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Statin use and survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide after docetaxel failure: the international retrospective observational STABEN study

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Oncotarget. 2018; 9:19861-19873. https://doi.org/10.18632/oncotarget.24888

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Jacob A. Gordon, Carlo Buonerba, Gregory Pond, Daniel Crona, Silke Gillessen, Giuseppe Lucarelli, Sabrina Rossetti, Tanya Dorff, Salvatore Artale, Jennifer A. Locke, Davide Bosso, Matthew Ivan Milowsky, Mira Sofie Witek, Michele Battaglia, Sandro Pignata, Cyrus Cherhroudi, Michael E. Cox, Pietro De Placido, Dario Ribera, Aurelius Omlin, Gaetano Buonocore, Kim Chi, Christian Kollmannsberger, Daniel Khalaf, Gaetano Facchini, Guru Sonpavde, Sabino De Placido, Bernhard J. Eigl and Giuseppe Di Lorenzo _

Abstract

Jacob A. Gordon1,*, Carlo Buonerba2,3,*, Gregory Pond4, Daniel Crona5, Silke Gillessen6, Giuseppe Lucarelli7, Sabrina Rossetti8, Tanya Dorff9, Salvatore Artale10, Jennifer A. Locke1, Davide Bosso2, Matthew Ivan Milowsky5, Mira Sofie Witek6, Michele Battaglia7, Sandro Pignata11, Cyrus Cherhroudi12, Michael E. Cox1, Pietro De Placido2, Dario Ribera2, Aurelius Omlin6, Gaetano Buonocore13, Kim Chi14, Christian Kollmannsberger14, Daniel Khalaf14, Gaetano Facchini8, Guru Sonpavde15, Sabino De Placido2, Bernhard J. Eigl14,# and Giuseppe Di Lorenzo2,#

1Vancouver Prostate Center, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada

2Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

3Istituto Zooprofilattico Sperimentale del Mezzogiorno, Portici, Italy

4McMaster University, Hamilton, Ontario, Canada

5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA

6Department of Medical Oncology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland

7Department of Emergency and Organ Transplantation, Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy

8S.S.D Oncologia Clinica Sperimentale Uro-Andrologica, Dipartimento Corp-S Assistenziale dei Percorsi Oncologici Uro-Genitale, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy

9University of Southern California Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California, USA

10Oncology Department, Ospedale di Gallarate ASST Valle Olona, Gallarate, Italy

11Division of Medical Oncology, Department of Uro-Gynecologi cal Oncology, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy

12Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

13Hospital Directorate, Azienda Ospedaliera Universitaria Federico II of Naples, Naples, Italy

14BC Cancer, Vancouver, British Columbia, Canada

15Genitourinary Oncology Section, Dana Farber Cancer Institute, Boston, Massachusetts, USA

*These two authors equally contributed to this work

#These two authors share equal senior authorship

Correspondence to:

Giuseppe Di Lorenzo, email: [email protected]

Keywords: prostate cancer; abiraterone; enzalutamide; statins

Received: February 01, 2018     Accepted: February 27, 2018     Published: April 13, 2018

ABSTRACT

Background: Statins may potentiate the effects of anti-hormonal agents for metastatic castration-resistant prostate cancer (mCRPC) through further disruption of essential steroidogenic processes. We investigated the effects of statin use on clinical outcomes in patients with mCRPC receiving abiraterone or enzalutamide.

Materials and methods: This was a retrospective multicenter study including patients that received abiraterone or enzalutamide for mCRPC. The effect of concurrent statin use on outcomes was evaluated. The associations of statins with early (≤12 weeks) prostate-specific antigen (PSA) declines (> 30%), cancer-specific survival and overall survival (OS) were evaluated after controlling for known prognostic factors.

Results: Five hundred and ninety-eight patients treated with second-line abiraterone or enzalutamide after docetaxel for mCRPC were included. A total of 199 men (33.3%) received statins during abiraterone/enzalutamide treatment. Median OS was 20.8 months (95% CI = 18.3–23.2) for patients who received statins, versus 12.9 months (95% CI = 11.4–14.6) for patients who did not receive statins (P < 0.001). After adjusting for age, alkaline phosphatase, PSA, neutrophil-to-lymphocytes ratio, Charlson comorbidity score, Gleason score, visceral disease, hemoglobin, opiate use and abiraterone versus enzalutamide treatment, the use of statin therapy was associated with a 53% reduction in the overall risk of death (hazard ratio [HR] = 0.47; 95% CI = 0.35–0.63; P < 0.001). Statin use was also associated with a 63% increased odds of a > 30% PSA decline within the first 12 weeks of treatment (OR = 1.63; 95% CI = 1.03–2.60; P = 0.039).

