Abstract
Background/Aim: In patients with metastatic castration-sensitive prostate cancer (mCSPC), upfront treatment intensification with the addition of new hormonal agents and/or docetaxel to androgen deprivation therapy (ADT) is recommended. However, this modality is potentially excessive in a subset of these patients. This study aimed to identify patients who may be eligible to omit upfront treatment intensification. Patients and Methods: Patients with mCSPC who underwent ADT were enrolled. The association between undetectable prostate-specific antigen (PSA) (<0.2 ng/ml) after ADT initiation and overall or castration-resistance-free survival was evaluated. Results: Ninety-seven out of the 242 enrolled patients had low-risk and/or low-volume cancer and were further analyzed. Of these, 45 (46.4%) patients achieved undetectable PSA. The median follow-up period after ADT initiation was 70 months. The median overall survival among patients with undetectable PSA was quite long, reaching 226 months and significantly longer than that among patients with detectable PSA [71 months, hazard ratio (HR)=0.27, 95% confidence interval (CI)=0.15-0.49, p<0.001]. Time to development of castration-resistance was also long and significantly longer in the undetectable PSA group than that in the detectable PSA group (median: 124 vs. 17 months, HR=0.20, 95% CI=0.12-0.34, p<0.001). Conclusion: Patients with low-risk and/or low-volume mCSPC showed long-term survival when undetectable PSA was achieved during conventional ADT. In these patients, skipping upfront treatment intensification does not seem to negatively impact survival.
- Androgen deprivation therapy
- castration-sensitive metastatic prostate cancer
- treatment intensification
- undetectable PSA
Androgen deprivation therapy (ADT) has been the backbone therapy for metastatic prostate cancer for more than seven decades. The treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC) has evolved dramatically over the past several years. Upfront treatment intensification with the addition of androgen receptor signaling inhibitor (ARSI) and/or docetaxel to conventional ADT with a luteinizing hormone-releasing hormone (LH-RH) agonist or antagonist led to improved oncological outcomes in large-scale phase III trials (1-6). The CHAATED trial demonstrated that the combination of docetaxel and ADT improved overall survival (OS) for high-volume disease, defined as the presence of visceral metastases with or without ≥4 bone metastases and at least one metastatic lesion outside the vertebral column and pelvis (6). The LATITUDE study demonstrated the OS benefit of abiraterone in combination with LH-RH agonists for high-risk cancers, defined as those with at least two of the following three factors: Gleason score ≥8, ≥3 bone metastases, and visceral metastases (1). Later studies using ADT plus enzalutamide (2, 3), apalutamide (4), or darolutamide and docetaxel (5) also showed oncological benefits, including improved OS, in patients with mCSPC, irrespective of the cancer volume and risk. Based on these encouraging results, upfront combination therapy has become the standard of care and is recommended for all patients with mCSPC (7-9). However, combination therapies increase the risk of adverse events and financial toxicity. Previously, we reported that patients with PSA levels <2 ng/ml at 3 months after ADT initiation achieved long-term OS (median, 112 months), suggesting that they might not require combination therapies. However, approximately 50% of these patients progressed to castration-resistant disease and death by 5 years and 9 years after ADT initiation, respectively (10). Shore et al. (11) demonstrated that undetectable PSA levels (defined as <0.2 ng/ml) after treatment initiation was a strong predictor of long-term OS among patients enrolled in the ARASENSE trial that investigated the efficacy of triplet treatment, ADT plus docetaxel and darolutamide, in patients with mCSPC. In the present study, we investigated whether undetectable PSA levels could predict long-term OS among patients with mCSPC who underwent ADT without upfront treatment intensification and sought to accurately identify patients who would not require upfront intensified therapy.
Patients and Methods
Patients and treatment. We previously investigated the prognostic significance of PSA levels at 3 months after ADT initiation in patients with mCSPC who received ADT at the University of Occupational and Environmental Health Hospital and Kyushu University Hospital between April 2004 and December 2019 (10). The follow-up data of these patients were updated in the present study by reviewing their medical records or by telephone. All patients underwent primary ADT with medical or surgical castration with or without first-generation antiandrogens (bicalutamide or flutamide). PSA levels were measured every month after ADT initiation for several months, and then every 3 months in patients with undetectable and stable PSA levels. Imaging was performed at the discretion of the physician. Patients who received radiation therapy, chemotherapy, or later-generation ARSIs, such as abiraterone and enzalutamide, before progression to castration-resistant prostate cancer (CRPC) were excluded.
Outcome measure. CRPC was defined according to the European Association of Urology guideline (8) as follows: castration levels of serum testosterone ≤50 ng/dl and either biological progression (three consecutive rises in PSA one week apart resulting in two 50% increases over the nadir, and a PSA >2 ng/ml) or radiological progression. CRPC-free survival was defined as the time from the initiation of ADT to disease progression to CRPC. OS was defined as the time from ADT initiation to the date of death or last follow-up for survivors.
