The efficacy and safety of androgen receptor signaling inhibitors in patients with non-metastatic castration resistant prostate cancer

doi:10.21203/rs.3.rs-3634411/v1

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The efficacy and safety of androgen receptor signaling inhibitors in patients with non-metastatic castration resistant prostate cancer

https://doi.org/10.21203/rs.3.rs-3634411/v1

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BACKGROUND

The treatment paradigm for non-metastatic castration resistant prostate cancer (nmCRPC) has changed in recent years. An observational multicenter study was conducted to evaluate the effectiveness of androgen receptor signaling inhibitors (ARSI) as a first-line treatment for patients with nmCRPC.

METHODS

The primary endpoint of this study was to evaluate the efficacy and safety of ARSI in native Japanese patients who received ARSI as a first-line treatment for nmCRPC. The secondary endpoint was to develop a novel system to stratify the prognoses of these patients.

RESULTS

In total, 160 patients were enrolled in this study. Within a median follow-up period of 23 months, the median overall survival (OS) was not reached, whereas the median progression-free survival was 26 months. Multivariate Cox regression analyses showed that the time to CRPC, PSA level at the initiation of nmCRPC treatment, and Geriatric Nutritional Risk Index (GNRI) were independent predictors of OS. The patients were subsequently divided into three groups as follows: Group 1, 57 patients with negative or one positive independent OS predictor; Group 2, 38 patients with two positive independent OS predictors; and Group 3, 10 patients with three independent OS predictors. The OS differed significantly among the three groups (p < 0.0001).

CONCLUSION

ARSI may provide favorable outcomes for Japanese patients with nmCRPC as a first-line treatment. Time to CRPC, PSA level at the initiation of nmCRPC treatment, and GNRI are potential predictors of OS in Japanese patients with nmCRPC who received ARSI as a first-line treatment.

multicenter retrospective cohort study

nmCRPC

ARSI

time to CRPC

PSA level

GNRI

According to recent studies, approximately 30% of patients with prostate cancer (PCa) undergoing surgery and 40% of patients undergoing radiation therapy experience biochemical recurrence (BCR) within 10 years following local therapies [1]. Patients with BCR have variable prognoses, with metastasis-free survival ranging from 1 to > 15 years [2].

Non-metastatic castration-resistant prostate cancer (nmCRPC) is defined as an increase in prostate-specific antigen (PSA) in the setting of castrate testosterone levels with no detectable metastases on conventional imaging. Currently, the most accepted definition of progression on androgen deprivation therapy (ADT) is based on PSA increase and follows the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) consensus, which is primarily intended to define endpoints for clinical trial design [3].

Recently, three phase 3 trials (ARAMIS, PROSPER, and SPARTAN) of nmCRPC demonstrated statistically significant improvements in the primary endpoints of metastasis-free survival and overall survival (OS) among patients who received androgen receptor signaling inhibitors (ARSI; darolutamide, enzalutamide, or apalutamide) [4–6]. Moreover, treatment with abiraterone acetate (1,000 mg) plus prednisone (5 mg) resulted in a significant reduction in ≥ 50% reduction of PSA, with encouraging results for time to PSA progression, time to radiographic evidence of disease progression, and safety in patients with high-risk nmCRPC [7]. Although it is not possible to directly compare these novel ARSI, these pivotal trials have significant differences in adverse event reporting and absolute adverse event risks between the placebo arms [8].

Considering these findings, it is necessary to understand the prognostic factors of ARSI for the first-line treatment of patients with nmCRPC. Therefore, in the current study, we retrospectively analyzed the prognostic outcomes on Japanese patients with nmCRPC who received ARSI as a first-line treatment. Moreover, we developed a novel system to stratify the prognoses of these patients.

In the current study, we retrospectively analyzed the clinical data of 160 Japanese patients with nmCRPC who received ARSI as a first-line treatment between January 2014 and December 2022 at four institutions belonging to the Tokai Urologic Oncology Research Seminar group, including the Fujita Health University School of Medicine, Nagoya City

University Graduate School of Medical Sciences, Hamamatsu University School of Medicine and Gifu University Graduate School of Medicine. The study design was approved by the ethics committees of the four institutions < approval no: HM23-098 (Fujita Health University School of Medicine), 60-23-0089 (Nagoya City University Graduate School of Medical Sciences), 23–049 (Hamamatsu University School of Medicine), and 023–120 (Gifu University Graduate School of Medicine)>. The requirement for informed consent from all patients included in this study was waived due to the retrospective design.