Conclusions: In this retrospective cohort, statin use was significantly associated with both prolonged OS and cancer-specific survival and increased early > 30% PSA declines. Prospective validation is warranted.


INTRODUCTION

In developed countries, prostate cancer is the most prevalent malignancy in men, with 142,000 patients dying each year, and an 8.8% cumulative life-time incidence [1]. Statins are a therapeutic class of medications that are commonly prescribed to lower circulating cholesterol levels through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase [2], and have an established role in primary and secondary cardiovascular prevention [3]. Over the past decade, a preponderance of evidence from numerous studies, mostly conducted in patients with hormone-sensitive disease, has shown that statin use in prostate cancer patients is associated with longer cancer-specific and overall survival (OS) [4]. The putative mechanism for this observed improvement in survival is that statins may impair prostate cancer growth via multiple cholesterol- and non-cholesterol-mediated effects [4]. In a recently published study of a large, registry-based cohort, which included >30,000 prostate cancer patients [5], statin use was predictive of improved cancer-specific and OS, after adjusting for stage, Gleason score and primary treatment at diagnosis. Conversely, there is little evidence regarding the effects of statins among patients with castration-resistant prostate cancer (CRPC), and the potential synergism with active systemic treatments (e.g., abiraterone and enzalutamide).

Abiraterone works by inhibiting residual adrenal and intra-tumoral androgen synthesis via CYP17A blockade [6], while enzalutamide acts by inhibiting binding of testosterone to the androgen receptor (AR) as well as by blocking androgen-mediated change and nuclear translocation of AR [7]. In one small retrospective study, statin use was significantly associated with longer OS and early PSA declines in men who received abiraterone [8]. In contrast, this OS advantage has not been consistently observed in other studies [9, 10]. Furthermore, there is prospective evidence from a phase III trial suggesting that statins may be discontinued in the palliative care setting with no detrimental effect on survival [11].

In view of the potential additive effect of statins with novel hormonal agents and of the unknown value of continuing versus discontinuing statin therapy in patients with metastatic CRPC (mCRPC), a multi-center retrospective study was conducted to further explore the effects of statin use on PSA response and survival outcomes during second-line (post-docetaxel) treatment with abiraterone or enzalutamide, after adjusting for multiple known predictive factors in the second-line setting [12].

RESULTS

Patients’ characteristics and outcomes

Six hundred and forty-two patients were initially included in this dataset. Of these, 44 patients were excluded because statin use could not be ascertained. Baseline characteristics and outcomes are presented for the remaining 598 patients in Table 1A1D. Notably, > 50% of patients came from one treatment center (BCCA) and an additional 21% of patients came from a second center (Federico II Napoli). Median age of the population was 72 years (range, 42–96). Most of the study patients received abiraterone. Median duration of second-line treatment with abiraterone or enzalutamide was 8.3 months (range, 0.4–47.5), with 52% of patients having a > 30% PSA decrease within the first 12 weeks of treatment. At the time of this analysis, 513 (85.8%) patients had died, with a median OS of 16.1 months (95% confidence interval [CI] = 13.8–17.0). Cancer-specific survival was 16.2 months (95% CI: 14.3–17.1).

Table 1A: Summary statistics

Characteristic

Statistic

N

All Patients

Abiraterone

Enzalutamide

Site

Federico II Napoli

Pascale Napoli

University Bari

St. Gallen

UNC

UCLA

BCCA

Gallarate

598

127 (21.2)

17 (2.8)

21 (3.5)

29 (4.9)

41 (6.9)

15 (2.5)

342 (57.2)

6 (1.0)

91 (19.0)

14 (2.9)

13 (2.7)

27 (5.6)

20 (4.2)

9 (1.9)

301 (62.7)

5 (1.0)

36 (30.5)

3 (2.5)

8 (6.8)

2 (1.7)

21 (17.8)

6 (5.1)

41 (34.8)

1 (0.9)

Age

Mean (std dev)

Median (range)

598

72.5 (9.0)

72 (42, 96)

72.6 (9.0)

72 (42, 96)

72.0 (8.8)

72 (43, 90)

Gleason Score

N (%) ≥8

540

306 (56.7)

248/431 (57.5)

58/109 (53.2)

Charlson Score

Median (range)

N (%) ≥10

598

10 (6, 17)

341 (57.0)

10 (6, 17)

274/480 (57.1)

10 (6, 15)

67/118 (56.8)

Baseline PSA

Median (range)

588

87.3 (0, 7938)

