Research ArticleClinical Studies

Is it Necessary to Treat all Metastatic Prostate Cancer With Upfront Androgen Receptor Axis-targeted Agents?

RYUNOSUKE NAKAGAWA, HIROAKI IWAMOTO, RENATO NAITO, SUGURU KADOMOTO, HIROSHI YAEGASHI, SHOHEI KAWAGUCHI, TAKAHIRO NOHARA, KAZUYOSHI SHIGEHARA, KOUJI IZUMI, YOSHIFUMI KADONO and ATSUSHI MIZOKAMI
Anticancer Research March 2023, 43 (3) 1351-1359; DOI: https://doi.org/10.21873/anticanres.16283

Abstract

Background/Aim: In recent years, initial treatment for patients with high-risk metastatic castration-sensitive (mCS) prostate cancer (PC) has been shifting from vintage hormone therapy to upfront androgen receptor axis-targeted agents (ARAT), but the proportion of Asian patients enrolled in clinical trials investigating the effectiveness of ARAT use is low. We examined the outcomes of Japanese patients with mCSPC who received ARAT as second-line therapy or afterwards. Patients and Methods: Among the PC patients receiving treatment at Kanazawa University Hospital from 2000 to 2019, 190 patients with mCSPC were enrolled in the study. Their characteristics and prognosis were retrospectively investigated. Results: All patients received androgen deprivation therapy (ADT) as initial treatment. A total of 142 (74.3%) of 190 patients had progression to castration-resistant PC (CRPC), of whom 77 (54.2%) received ARAT as second-line therapy or afterwards. The median overall survival (OS) of CRPC patients was 70.57 months and the median OS from CRPC was 44.88 months. The median OS of LATITUDE high-risk patients that used ARAT after the second-line treatment was 56.15 months, which was significantly longer than that of patients who did not use ARAT (hazard ratio=0.68, 95% confidence interval=0.40-1.15; p=0.0089). Conclusion: The prognosis of LATITUDE high-risk patients with CRPC selected for initial ADT therapy had a good prognosis compared to findings in other studies. These results suggest that there is a possibility that a certain number of patients with LATITUDE high-risk may have good prognosis even if only conventional ADT is performed and ARAT is used after CRPC.

Key Words:

Since the establishment of androgen deprivation therapy (ADT) for prostate cancer (PC) in 1941 (1), ADT remains the main therapeutic approach for metastatic castration-sensitive PC (mCSPC). However, ADT gradually becomes ineffective in a certain number of patients, facilitating the transition to castration-resistant PC (CRPC), which often leads to fatal outcomes. However, and until the development of androgen receptor axis-targeted agents (ARATs), such as abiraterone and enzalutamide, as second-line therapy for patients with CRPC, there had been no established sequential therapy after the introduction of ADT (2, 3). Recently, upfront ARATs have become the first-line treatment for mCSPCs, replacing traditional ADT. Fizazi et al. reported that the combination of abiraterone acetate and prednisone could significantly prolong overall survival (OS) compared to ADT alone in high-risk mCSPC patients (4). The ENZAMET trial reported that first-line therapy with enzalutamide for patients with mCSPC could significantly prolong progression-free survival (PFS) and OS compared to standard antiandrogen therapy (5). Furthermore, Chi et al. showed that apalutamide used as first-line therapy for mCSPC exhibited better OS and radiographic PFS compared to conventional ADT (6). Based on these results, the worldwide standard of care for patients with mCSPC shifted from ADT to ARATs. However, the use of ARATs to all patients is rather questionable. One factor to consider is race. For example, only 86 (7.2%) of the 1,199 registered participants in the LATITUDE trial and 229 (21.7%) of the 1,052 enrolled patients in the TITAN trial were of Asian origin (4). Consequently, the effectiveness of upfront ARAT in Asian patients remains unknown. Furthermore, it has been reported that ARATs could induce visceral metastases, rendering unrestricted administration of ARATs to all patients questionable (7).

In this study, we examined the efficacy of initial treatment with ADT and sequential treatment with ARAT after CRPC in Japanese patients and compared our results with previous reports.

Patients and Methods

Among the PC patients receiving treatment at Kanazawa University Hospital from 2000 to 2019, 190 patients with mCSPC were enrolled in the study. All patients were pathologically diagnosed with PC, and distant metastasis was detected by computed tomography and/or bone scans performed at the time of diagnosis. Patients with a pathological diagnosis of adenocarcinoma were included, while those with other pathological diagnoses, such as small cell carcinoma, were excluded.