Statistical analysis. Patient characteristics were compared between the groups using the Mann–Whitney U-test and Chi-square test for continuous and categorical variables, respectively. Survival curves were generated using the Kaplan–Meier method, and a log-rank test was used to compare survival between the groups. Univariate and multivariate Cox proportional hazard regression analyses for CRPC-free survival and OS were performed using EZR (Easy R, Vienna, Austria), a graphical user interface for R (The R Foundation for Statistical Computing). A value of p<0.05 was considered statistically significant.
Ethics approval. The Institutional Review Boards of University of Occupational and Environmental Health (UOEHCRB19-050) and Kyushu University (29-438) approved this study.
Results
Patient characteristics and grouping according to cancer risk and volume. Of 317 patients with mCSPC who received primary ADT, 242 were eligible for analysis (10). Of these, 238 and 4 received castration plus first-generation antiandrogens and castration alone, respectively. These included 167 high-risk (HR) patients and 75 low-risk (LR) patients, while 156 and 86 had high-volume (HV) and low-volume (LV) diseases, respectively (Table I). Our cohort was, thus, divided into four groups according to disease risk and volume: HR and HV (HRHV; N=145), LR and HV (LRHV; N=22), HR and LV (HRLV; N=11), and LR and LV (LRLV; N=64). The median follow-up time after ADT initiation was 70 months [interquartile range (IQR)=38-113 months].
Number of patients in cancer risk and volume group (N=242).
The OS of HR patients was significantly worse than that of LR patients (p<0.001). Similarly, HV disease was associated with a worse OS (vs. LV disease, p<0.001). The median OS for HRHV, LRHV, HRLV, or LRLV was 45 months, not reached, 75.6 months, or 104 months, respectively. The rates of OS for the LRHV, HRLV, and LRLV groups were not significantly different and were better than that for the HRHV group (p<0.0001, Figure 1). Most patients with long-term survival had LR and/or LV (HRLV, LRHV, LRLV) disease, and we focused on these groups to identify patients who had considerably favorable outcomes with ADT alone.
Overall survival in patients with high-risk and high-volume (red), high-risk and low-volume (violet), low-risk and high-volume (green), or low-risk and low-volume (blue) disease.
Undetectable PSA and survival. Of 97 patients with LR and/or LV disease, 45 (46.4%) achieved undetectable PSA after initiation of ADT. The median time from ADT initiation to undetectable PSA was 10 (IQR=6.5-13) months. Table II lists the baseline characteristics of patients with or without undetectable PSA. PSA levels before ADT initiation (p=0.033), Grade group (p=0.001), and the rate of lymph node metastasis (p=0.037) were significantly lower in the undetectable PSA group. Cancer risk and volume were not significantly different between the groups.
Baseline characteristics of patients with low-risk and/or low-volume cancer (N=97).
The median OS for patients with undetectable was extremely long, reaching 226 months and significantly longer than that for patients with detectable PSA (71 months, HR=0.26, 95% CI=0.13-0.50, p<0.001, Figure 2A). The estimated five- and 10-year OS for the undetectable PSA group were 87.9% and 67.8 %, respectively. The time to CRPC development was also quite long and significantly longer in the undetectable PSA group compared to the detectable PSA group (median: 124 vs. 17 months, HR=0.21, 95% CI=0.12-0.36, p<0.001, Figure 2B). The estimated five- and 10-year CRPC-free survival for the undetectable PSA group were 60.4% and 50.0%, respectively.
Overall survival (OS) (A) and castration-resistant prostate cancer (CRPC)-free survival (B) for low-risk and/or low-volume disease according to undetectable (blue) or detectable (red) prostate-specific antigen (PSA).
Multivariate analysis was then performed to determine if undetectable PSA, along with other prognosticators, was an independent factor for patient outcomes (Table III). In the Cox model, undetectable PSA was associated with significantly longer CRPC-free survival (HR=0.16, 95% CI=0.08-0.31, p<0.001) or OS (HR=0.19, 95% CI=0.08-0.41, p<0.001).
Univariate and multivariate analyses to predict CRPC-free and overall survival.
Discussion
The guidelines and most of published articles strongly recommend upfront treatment intensification using combination with conventional ADT and ARSIs or docetaxel for all patients with mCSPC, considering the consistently improved OS among patients in the clinical trials (2-5). However, whether upfront combination therapy is mandatory for all patients, especially older or frail adults, is questionable. Indeed, a substantial number of patients with mCSPC undergo ADT without ARSIs or docetaxel (12-14). For example, a real-world survey conducted between January and August 2020 in the United States, five European countries, and Japan revealed that the most common first-line global regimen was conventional ADT alone, and 34%-78% of patients with mCSPC were treated with ADT without combination therapy. Physicians often prescribe conventional ADT drugs only rather than ADT in conjunction with chemotherapy after considering performance status, quality of life (QOL), compliance challenges, and adverse events. The key clinical reason why physicians use ADT alone without combined ARSI is compliance challenges (14). Populations in the real world are older, less physically fit, and have more comorbidities than those enrolled in clinical trials. For example, the median age of patients in clinical trials is 63-70 years (1-6), whereas that in the real world is 70-75 years (10, 12, 14-17). In addition, financial toxicity caused by expensive ARSIs and physicians’ experience of favorable outcomes with ADT may also play a role in the choice of treatment options. Moreover, the goal of treatment for many patients, especially the elderly with comorbidities, is to maintain QOL rather than longer survival. Adverse events caused by treatment intensification may exceed the benefits in some patients.