97.8 (0, 7938)

61 (1.9, 2220)

Alkaline Phosphatase

Median (range)

448

119 (8.9, 2189)

120 (8.9, 2189)

105 (39, 1791)

LDH

Median (range)

259

264 (90, 2598)

262 (90, 2598)

266 (103, 2219)

Neutrophils/Lymphocyte Ratio

Median (range)

530

3.4 (0.2, 37.5)

3.5 (0.2, 34.5)

2.7 (1.0, 37.5)

Hemoglobin

Median (range)

555

11.9 (5.7, 15.8)

11.9 (5.7, 15.8)

11.8 (7.1, 15.6)

Months, Castration-sensitive Disease

Median (range)

390

18.4 (0.2, 65.5)

18.6 (0.2, 65.5)

16.0 (0.8, 59.8)

Months, Diagnosis to Mets

Median (range)

474

37.0 (0, 162.0)

39.3 (0, 161.3)

25.0 (0, 162.0)

Opiate Use

N (%) Yes

587

191/587 (32.5)

152/476 (31.9)

39/111 (35.1)

Visceral Disease

N (%) Yes

598

46 (7.7)

31/480 (6.5)

15/118 (12.7)

Treatment with abiraterone/enzalutamide ± statins

Treatment

N (%) Abiraterone

598

480 (80.3)

480 (100.0)

0 (0.0)

Concomitant Statins

N (%) Yes

Atorvastatin

Lovastatin

Pravastatin

Rosuvastatin

Simvastatin

Unknown

598

199/598 (33.3)

107 (53.8)

3 (1.5)

11 (5.5)

33 (16.6)

22 (11.1)

23 (11.6)

157/480 (32.7)

93 (59.2)

2 (1.3)

8 (5.1)

30 (19.1)

20 (12.7)

4 (2.6)

42/118 (35.6)

14 (33.3)

1 (2.4)

3 (7.1)

3 (7.1)

2 (4.8)

19 (45.2)

Dose of Statins

Median (range)

122

20 (5, 80)

20 (5, 80)

20 (5, 40)

Simvastatin Equivalent Dose

Median (range)

122

30 (8, 120)

30 (8, 120)

30 (10, 60)

Statins Prior to Abiraterone/Enzalutamide

N (%) Yes

196

191/196 (97.5)

151/154 (98.1)

40/42 (95.2)

Statin Use Suspended during abiraterone/enzalutamide treatment

N (%) Yes

196

3/196 (1.5)

2/154 (1.3)

1/42 (2.4)

Months, Duration of Abiraterone/Enzalutamide Treatment

Median (range)

183

8.3 (0.4, 47.5)

8.5 (0.4, 47.5)

7.1 (1.4, 33.4)

Use Hydrophilic Statin

N (%) Yes

176

44 (25.0)

38/153 (24.8)

6/23 (26.1)

Source of Statin Use Data

Prescription data

Claims

598

543 (90.8%)

55 (9.2%)

444 (92.5%)

36 (7.5%)

99 (83.8%)

19 (16.1%)

Characteristics of the study population grouped by treatment.

Table 1B: Outcomes of the study population, grouped by treatment

Characteristic

Statistic

N

All Patients

Abiraterone

Enzalutamide

Outcomes

>30% PSA Decline at Week 4

N (%) Yes

519

209 (40.3)

169/419 (40.3)

40/100 (40.0)

>30% PSA Decline at Week 8

N (%) Yes

480

223 (46.5)

184/391 (47.1)

39/89 (43.8)

>30% PSA Decline at Week 12

N (%) Yes

469

231 (49.3)

184/383 (48.0)

47/86 (54.7)

>30% PSA Decline at 4,8 or 12 Weeks†

N (%) Yes

574

299/574 (52.1)

243/465 (52.3)

56/109 (51.4)

Overall Survival

N (%) Deaths

Median (95% CI)

6-mo OS (95% CI)

1-year OS (95% CI)

2-year OS (95% CI)

598

513 (85.8)

16.1 (13.8, 17.0)

81.7 (78.3, 84.6)

61.0 (56.9, 64.8)

31.2 (27.5, 35.1)

424 (88.3)

15.8 (13.7, 17.0)

82.4 (78.7, 85.6)

61.3 (56.7, 65.5)

30.5 (26.3, 34.7)

89 (75.4)

16.5 (12.1, 20.1)

78.5 (69.9, 84.9)

59.7 (50.1, 68.1)

34.7 (25.8, 43.7)

Cause of Death

Prostate Cancer

598

468 (91.2)

390/424 (92.0)

78/89 (87.6)

