, our study has a number of limitations, including those typical of retrospective studies and a lack of data for previous exposure to statins, statin type and treatment duration, comorbidities, serum lipid levels, cardiovascular events, and prostate cancer–specific survival. Nevertheless, the study by Boegemann et al [28] included only 21 patients treated with abiraterone plus statins, which may provide inadequate power for detection of any differences, while our study included 71 patients on abiraterone plus statins. 5.
Conclusions
In conclusion, our study is the largest full report exploring the prognostic value of statin use at the time of abiraterone treatment initiation. We note that the magnitude of the effect on survival associated with statin use in our patient population is consistent with previously published data in prostate cancer patients [29,30] and that statin use was associated with better odds of having PSA declines. Despite the multiple limitations of our study, our data suggest a potential protective effect of statins in patients undergoing abiraterone treatment. Given the potential utility of continuing statin administration in selected cancer patients with advanced disease [37] as well as the inexpensiveness and safety of statins, we believe that our findings add to the existing evidence supporting a prospective interventional study comparing abiraterone plus statins versus abiraterone alone in selected mCRPC patients. Further studies are required not only to confirm such an association but also to assess whether statins may be beneficial in all mCRPC patients or only in those receiving abiraterone.
Author contributions: Giuseppe Di Lorenzo had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Buonerba, Di Lorenzo. Acquisition of data: All authors. Analysis and interpretation of data: Buonerba, Di Lorenzo, Pond, Sonpavde. Drafting of the manuscript: Buonerba. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Pond. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: De Placido. Other: None.Financial disclosures: Giuseppe Di Lorenzo certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Guru Sonpavde has received consultant fees from Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, AstraZeneca, Merck, Genentech, Argos, and Agensys; institutional research support from Bayer, Onyx, Celgene,
Please cite this article in press as: Di Lorenzo G, et al. Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.03.015
EUF-314; No. of Pages 6 6
E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X
Boehringer-Ingelheim, Merck, and Pfizer; author fees from Uptodate; and speaker fees from Clinical Care Options. The remaining authors have nothing to disclose.
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Funding/Support and role of the sponsor: None.
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Please cite this article in press as: Di Lorenzo G, et al. Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.03.015