Although the use of doublet or triplet combination therapies has increased over time, ADT as monotherapy remains a viable treatment option for a subset of patients with mCSPC. Therefore, identifying patients who respond favorably to conventional ADT alone and do not require intensive upfront therapy is an important clinical challenge.
The present study demonstrated that patients with low-risk and/or low-volume disease had long-term survival (>18 years) when their PSA was undetectable. The estimated five-year and 10-year survival rates in the undetectable PSA group were 87.9% and 67.8%, respectively. The five-year and 10-year survival rates of Japanese men aged 73 years, which was the median age of our undetectable patient group, were estimated 63.9% and 32.6%, respectively (18). Thus, the survival of the undetectable group was not inferior to that of the Japanese population. Upfront treatment intensification by combination therapy may be excessive, and deferred combination therapy should be a promising option. Specifically, ADT alone can be initiated for patients with low-risk and/or low-volume disease, and can be used to monitor PSA levels. In patients with undetectable PSA, ADT as monotherapy can be continued until disease progression. When undetectable PSA is not achieved, ARSI or docetaxel should be initiated immediately.
Several prognostic models have been developed for patients with mCSPC who have undergone conventional ADT alone (15-17). These models are helpful in determining the appropriate initial treatment; however, they have several limitations. The prognosis largely depends on the response to treatment. Treatment responses and outcomes are heterogeneous among patients with similar clinical features. Generally, to establish prognostic models, the selection of parameters (pretreatment biomarkers) and their cut-off values are usually determined arbitrarily and not according to definite rules. For example, the cut-off values of laboratory tests are usually determined by the median value or the results of the receiver operating characteristic (ROC) curve in the study cohort. Cut-off levels for clinicopathological findings, such as the Gleason score and tumor extent, were determined arbitrarily, and different cut-off levels were used in different studies (15-17). There are various pretreatment biomarkers and prognostic models, and the most useful for determining the appropriate treatment is still unknown. Although ADT plus ARSIs has been implicated in improved OS for LV or LR mCSPC (vs. ADT alone; HR of 0.42 to 0.72) (19), LV or LR mCSPC is heterogeneous, in terms of response to ADT and survival. In our cohort, patients with LR and/or LV cancer had poor OS when undetectable PSA was not achieved, indicating that pretreatment biomarkers alone may be insufficient to predict an accurate prognosis. On-treatment biomarkers provide real-time information on therapeutic response and are helpful in determining the most appropriate modality. We used the LATITUDE risk and CHAARTED volume categories, which are quite simple and frequently used, as pretreatment biomarkers for mCSPC. PSA levels of 0.2 ng/ml as a cut-off value was used as an on-treatment biomarker. Our findings thus suggest that the combination of pre- and on-treatment biomarkers could predict prognosis more precisely than each biomarker alone.
This study had several limitations. Of all patients included in this study, 98% were treated with combined androgen blockade (CAB) using medical or surgical castration plus bicalutamide or flutamide, not with castration alone. A phase III clinical trial comparing CAB and castration alone demonstrated that the OS of patients with mCSPC was not significantly different between the two treatment groups (p=0.83) (20). A meta-analysis also revealed that the survival benefit of CAB compared to that of castration alone was very limited for mCSPC (21). Thus, we consider that our results can be applied to patients receiving CAB and ADT alone. In addition, all the patients in our cohort were Japanese. Because the response to ADT may differ among ethnicities (22-24), validation in other races may be desirable for the generalization of the results of the present study.
Conclusion
Patients with low-risk and/or low-volume mCSPC who achieved undetectable PSA had long-term (>18 years) survival with conventional ADT. The omission of upfront treatment intensification does not appear to negatively impact the oncological outcomes and may be excessive for these patients. For patients having favorable risk cancer, initiating ADT as monotherapy, with subsequent consideration of treatment intensification if undetectable PSA is not achieved would be a valid clinical strategy.
Acknowledgements
The Authors would like to thank Editage (www.editage.com) for English language editing.
Footnotes
Authors’ Contributions
N.F.: Conceptualization, design, acquisition of data and the analysis, writing – original draft preparation; Y.N., MS, A.M., I.T., M.E.: Acquisition of data and the analysis; K.H.: Review and editing; H.M.: Supervision, review, and revision of the manuscript; All Authors read and approved the final version of the manuscript.
Conflicts of Interest
Masaki Shiota has received honoraria from Janssen Pharmaceutical, AstraZeneca, Astellas Pharma, Sanofi, Bayer Yakuhin, Nippon Shinyaku, and Takeda Pharmaceutical, and research funding support from Daiichi Sankyo. Hiroshi Miyamoto has received research funding from Astellas Scientific and Medical Affairs, Ferring Research Institute, and Bristol-Myers Squibb. Other Authors report no conflicts of interest regarding this work.
- Received May 25, 2024.
- Revision received June 24, 2024.
- Accepted July 10, 2024.
- Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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