Cancer-Specific Survival

Median (95% CI)

6-mo OS (95% CI)

1-year OS (95% CI)

2-year OS (95% CI)

598

16.5 (15.3, 17.7)

82.7 (79.4, 85.6)

63.2 (59.1, 67.0)

33.8 (29.8, 37.8)

16.4 (14.6, 17.7)

83.4 (79.7, 86.5)

63.3 (58.7, 67.5)

33.0 (28.6, 37.4)

17.6 (13.6, 21.4)

80.0 (71.4, 86.2)

63.2 (53.5, 71.4)

37.4 (28.0, 46.8)

Vascular Events

Cardiovascular N (%)

Cerebrovascular N (%)

Either N (%)

598

20 (3.3)

13 (2.2)

33 (5.5)

15 (3.1)

12 (2.5)

27 (5.6)

5 (4.2)

1 (0.9)

6 (5.1)

denominator is number of patients with a PSA assessment at week 4, 8 or 12.

Table 1C: Summary statistics

Characteristic

Statistic

N

No Statins

N

Statins

Site

Federico II of Napoli

Pascale Napoli

University of Bari

St. Gallen

UNC

UCLA

BCCA

Gallarate

399

74 (18.6)

8 (2.0)

14 (3.5)

25 (6.3)

27 (6.8)

7 (1.8)

241 (60.4)

3 (0.8)

199

53 (26.6)

9 (4.5)

7 (3.5)

4 (2.0)

14 (7.0)

8 (4.0)

101 (50.8)

3 (1.5)

Age

Mean (std dev)

Median (range)

399

71.9 (9.4)

72 (42, 96)

199

73.8 (7.9)

74 (43, 94)

Gleason Score

N (%) ≥8

354

204 (57.6)

186

102 (54.8)

Charlson Score

Median (range)

N (%) ≥10

399

10 (6, 15)

206 (51.6)

199

10 (6, 17)

135 (67.8)

PSA at Diagnosis

Median (range)

391

95.3 (0, 7149)

197

80 (0.2, 7938)

Alkaline Phosphatase

Median (range)

312

113 (8.9, 2189)

136

120 (25, 1791)

LDH

Median (range)

175

260 (103, 2598)

136

272 (90, 2219)

Neutrophils/Lymphocyte Ratio

Median (range)

358

3.4 (0.2, 34.5)

172

3.3 (0.2, 37.5)

Hemoglobin

Median (range)

373

11.9 (5.7, 15.8)

182

12.0 (7.9, 15.5)

Months, Castration-sensitive Disease

Median (range)

259

18.4 (0.2, 65.5)

131

18.4 (0.6, 65.4)

Months, Diagnosis to Metastases

Median (range)

306

33.3 (0, 162.0)

168

43.5 (0, 161.3)

Opiate Use

N (%) Yes

389

124 (31.9)

198

67 (33.8)

Visceral Disease

N (%) Yes

399

33 (8.3)

199

13 (6.5)

Treatment

Treatment

N (%) Abiraterone

399

323 (81.0)

199

157 (78.9)

Concomitant Statins

N (%) Yes

Atorvastatin

Lovastatin

Pravastatin

Rosuvastatin

Simvastatin

Unknown

0

199

199 (33.3)

107 (53.8)

3 (1.5)

11 (5.5)

33 (16.6)

22 (11.1)

23 (11.6)

Dose of Statins

Median (range)

0

122

20 (5, 80)

Simvastatin Equivalent Dose

Median (range)

0

122

30 (8, 120)

Statins Prior to Abiraterone/Enzalutamide

N (%) Yes

0

196

191 (97.5)

Statin Use Suspended during abiraterone/enzalutamide treatment

N (%) Yes

0

196

3 (1.5)

Months, Duration of Abiraterone/Enzalutamide Treatment

Median (range)

0

183

8.3 (0.4, 47.5)

Use of a Hydrophilic Statin

N (%) Yes

0

176

44 (25.0)

Characteristics of the study population, grouped by statin use.

denominator is number of patients with a PSA response assessment at week 4, 8 or 12.