The characteristics, OS and CRPC-free survival of the included patients were retrospectively investigated. Risk classification was performed according to the LATITUDE trial (4). Patients were classified as high-risk if they had a Gleason score of ≥8, three or more bone lesions or visceral metastases, at least two of which were applicable. OS was measured from PC diagnosis until death or last follow up. Follow up was terminated on October 24, 2021. Clinical stage was determined based on the 8th edition of the Union for International Cancer Control Tumour, Node, Metastasis classification published in 2017.

OS and CRPC-free survival were estimated using the Kaplan–Meier method, and differences were compared using log-rank tests. We evaluated the predictive impact of several potential factors on OS using the Cox proportional hazards model. Furthermore, the hazard ratio (HR) and 95% confidence intervals (CI) were calculated. Statistical analyses were performed using the commercially available software Prism 8 (GraphPad, San Diego, CA, USA) and SPSS ver. 25.0 (SPSS Inc), with p-values of <0.05 indicating statistical significance.

This study was approved by the institutional review board of the Kanazawa University Hospital (2016-328). Informed consent was obtained in the form of opt-out posted at our facility allowed by Medical Ethics Committee of Kanazawa University. All methods were performed in accordance with relevant guidelines and regulations.

Results

All patients received ADT as the initial treatment and 142 (74.3%) of 190 patients with disease progression to CRPC. The CRPC rate for low and high-risk (LATITUDE) patients was 69.0% and 77.7%, respectively. Time to CRPC was significantly shorter in high-risk (LATITUDE) patients (HR=1.97, 95%CI=1.45-2.74; p<0.001, Figure 1A). The median OS in patients without disease progression to CRPC was 162 months (Figure 1B). Furthermore, OS was significantly shorter in high-risk patients (HR=6.29, 95%CI=1.26-31.46; p=0.025, Figure 1C).

Figure 1.
Figure 1.

Kaplan–Meier curves in castration-resistant prostate cancer (CRPC) and overall survival (OS) of patients without disease progression to CRPC. A) Comparison of time to CRPC between low- and high-risk (LATITUDE) patients. B) OS in patients without disease progression to CRPC. C) Comparison of OS between low and high-risk (LATITUDE) patients without disease progression to CRPC.

The characteristics of the 142 CRPC patients included in the present study are shown in Table I. One hundred patients (70.4%) were classified as high-risk (LATITUDE). The median time to CRPC was 12.6 months, the median OS was 70.6 months and the median OS from CRPC was 44.9 months. Low risk (LATITUDE) patients had significantly longer OS (HR=2.40, 95%CI=1.52-3.78; p<0.001, Figure 2A) and OS from CRPC (HR=2.14, 95%CI=1.35-3.39; p=0.0027) than high-risk patients (Figure 2B).

View this table:
Table I.

Characteristics of patients with castration-resistant prostate cancer (CRPC).

Figure 2.
Figure 2.

Comparison of overall survival (OS) and OS from castration-resistant prostate cancer (CRPC) between low- and high-risk (LATITUDE) patients with CRPC. A) OS. B) OS from CRPC.

Next, we compared patients who received ARATs as second or subsequent therapy (ARAT+ group) with the group that did not receive ARAT (ARAT− group). Patient characteristics are shown in Table II. The ARAT+ group was significantly younger than the ARAT− group (73 vs. 68 years, p<0.001). The ARAT+ group had significantly longer OS than the ARAT− group (HR=0.58, 95%CI=0.36-0.94; p=0.016, Figure 3A). Furthermore, the OS from CRPC was significantly prolonged in the ARAT+ group (HR=0.51, 95%CI=0.31-0.83; p<0.001, Figure 3B). Univariate and multivariate analysis revealed that International Society of Urological Pathology (ISUP) grade 5 (HR=2.11, 95%CI=1.29-3.45; p=0.003), high-risk (LATITUDE) (HR=2.17, 95%CI=1.24-3.80; p=0.007), and use of ARAT (HR=0.57, 95%CI=0.36-0.90; p=0.015) were prognostic factors of OS (Table III). ISUP grade 5 (HR=2.09, 95%CI=1.28-3.44; p=0.004) and use of ARAT (HR=0.54, 95%CI=0.34-0.85; p=0.008) were also identified as prognostic factors of OS in patients with CRPC (Table IV). Age, which was significantly different among patients, was not found to be a prognostic factor of both OS and OS in patients with CRPC.