Clinical characteristics and blood data, including age, body mass index (BMI), PSA, PSA doubling time (PSADT), Gleason score, treatment, Eastern Cooperative Oncology Group–Performance status (ECOG-PS), Hb, ALP, LDH, neutrophil-to-lymphocyte ratio (NLR), and Geriatric Nutritional Risk Index (GNRI) were assessed. GNRI was proposed by Bouillanne et al. in 2005, and has been widely used for nutritional assessment in older patients [9]. Calculation of GNRI was as follow: GNRI = 14.89 X serum albumin (g/dL) + 41.7 X BMI/22. Patients also underwent radiological examinations, including pelvic magnetic resonance imaging, computed tomography, and radionuclide bone scanning. Clinical staging of PCa was determined according to the 8th edition of the American Joint Committee on Cancer manual [10]. Clinically, biochemically, or radiographically progressive disease was defined according to the criteria of the PCWG3.

The primary endpoint of the study was to evaluate the efficacy and safety of ARSI in patients with nmCRPC. The secondary endpoint was to develop a novel system to stratify the prognoses of these patients.

All data were analyzed using IBM SPSS Statistics version 23 (SPSS Japan, Tokyo, Japan). Each optimum cut-off value was determined from the receiver operating characteristic (ROC) curve using Youden’s index. Statistical significance was set at p < 0.05. OS and progression-free survival (PFS) were estimated using the Kaplan–Meier method, and differences were determined using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards regression.

In the present study, we retrospectively analyzed 160 patients who received ARSI as a first-line treatment for nmCRPC between January 2014 and December 2022 at four institutions belonging to the Tokai Urologic Oncology Research Seminar group. The clinical characteristics of the 160 patients are shown in Table 1.

Table 1

Baseline patient characteristics.
Baseline Patient Characteristics	n = 160
Age, y/o, Median (IQR)	79 (73–83)
BMI, kg༏m², Median (IQR)	23.2 (20.5–25.5)
initial PSA, ng/ml, Median (IQR)	20.5 (10.2–74.0)
Primary Gleason score, (%) 3 + 3	9 (5.6)
3 + 4	17 (10.6)
4 + 3	17 (10.6)
4 + 4	44 (27.5)
4 + 5	27 (16.9)
5 + 4	27 (16.9)
5 + 5	10 (6.3)
unknown	9 (5.6)
Intial treatment, (%) ADT	12 (7.5)
CAB	89 (55.6)
RP	25 (15.6)
ADT + RP	6 (3.8)
Extrabeam	6 (3.8)
ADT or CAB + Extrabeam	17 (10.6)
BT	1 (0.6)
ADT or CAB + BT + Extrabeam	4 (2.5)
Time to CRPC, month, Median (IQR)	48 (19–86)
PSA at nmCRPC, ng/ml, Median (IQR)	3.7 (2.3–7.6)
PSA doubling time, month, (%) ~ 6	83 (51.9)
6 ~	6 (3.8)
unknown	71 (44.4)
cN at nmCRPC, (%) 0	131 (81.9)
1	26 (16.3)
unknown	3 (1.9)
nmCRPC 1st line treatment, (%) Enzamutamide	90 (56.3)
Abiraterone	28 (17.5)
Apalutamide	22 (13.8)
Darolutamide	20 (12.5)
ECOG PS, (%) 0	103 (64.4)
1	33 (20.6)
2	4 (2.5)
3	1 (0.6)
unknown	19 (11.9)
Hb, g/dl, Median (IQR)	12.7 (11.9–13.5)
ALP, IU/ml, Median (IQR)	120.5 (86-245.5)
LDH, IU/L, Median (IQR)	198.5 (175.3–229.0)

Within a median follow-up period of 23 months, the median OS was not reached, whereas the median PFS was 26 months (Fig. 1). The OS and PFS rates were 84.4% and 55.0%, respectively.

Next, we performed Cox regression analyses for OS to evaluate the prognostic significance of ARSI as a first-line treatment. Univariate analysis demonstrated that the time to CRPC, PSA level at the initiation of nmCRPC treatment, Hb level, and GNRI affected OS (p = 0.009, 0.021, 0.016, and 0.003, respectively). Multivariate Cox regression analyses showed that the time to CRPC, PSA level at the initiation of nmCRPC treatment, and GNRI were independent predictors of OS (p = 0.045, 0.031, and 0.018, respectively) (Table 2).