Table 1D: Outcomes of the study population, grouped by statin use

Characteristic

Statistic

N

No Statins

N

Statins

Outcomes

>30% PSA Decline at Week 4

N (%) Yes

349

130 (37.3)

170

79 (46.5)

>30% PSA Decline at Week 8

N (%) Yes

311

136 (43.7)

169

87 (51.5)

>30% PSA Decline at Week 12

N (%) Yes

305

148 (48.5)

164

83 (50.6)

>30% PSA Decline at 4,8 or 12 Weeks†

N (%) Yes

380

186 (49.0)

194

113 (58.3)

Overall Survival

N (%) Deaths

Median (95% CI)

6-mo OS (95% CI)

1-year OS (95% CI)

2-year OS (95% CI)

399

347 (87.0)

12.9 (11.4, 14.6)

78.6 (74.2, 82.3)

53.8 (48.7, 58.7)

25.9 (21.6, 30.5)

199

166 (83.4)

20.8 (18.3, 23.2)

87.8 (82.3, 91.6)

75.0 (68.3, 80.5)

41.6 (34.5, 48.4)

Cause of Death

Prostate Cancer

347

324 (93.4)

166

144 (86.8)

Cancer-Specific Survival

Median (95% CI)

6-mo OS (95% CI)

1-year OS (95% CI)

2-year OS (95% CI)

399

13.4 (12.1, 15.8)

79.3 (74.9, 83.0)

56.0 (50.9, 60.9)

27.8 (23.2, 32.5)

199

22.3 (19.2, 24.7)

89.7 (84.5, 93.2)

77.6 (71.0, 82.8)

45.5 (38.1, 52.6)

Vascular Events

Cardiovascular N (%)

Cerebrovascular N (%)

Either N (%)

399

8 (2.0)

3 (0.8)

11 (2.8)

199

12 (6.0)

10 (5.0)

22 (11.1)

Statin use

Approximately one-third of the evaluable study population (199 of 598 patients) received statins during treatment, with 107 patients receiving atorvastatin (18% of patients). Importantly, statin use was documented by the local investigator using prescription data in almost 91% of cases. Only eleven patients were reported to have started statin after abiraterone or enzalutamide or to have interrupted statins before suspending abiraterone/enzalutamide treatment (2% of patients). The median simvastatin-equivalent daily dose administered was 30 mg.

Association of statins with OS and cancer-related survival

Median OS was significantly improved for mCPRC patients who received concomitant statins, when compared to patients not treated with statins (20.8 versus 12.9 months; hazard ratio [HR] = 0.57, 95% CI = 0.46–0.71, P < 0.001) (Figure 1). Table 2A summarizes the results of univariable and multivariable models for OS. In the multivariable model, statin use remained strongly associated with OS with a 53% reduction in the risk of death. This association was similar in subgroup analyses and in the landmark analyses. Among the study patients who had died (n = 513), over 91% of the deaths were attributable to prostate cancer, and thus the cancer-specific survival was similar to OS. Median cancer-specific survival was also significantly improved for patients who received concomitant statins, when compared to patients not treated with statins (22.3 versus 13.4 months; HR = 0.43, 95% CI = 0.32 to 0.58, P < 0.001) (Table 2B).

The Kaplan Meier curves for survival in patients receiving statins versus patients not receiving statins during abiraterone or enzalutamide treatment.

Figure 1: The Kaplan Meier curves for survival in patients receiving statins versus patients not receiving statins during abiraterone or enzalutamide treatment.

Table 2A: Cox regression analyses, outcome = overall survival

Table 2B: Cox regression analyses, outcome = cancer-specific survival

No statistically significant treatment effects were observed between enzalutamide versus abiraterone, nor were treatment differences observed based on type (atorvastatin versus other) or dose of statin.

Association of statins with PSA response

Among the 574 patients with available information, 299 (52.1%) experienced a PSA response (> 30% decline) within 12 weeks of abiraterone or enzalutamide initiation. Early PSA responses were observed significantly more often in patients that received statins, when compared to patients who did not receive statin therapy ( 58% versus 49%; odds ratio [OR] = 1.46, 95% CI = 1.02–2.08, P = 0.04) (Table 3). The association between early PSA response and statin use remained significant in the multivariable analysis (OR = 1.63, 95% CI = 1.03–2.60, P = 0.04).

Table 3: Logistic regression analyses, outcome = early 30% PSA decline

Association of statin use and cardiovascular or cerebrovascular events

Thirty-three study patients experienced a cardiovascular or cerebrovascular event during the time period analyzed. Timing of events was not consistently reported, and therefore time-to-event analyses could not be performed. Among the 199 patients prescribed statins, 12 (6.0%) experienced a cardiovascular event, and 10 (5.0%) experienced a cerebrovascular event. In contrast, among the 399 patients not prescribed statin therapy, 8 (2.0%) experienced a cardiovascular event, and 3 (0.8%) experienced a cerebrovascular event. After adjusting for other factors in a multivariable model, concomitant statin use remained a significant predictive factor of increased risk of cardiovascular or cerebrovascular events (OR = 3.24, 95% CI = 1.15–9.17, p-value = 0.03) (Table 4).