Figure 3.
Figure 3.

Comparison of overall survival (OS) and OS from castration-resistant prostate cancer (CRPC) between the androgen receptor axis-targeted agents (ARAT)+ and ARAT− groups. A) OS. B) OS from CRPC.

View this table:
Table II.

Characteristics of patients in the androgen receptor axis-targeted agent (ARAT)- and ARAT+ groups.

View this table:
Table III.

Univariate and multivariate analysis of prognostic factors of overall survival.

View this table:
Table IV.

Univariate and multivariate analysis of prognostic factors of overall survival in patients with castration-resistant prostate cancer (CRPC).

We focused on high-risk (LATITUDE) patients and compared the results with and without use of ARAT. The characteristics of patients in each group are shown in Table V. The ARAT+ group tended to have higher ISUP grades than the ARAT− group (p=0.18). There was no significant difference in CRPC-free survival between the two groups (HR=0.92, 95%CI=0.62-1.36; p=0.66, Figure 4A). However, OS was significantly prolonged in the ARAT+ group (HR=0.68, 95%CI=0.40-1.15; p=0.0089, Figure 4B). In addition, OS from CRPC tended to be longer in the ARAT+ group (HR=0.65, 95%CI=0.38-1.11; p=0.095, Figure 4C).

View this table:
Table V.

Characteristics of high-risk (LATITUDE) patients in the androgen receptor axis-targeted agent (ARAT)- and ARAT+ groups.

Figure 4.
Figure 4.

Comparison of time to castration-resistant prostate cancer (CRPC), overall survival (OS) and OS from CRPC between androgen receptor axis-targeted agents (ARAT)+ and ARAT- groups in high-risk (LATITUDE) patients. A) Time to CRPC. B) OS. C) OS from CRPC.

Discussion

In this study, time to CRPC was significantly shorter in high-risk (LATITUDE) patients than that in low risk patients. The OS of patients without disease progression to CRPC was also significantly shorter in high-risk (LATITUDE) patients. In contrast, 48 (25.7%) of the 190 mCSPC patients did not progress to CRPC. Furthermore, 23.3% of high-risk (LATITUDE) patients did not progress to CRPC even when ADT treatment was used alone. These results indicate that initial treatment with ADT can be sufficient for a certain number of high-risk (LATITUDE) patients.

We also focused on patients with CRPC. Following classification of these patients according to the LATITUDE risk criteria, the present study found that the OS and OS from CRPC were significantly prolonged in the high-risk group. Also, the median OS of patients classified as high-risk by LATITUDE risk criteria was 52.93 months, which was comparable to the OS of patients who received abiraterone acetate and prednisolone upfront in the LATITUDE trial (53.3 months) (4), even though all patients selected CAB or ADT as first-line therapy. One possible explanation for the similarity between conventional hormone therapy outcomes and those of previous upfront ARATs may be the difference in sensitivity to hormone therapy among different racial groups. Fukagai et al. reported that Asian patients with metastatic PC were more sensitive to castration and had significantly longer survival than other ethnic groups (8).

Patients who received ARAT as second or subsequent therapy had significantly longer OS and OS from CRPC than those who did not receive ARAT. Univariate and multivariate analyses also found ARAT used to be a prognostic factor in OS and OS from CRPC. In the COU-AA-301 trial, abiraterone treatment in patients with CPRC significantly prolonged OS compared to the placebo group (2). The AFFIRM trial also found that enzalutamide significantly prolonged OS in CRPC patients after chemotherapy compared to the placebo group (3). The present study, as well as the results of these trials, found that the use of ARATs could significantly improve patients’ prognosis.

High-risk (LATITUDE) patients who received ARAT after CRPC also had significantly longer OS than those who did not receive ARAT, despite a trend toward worse ISUP grades. In addition, our findings revealed a trend toward prolongation of OS from CRPC. In the LATITUDE trial, the 3-year survival rate for patients treated with upfront abiraterone was approximately 65% (4), and survival was better for patients treated with ARAT after CRPC in this study. These results also suggest that there is a possibility that a certain number of high-risk (LATITUDE) patients may have good prognosis even if only conventional ADT is performed and ARAT is used after CRPC. We recommend that clinicians should be cautious when treating high-risk patients with upfront ARATs.