Table 2

Univariate and multivariate analyses of the clinical parameters of overall survival (OS).
	Univariate analysis		Multivariate analysis
	HR (95%CI)	P-value	HR (95%CI)	P-value
Age (≥ 70 vs < 70, y)	0.467 (0.110–1.984)	0.302
initial PSA (≥ 41.7 vs < 41.7, ng/ml)	0.337 (0.150–0.754)	0.008	0.786 (0.205–3.011)	0.725
Existence of Gleason pattern 5 (yes vs no)	2.255 (0.671–7.582)	0.189
Initial treatment ADT		0.859
CAB	0.987 (0.000-5.541E + 146)	1.000
RP	13718 (0.000-1.290E + 83)	0.918
ADT + RP	4546 (0.000-4.296E + 82)	0.928
Extrabeam	0.995 (0.000-8.248E + 109)	1.000
ADT or CAB + Extrabeam	9418 (0.000-8.948E + 82)	0.921
BT	5918 (0.000-5.592E + 82)	0.925
ADT or CAB + BT + Extrabeam	1.027 (0.000-1.776E + 230)	1.000
Time to CRPC (< 38 vs ≥ 38, month)	0.297 (0.119–0.743)	0.009	0.244 (0.062–0.968)	0.045
PSA at nmCRPC (≥ 2.89 vs < 2.89, ng/ml)	0.303 (0.110–0.834)	0.021	0.116 (0.016–0.818)	0.031
cN (+ vs -)	0.436 (0.166–1.140)	0.090
nmCRPC 1st line treatment Enzamutamide		0.453
Abiraterone	0.821 (0.103–6.552)	0.852
Apalutamide	1.660 (0.199–13.817)	0.639
Darolutamide	0.000 (0.000-1.251E + 233)	0.965
ECOG PS (≥ 1 vs 0)	0.625 (0.241–1.623)	0.335
Hb (< 12.6 vs ≥ 12.6, g/dl)	0.319 (0.125–0.809)	0.016	0.514 (0.153–1.719)	0.280
ALP (≥ 174 vs < 174, IU/ml)	0.720 (0.296–1.754)	0.470
LDH (≥ 212 vs < 212, IU/L)	0.612 (0.259–1.449)	0.265
NLR (≥ 2.45 vs < 2.45, IU/ml)	2.638 (0.755–9.212)	0.128
GNRI (< 101.6 vs ≥ 101.6)	0.214 (0.076–0.601)	0.003	0.225 (0.066–0.774)	0.018

Next, we stratified the 105 patients into three groups according to these three independent predictors of OS as follows: Group 1, 57 patients with negative or one positive independent OS predictor; Group 2, 38 patients with two positive independent OS predictors; and Group 3, 10 patients with three independent OS predictors. The OS was significantly different among the three groups (p < 0.0001; 0 or 1 factor vs. 2 factors: p = 0.0058; 0 or 1 factor vs. 3 factors: p < 0.0001; 2 factors vs. 3 factors: p = 0.0029; Fig. 2).

nmCRPC is defined as PSA progression in the setting of castration levels of testosterone, with no evidence of metastases on conventional imaging. Although most patients with nmCRPC are asymptomatic, the early use of ARSI, not deferred ARSI after CRPC progression, may improve OS, PFS, and PSA response in nmCRPC [11]. Moreover, first-generation antiandrogen monotherapy (i.e., bicalutamide) and switching or withdrawal of antiandrogens also provide short-term PSA responses; however, no clinical trial has demonstrated a survival benefit using such approaches [12–14].

As described above, regarding the treatment of nmCRPC, the recent approval of potent ARSI is specifically linked to the nmCRPC disease state, and these drugs have been shown to provide better outcomes in patients with nmCRPC [4–7]. In these three pivotal randomized phase III trials of nmCRPC, approximately 50% of patients had previously received radical local treatment (radiation therapy or prostatectomy) [15]. To date, little is known about whether such patients benefit from local treatment of the primary tumor. Collectively, further prognostication should be carried out to provide more precise information regarding the Japanese patients with nmCRPC who received ARSI as a first-line treatment.