Table 4: Logistic regression analyses of cardiovascular or cerebrovascular events

All Patients

Type

N

OR (95% CI)

P

Age

/decade

598

2.24 (1.46, 3.46)

<0.001

Months, Castration-sensitive Disease

<12 mos vs ≥12 mos

390

0.55 (0.16, 1.97)

0.36

Months, Disease-Metastases

<36 mos vs ≥36 mos

474

1.14 (0.51, 2.55)

0.75

Alk Phos

Log-transformed

448

0.94 (0.54, 1.64)

0.83

LDH

Log-transformed

259

0.89 (0.26, 3.03)

0.85

Neutrophils/Lymphocyte Ratio

Log-transformed

530

1.38 (0.81, 2.36)

0.24

Hemoglobin

/unit

555

1.02 (0.80, 1.31)

0.85

PSA at Diagnosis

Log-transformed

587

0.94 (0.74, 1.18)

0.57

Charlson Score

/unit

≥10 vs <10

598

1.54 (1.29, 1.84)

4.51 (1.72,11.85)

<0.001

0.002

Gleason Score

≥8 vs <8

540

0.57 (0.27, 1.19)

0.13

Visceral Disease

Yes vs No

598

0.36 (0.05, 2.71)

0.32

Opiate Use

Yes vs No

587

0.68 (0.30, 1.54)

0.35

Treatment

Enzalutamide vs Abiraterone

598

0.90 (0.36, 2.23)

0.82

Concomitant Statins

Yes vs No

598

4.38 (2.08, 9.24)

<0.001

Statin Type

Atorvastatin vs Other

199

1.58 (0.63, 3.96)

0.33

Dose of Statins

/mg

123

1.02 (0.99, 1.04)

0.22

Use of a hydrophilic statin

Yes vs No

176

0.73 (0.23, 2.30)

0.58

Multivariable Analysis

Age

/decade

387

2.56 (1.11, 5.89)

0.028

Alk Phos

Log-transformed

1.39 (0.61, 3.19)

0.43

Neutrophils/Lymphocyte Ratio

Log-transformed

1.24 (0.52, 2.94)

0.63

Hemoglobin

/unit

1.11 (0.73, 1.70)

0.62

PSA at Diagnosis

Log-transformed

0.65 (0.45, 0.93)

0.020

Charlson Score

≥10 vs <10

1.56 (0.43, 5.70)

0.50

Gleason Score

≥8 vs <8

0.77 (0.24, 2.46)

0.66

Visceral Disease

Yes vs No

0.64 (0.07, 6.28)

0.70

OpiateUse

Yes vs No

0.72 (0.22, 2.38)

0.59

Treatment

Enzalutamide vs Abiraterone

0.58 (0.12, 2.78)

0.50

Concomitant Statins

Yes vs No

3.24 (1.15, 9.17)

0.027

DISCUSSION

Although statin use has been associated with reduced cancer-related mortality in a variety of malignancies [13], the potential synergism of statins with anti-cancer medications has been prospectively investigated only in a few clinical trials. Data from the recently published phase III double-blind, placebo-controlled LUNGSTAR trial failed to detect an OS or progression-free survival (PFS) benefit when pravastatin was added to first-line standard chemotherapy in patients with small-cell lung cancer [14]. Similarly, no benefit in overall survival associated with the use of statins added to chemotherapy was reported in two additional phase III trials conducted in advanced gastric [15] and colorectal [16] cancer patients, respectively.

Biologically, statins can potentiate the efficacy of anti-androgen treatments, such as abiraterone and enzalutamide, in mCRPC through a number of potential mechanisms, including: inhibition of intra-tumoral de novo steroid biosynthesis [17], inhibition of biosynthesis of isoprenoids [18], as well as inhibition of the organic anionic transporters (e.g., SLCO2B1) [19] that are responsible for adrenal androgen dehydroepiandrosterone (DHEA) influx into cancer cells [20].

In one translational study, Harshman et al. [21] showed that statins impaired DHEA influx through competitive inhibition of the SLCO2B1 transporter both in both androgen-dependent (LNCaP) and partially androgen-dependent (22RV1) prostate cancer cell lines. This was supported by their retrospective clinical study of 926 patients, treated with androgen deprivation, which demonstrated that patients who received statin therapy experienced longer median time to progression, when compared to patients not treated with a statin (27.5 versus 17.4 months; P < 0.001). Because abiraterone is also a SLCO2B1 substrate, the same research group [10] hypothesized that statin use could be a negative predictive factor for patients taking abiraterone. However, their retrospective study of 224 abiraterone-treated patients demonstrated that statin use trended toward longer treatment duration (14.2 versus 9.2 months; HR: 0.79, 95% CI, 0.57–1.09, P = 0.14). Despite lack of validation in an independent cohort of 270 abiraterone-treated patients [10], the authors concluded that concomitant stain use did not negatively impact survival.

