Oncological Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide with versus without Confirmatory Bone Scan

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Cancer Res Treat. 2024;56(2):634-641

Publication date (electronic) : 2023 December 5

doi : https://doi.org/10.4143/crt.2023.848

Chang Wook Jeong¹, Jang Hee Han¹, Dong Deuk Kwon², Jae Young Joung³, Choung-Soo Kim⁴, Hanjong Ahn⁴, Jun Hyuk Hong⁴, Tae-Hwan Kim⁵, Byung Ha Chung⁶, Seong Soo Jeon⁷, Minyong Kang⁷, Sung Kyu Hong⁸, Tae Young Jung⁹, Sung Woo Park¹⁰, Seok Joong Yun¹¹, Ji Yeol Lee¹², Seung Hwan Lee¹³, Seok Ho Kang¹⁴, Cheol Kwak¹

¹Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

²Department of Urology, Chonnam National University Hwasun Hospital, Hwasun, Korea

³Center for Prostate Cancer, National Cancer Center, Goyang, Korea

⁴Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

⁵Department of Urology, Kyungpook National University Chilgok Hospital, Kyungpook National University School of Medicine, Daegu, Korea

⁶Department of Urology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

⁷Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

⁸Department of Urology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

⁹Department of Urology, Veterans Health Service Medical Center, Seoul, Korea

¹⁰Department of Urology, Pusan National University Yangsan Hospital, Yangsan, Korea

¹¹Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea

¹²Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Korea

¹³Department of Urology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

¹⁴Department of Urology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea

Correspondence: Cheol Kwak, Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: 82-2-2072-0817 Fax: 82-2-762-2428 E-mail: mdrafael@snu.ac.kr

*Chang Wook Jeong and Jang Hee Han contributed equally to this work.

Received 2023 July 17; Accepted 2023 December 3.

Abstract

Introduction

Metastatic castration-resistant prostate cancer (mCRPC) rates are increasing worldwide. This cancer has a dismal prognosis, with a 5-year survival of approximately 30% [1]. After docetaxel was first approved as treatment with survival benefit for mCRPC, many drugs were actively developed, such as abiraterone, enzalutamide, cabazitaxel, and radium-223 [2,3]. Enzalutamide is one of the approved drugs that inhibit androgen-receptor signaling. The PREVAIL and AFFIRM randomized clinical trials have demonstrated the safety and efficacy of enzalutamide in men with mCRPC, both those who are chemotherapy-naïve and post-chemotherapy [4-6].

Due to the innate bone tropism of prostate cancer (PCa), approximately 90% of mCRPC patients have detectable bone metastases on imaging studies [7]. The Prostate Cancer Working Group (PCWG)-2 established specific assessment criteria for bone lesion evaluation [8]. They took into account the bone scan flare phenomenon, which is defined as unconfirmed new bone scan lesions with stable or responding disease, based on prostate-specific antigen (PSA) changes or soft-tissue imaging in PCa [6,9-11]. This indicates a favorable osteoblastic reaction, representing a healing process. However, without confirmatory bone scans performed at specific intervals after initial assessment, this can easily be mistaken for progression, and is termed pseudoprogression, which occurs in 10%-50% during various PCa treatments (androgendeprivation therapy [ADT], abiraterone, radium-223, and enzalutamide) [12]. Accordingly, pivotal randomized trials (PREVAIL and AFFIRM) clearly protocolized mandatory confirmatory bone scans when new bone lesions were encountered during enzalutamide treatment [4,5]. A post-hoc, secondary analysis of the trial data indeed supported the favorable treatment response in the pseudoprogression group [13]. Nevertheless, clinical data in a real practice setting on whether a confirmatory bone scan is appropriately performed to distinguish pseudoprogression from the true progression, or whether the performance of confirmatory bone scan itself affects survival outcome, are lacking.

In this study, we investigated the performance rate of confirmatory bone scans in real clinical practice for patients with mCRPC receiving enzalutamide, using a multicenter cohort. We hypothesized that not performing a confirmatory bone scan may be associated with worse oncological outcomes in chemotherapy-naïve or post-docetaxel settings. We also hypothesized that the pseudoprogression group would have similar oncological outcomes to those who responded to treatment as assessed by other means.