Several studies have compared the outcomes of upfront ARAT and ADT in Japanese mCSPC patients. Naiki et al. reported that patients treated with upfront abiraterone had significantly prolonged PFS compared with patients treated with ADT. However, there was no significant difference in the OS between the two groups (9). Yanagisawa et al. also reported that first-line treatment with upfront abiraterone could significantly prolong time to CRPC compared to ADT, but had no effect on OS (10). These results suggest that CRPC after treatment with upfront ARAT and CRPC after treatment with ADT may have a different disease progression status. There is a concern that administration of ARATs may impair patients’ quality of life and increase the burden of medical costs due to side effects. In the case of abiraterone, the incidence of grade 3 or 4 adverse events was 63% in the abiraterone group and 48% in the placebo group (11). We believe that this difference in the incidence rates of adverse events is not optimistic and indicates that administration of ARATs may deteriorate patients’ quality of life.

There is an urgent need to develop a risk classification system that is specific to the Japanese population when making treatment choices in patients with mCSPC. Shiota et al. reported that the proportion of biopsy-positive cores, biopsy Gleason grade group, T-stage, and N-stage were prognostic factors in Japanese mCSPC patients (12). Narita et al. reported that four factors, namely Gleason score ≥9, lymph node metastasis, extent of disease score ≥2 and serum LDH ≥220 IU, were associated with both CRPC-free survival and OS in mCSPC patients (13). Furthermore, Kobayashi et al. reported that serum lactate dehydrogenase (LDH) and alkaline phosphatase were significantly associated with OS (14). Nakagawa et al. also developed a prognostic model for OS in Japanese mCSPC patients and reported that Gleason pattern 5, bone scan index ≥ 1.5 and LDH ≥300 IU were independently associated factors (15). In the future, it is necessary to identify patients with risk factors who truly require upfront ARAT and conduct prospective trials to examine the efficacy of such treatment, using these prognostic factors in Japanese patients with mCSPC as a reference.

There are some limitations to this study. This study was retrospective and treatment selection was left to the individual physicians, which may have resulted in bias. In addition, all patients included in this study were Japanese. Therefore, these results may not apply to other populations. The patients enrolled in this study ranged from 2000 to 2019, i.e., before the introduction of ARAT and chemotherapy when patients did not have the option of receiving that treatment. Therefore, the addition of ARAT and chemotherapy as new treatment options during the last twenty years is a limitation of the present study.

Conclusion

The prognosis of high-risk (LATITUDE) patients with CRPC who were selected for initial ADT therapy had a good prognosis. Prolongation of prognosis can also be expected with ARAT as a second-line treatment or afterwards. We suggest that treatment strategies for mCSPC require the development of a risk classification system specific to the Japanese population, and prospective trials based on this classification are bound to be an important issue to consider in the future.

Footnotes

  • Authors’ Contributions

    Conceptualization, H.I. and A.M.; software, K.S.; formal analysis, R.N. (Ryunosuke Nakagawa); investigation, R.N. (Ryunosuke Nakagawa), H.Y., S.K. (Shohei Kawaguchi) and T.N.; data curation, R.N. (Renato Naito) and S.K. (Suguru Kadomoto); writing – original draft preparation, R.N. (Ryunosuke Nakagawa); writing – review and editing, H.I. and A.M.; visualization, S.K. (Shohei Kawaguchi), T.N. and K.I.; supervision, Y.K. and A.M. All Authors have read and agreed to the published version of the manuscript.

  • Conflicts of Interest

    All Authors declare that there are no potential conflicts of interest relevant to this article.

  • Funding

    This work was supported by JSPS KAKENHI (Grant Number 21K16728 to H. Iwamoto).

  • Received December 30, 2022.
  • Revision received January 10, 2023.
  • Accepted January 11, 2023.

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Is it Necessary to Treat all Metastatic Prostate Cancer With Upfront Androgen Receptor Axis-targeted Agents?
RYUNOSUKE NAKAGAWA, HIROAKI IWAMOTO, RENATO NAITO, SUGURU KADOMOTO, HIROSHI YAEGASHI, SHOHEI KAWAGUCHI, TAKAHIRO NOHARA, KAZUYOSHI SHIGEHARA, KOUJI IZUMI, YOSHIFUMI KADONO, ATSUSHI MIZOKAMI
Anticancer Research Mar 2023, 43 (3) 1351-1359; DOI: 10.21873/anticanres.16283
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