In our previous retrospective observational study (n = 187 mCRPC patients from 10 participating centers who received abiraterone), statin use was associated with longer OS in univariate (HR = 0.51, 95% CI = 0.37–0.72, P < 0.001) and multivariate analyses (HR = 0.40, 95% CI = 0.27–0.59, P < 0.001). Statin use was also significantly associated with early PSA declines (>50% declines at week 12 in statin users versus non-users: 72.1% vs. 38.5; P < 0.001). This study was limited by several factors, including the relatively small sample size, the lack of information about statin type and statin treatment duration, comorbidities, cardiovascular events, and prostate cancer–specific survival. To overcome these limitations, we designed a retrospective observational study to be conducted in an international setting that could better define concomitant treatment with statins. One of the purposes of the STABEN trial was to assess whether the potential advantage associated with statin use could be related to their known cardiovascular and cerebrovascular protective effect, of particular potential importance in an elderly population receiving abiraterone – an agent with known cardiovascular toxicity [22]. In the present retrospective study, multivariable models that included known prognostic factors in prostate cancer (e.g., baseline PSA levels, hemoglobin levels, Gleason score, alkaline phosphatase and LDH levels [23], visceral involvement [24] and neutrophil to lymphocyte ratio [25]) revealed that statin use was associated with a 53% reduction in the risk of all-cause mortality, and a 57% reduction in the risk of prostate cancer-specific mortality. It also appeared that statin co-administration increased the odds of having an early >30% PSA decrease, which is consistent with our previously reported findings and adds strength to the hypothesis of a potential synergism with abiraterone/enzalutamide.

Notably, the positive effect of statins on survival did not appear to be influenced by the known protective statin effect against vascular events. While the observed incidence of cardiovascular events reported in this study are consistent with previously reported rates of grade 2 or higher abiraterone-associated cardiovascular events [22], mCRPC patients from this study who were prescribed statin therapy appeared to be at an approximately 4-fold greater risk of experiencing a vascular event. Although such analyses did not account for time-to-event, competing risks, or a history of pre-existing cardiac conditions, this finding could be explained by the observation that patients prescribed statins often present with a greater number of co-morbidities and therefore a greater cardio- and cerebro-vascular risk, when compared to non-statin users [26]. Furthermore, the protective effect of statins was maintained after correcting for Charlson comorbidity index. Although statin consumption was modeled by using a binary variable, it must be noted that only a few patients were not prescribed statins throughout the entire abiraterone or enzalutamide treatment duration, which does not make useful to model statin exposure as a time-dependent variable. Finally, the novelty of the STABEN study also relies in the increased survival in mCRPC patients receiving concomitant enzalutamide and statins vs. enzalutamide alone, which is consistent with the multiple putative pharmacodynamic interactions of statins with anti-androgen receptor agents.

Despite its larger sample size versus published series [810], this study still suffers from the limitations that apply to retrospective studies, including the lack of data on some key factors such as LDH and time from castration-sensitive disease, as well as the non-systematic selection of participating centers.

CONCLUSIONS

In the large retrospective, observational STABEN study, we found a positive association of statin use with overall- and cancer specific- survival in patients receiving abiraterone or enzalutamide in the second-line setting after docetaxel failure. Statin use was documented by using high-quality prescription data in most patients. The positive association found in our patient cohort with survival was reported both in abiraterone- and enzalutamide-treated men and was consistent with early >30% PSA declines. Analyzed together with previous epidemiology and biological findings, the STABEN results may serve as the basis to design prospective clinical trials assessing the value of adding statins to abiraterone or enzalutamide in mCRPC patients. Optimizing statin use in patients with advanced prostate cancer represents a compelling clinical opportunity to improve survival via the addition of a safe and inexpensive drug.

MATERIALS AND METHODS

Inclusion criteria

Medical records were reviewed at eight participating centers for patients with diagnosed mCRPC who were treated with second-line abiraterone or enzalutamide between January 2011 and January 2016. Histologically-confirmed prostate cancer and previous docetaxel-based treatment were required for inclusion in this study. Castration-resistance was determined per Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria [22]. Patients who received at least one 28-day cycle of abiraterone or enzalutamide in the second-line setting were regarded as eligible for this study. Patient data including medical and prostate cancer history, demographic, and baseline characteristics were retrieved starting at the time of abiraterone or enzalutamide initiation. Data collected regarding statin use included: type and dose of statin prescribed, source of the data (claims versus prescription data), and dates of statin use initiation and discontinuation.