In the current study, we retrospectively analyzed the data of 160 Japanese patients with nmCRPC who received ARSI as first-line treatment. In the present study, we did not obtain sufficient patient information regarding PSADT. PSADT is a strong predictor of metastasis, all-cause mortality, and PCa-specific mortality in patients with nmCRPC. As with patients at earlier disease stages, < 3, 3–8.9, 9–14.9 and ≥ 15 months are reasonable PSADT thresholds for risk stratification in men with nmCRPC [16]. Considering this information about PSADT as a strong predictor in patients with nmCRPC, because more than half of the patients in the present cohort showed PSADT in less than 6 months, we considered that PSADT is not needed to assess OS.

Multivariate Cox regression analyses showed that the time to CRPC, PSA level at the initiation of nmCRPC treatment, and GNRI were independent predictors of OS, whereas local treatment, including radiation therapy or prostatectomy, did not affect OS. Considering these results of analyses, PSA level at the initiation of nmCRPC treatment might be prognostic alternatives to PSADT for the Japanese patients with nmCRPC who received ARSI as a first-line treatment. Regarding the time to CRPC, several recent investigators have advocated it as a significant prognosticator of OS [17–19].

The GNRI is a simple and objective screening tool for clinicians to screen patients’ nutritional status based on serum albumin levels, weight, and height. Bouillanne et al. first introduced the GNRI in 2005 to evaluate the 6-month midterm nutritional outcomes of elderly patients admitted to a rehabilitation unit. They divided the patients into four groups: a no-risk group (GNRI > 98), low-risk group (GNRI 92–98), moderate-risk group (GNRI 82 to < 92), and major risk group (GNRI < 82), suggesting that the risk of infectious complications or mortality was significantly higher in the major-, moderate-, and low-risk groups than in the no-risk group [9]. Considering this GNRI cutoff value, the cutoff value (101.6) obtained from the ROC curve in the present study was reasonable. Regarding PCa, Okamoto et al. reported that a GNRI < 92.0 was an independent prognostic factor for cancer-specific survival and OS in patients with metastatic hormone-naïve PCa [20]. Moreover, in the context of metastatic CRPC (mCRPC), Chang et al. demonstrated that poor nutritional status with a GNRI < 92 was associated with shorter PFS and OS in patients with mCRPC treated with docetaxel [21].

In the current study, to properly predict the clinical outcomes of Japanese patients with nmCRPC who received ARSI as a first-line treatment, we attempted to develop a novel system for the prognostic stratification of these patients using three independent OS predictors (time to CRPC, PSA at the initiation of nmCRPC treatment, and GNRI). We divided the patients into three groups based on the presence of none, one, two, or three independent OS predictors. We then compared the OS among these three groups and found that the OS was significantly different among them. The results of the present study support our novel stratification system, suggesting that the positive numbers of independent OS predictors could be a useful tool for Japanese patients with nmCRPC who received ARSI as first-line treatment.

This study had several limitations. First, it was retrospectively conducted with a small sample size; thus, a selection bias may have affected the results. Regarding the selection of ARSI as a first-line treatment for patients with nmCRPC, there was no criteria. Second, the cutoff points used in the current analyses should be assessed in a large-scale study. Third, we could not obtain sufficient patient information regarding PSADT. Prospective studies with larger sample sizes and longer follow-up periods are warranted to confirm our findings.

We identified that ARSI might provide favorable outcomes for Japanese patients with nmCRPC as a first-line treatment. Time to CRPC, PSA level at the initiation of nmCRPC treatment, and GNRI are potential predictors of OS in Japanese patients with nmCRPC who received ARSI as a first-line treatment. Furthermore, our novel stratification system based on the positive numbers of these three independent OS predictors could help guide decision-making for patients who received ARSI as a first-line treatment.

Conflict of Interest

Takahiro Yasui has financial relationships with 2021 Janssen Pharmaceutical K.K. Other authors declare no conflict of interest.

Acknowledgement

None.

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The efficacy and safety of androgen receptor signaling inhibitors in patients with non-metastatic castration resistant prostate cancer

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Version 1

Abstract

BACKGROUND

METHODS

RESULTS

CONCLUSION

Figures

Introduction

Materials and Methods

Results

Discussion

Conclusion

Declarations

Conflict of Interest

Acknowledgement

References

Status:

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