Data analysis

Summary statistics were used to describe patient outcomes. Time-to-event outcomes were calculated from the first date of treatment with abiraterone or enzalutamide.

The primary objective of this study was to determine whether concomitant statin therapy was predictive of OS improvement for mCRPC patients treated with second-line abiraterone or enzalutamide. The secondary objective of the study was to determine whether concomitant statin therapy was predictive of early (≤ 12 weeks) >30% PSA declines. The Kaplan-Meier method was used to estimate differences in survival between mCRPC patients treated who did and did not receive statin therapy, while Cox proportional hazards regression was used to investigate prognostic factors of overall survival. Logistic regression was used to investigate predictive factors of early >30% PSA declines. Using Cox proportional hazards, multivariable models were constructed to examine the effects of concomitant statins after adjusting for all other potential sources of variation. However, there were large numbers of missing data for some factors. Thus, a priori, it was decided to include only those factors which had <30% missing data and were significant on univariate analysis, or those factors with <15% missing data overall. The impact of statins was then assessed after adjusting for factors included in the multivariable model. Supportive analyses were performed by including only those treated with abiraterone (~80% of the cohort), only those treated with enzalutamide, by performing a cancer-specific survival analysis and by performing a landmark analysis using 3-months as the landmark time. For the purposes of the landmark analysis, any patient who was not prescribed statin therapy at the time of abiraterone or enzalutamide initiation, experienced interruption of statin therapy, or received less than 3 months of statin therapy, was deemed to not have received statins. Data modifications were performed for statistical purposes. Specifically, a logarithmic transformation was used on covariates which were highly non-normal. Duration from prostate cancer diagnosis to detection of metastases, and duration of prostate cancer diagnosis to determination of castration-resistant disease were dichotomized. All analyses included site as a stratification factor. All tests were two-sided and a p-value of 0.05 or less was considered statistically significant. No p-value adjustments were performed due to multiple testing; however, inferences were performed understanding that multiple analyses were performed.

ACKNOWLEDGMENTS AND FUNDING

The authors would like to acknowledge contribution by Isabella Ricci from the Gallarate Hospital; by Giuseppe Bassi, Antonio Verde, Francesca Vitrone, Luigi Marone, Simona Iaccarino, Mirta Mosca, Simona De Vivo, Francesco Amaniera, Antonella Mollo, Salvatore Cipolla and Chiara Rapolla from University Federico II of Naples; by Thomas De los Reyes from the Vancouver Cancer Center.

The study was partially supported by LILT sez. Napoli and Benevento.

CONFLICTS OF INTEREST

Omlin Aurelius: AO Advisory role (compensated, institutional): Astra Zeneca, Astellas, Bayer, Janssen, MSD, Pfizer, Roche, Sanofi Aventis. Research support (institutional): Teva, Janssen. Travel suport: Astellas, Bayer, Sanofi Aventis

Silke GIllesen: Speaker bureau (uncompensated,institutional):Astellas, Roche and Sanofi; Speaker bureau (compensated, institutional): Ferring, Janseen, Novartis; Consultant (compensated, institutional): AAA International; Astellas; Bayer; Bristol-Myers Squibb; Clovis; CureVac ; Ferring ; Janssen ; MaxiVax SA ; Roche ; Sanofi ; Consultant (uncompensated, institutional): ESSA Pharmaceuticals ; Nectar ; ProteoMediX

Guru Sonpavde: Consultant for Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, Astrazeneca, Merck, Genentech, Argos, Agensys, EMD Serono; Research support to institution from Bayer, Amgen-Onyx, Celgene, Boehringer-Ingelheim, Merck, Pfizer; Author for Uptodate; Speaker for Clinical Care Options, PER (Physicians Education Resource), RTP (Research To Practice), Onclive

Bernhard J. Eigl: Consultant for Janssen; Travel support for conferences from Janssen

Carlo Buonerba: Consultant for Sanofi; Travel support from Pfizer, Janssen, Sanofi; Research support to institution from Quercegen, Astellas, Sanofi

Giuseppe Di Lorenzo: Speaker bureau: Sanofi, Bristol-Meier-Squibb, Astellas, Janssen, Pfizer; Consultant for Sanofi; Research support to institution from Quercegen, Astellas, Sanofi

Tanya Dorff: Consultant for Janssen

All other authors declare they have nothing to disclose.

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