Materials and Methods

Results

1. Entire cohort of enzalutamide treatment

In total, 520 patients with mCRPC were included in this study, of whom 240 patients (46.2%) were chemotherapynaive, and 280 patients (53.8%) received enzalutamide after chemotherapy. Patients received a mean of 10.8 cycles of enzalutamide (S2 Table). Among them, 168 patients (32.3%) showed no decrease in PSA or soft-tissue progression, demonstrating non-responsiveness. Baseline patient demographics, treatment history before enzalutamide administration, and primary and metastatic characteristic differences were recorded between chemotherapy-naïve and post-chemotherapy treatment types (Table 1).

Table 1.

Characteristics of pre- and post-docetaxel enzalutamide

2. Association of confirmatory bone scan with oncological outcomes

Among the 352 enzalutamide responders, 92 patients (26.1%) showed new bone lesions during the course of enzalutamide treatment. Confirmatory bone scans were performed in 44.6% (41 patients). All baseline clinical characteristics were comparable between the groups with and without confirmatory bone scans (Table 2).

Table 2.

Characteristics of patients with/without confirmatory bone scan

Multivariate Cox regression analysis showed that confirmatory bone scan performance was an independent prognostic factor (OS) (HR, 0.35; 95% CI, 0.18 to 0.69; p=0.002) (Table 3). Confirmatory bone scan performance was associated with a significantly prolonged OS (median, 30.9 vs. 19.7 months; p < 0.001), time to PSA progression (median, 10.0 vs. 5.8 months; p < 0.001), and rPFS (median, 11.7 vs. 6.1 months; p < 0.001) (Fig. 1). In subgroup analysis, the group with confirmatory bone scans demonstrated OS benefit in both the chemotherapy naïve group (median survival, 47.2 vs. 20.5 months; p=0.011) and the post-chemotherapy group (median survival, 25.5 vs. 18.0 months; p=0.006) (Fig. 2).

Table 3.

Multivariate Cox regression analysis of overall survival

Fig. 1.

Kaplan-Meier curve of groups with (red) and without (blue) confirmatory bone scan (BS) for overall survival (A), radiographic progression-free survival (B), and prostate-specific antigen (PSA) progression-free survival (C) in cases with enzalutamide-treated metastatic castration-resistant prostate cancer.

Fig. 2.

Kaplan-Meier curve of groups with (red) and without (blue) confirmatory bone scan (BS) for overall survival in cases with predocetaxel (A), and post-docetaxel (B) enzalutamide-treated metastatic castration-resistant prostate cancer.

To exclude situations where PSA increase occurred at the time of observing unconfirmed bone lesions, additional analysis was conducted on patients who demonstrated consistent PSA responses to enzalutamide over the permissible period defined as six months in the definition of unconfirmed bone lesions. All baseline clinical characteristics were comparable between the groups with and without confirmatory bone scans (Table 2). All baseline clinical characteristics were comparable between the groups with and without confirmatory bone scans (S3 Table). Confirmatory bone scan performance was still associated with a significantly prolonged OS (median, 33.5 vs. 21.4 months; p < 0.001) (S4 Fig.).

Discussion

Since a Tc 99m–labeled methylene diphosphonate bone scan demonstrates osteoblastic activity derived from both the healing response and from cancer lesions, the PCWG (2-3) guidelines [17] recommend performing a confirmatory bone scan when new, unconfirmed bone lesions are detected on a first follow-up scan in mCRPC patients. This allows clinicians to distinguish true progression from pseudoprogression easily. This is clinically important because, without a confirmatory bone scan, patients showing a transient bone flare may be misdiagnosed as harboring resistance to an androgen receptor–targeting agent. Two global enzalutamide clinical trials, PREVAIL and AFFIRM, were thoroughly designed in accordance with these PCWG2 guidelines [18], so that only 16 men in the PREVAIL and no men in the AFFIRM study discontinued enzalutamide treatment for unconfirmed bone lesions, i.e., without first obtaining confirmatory bone scans. Such trial study results may not fully reflect real-world data. In support of this, a recent retrospective study presented by the Memorial Sloan Kettering Cancer Center group showed that 42 of 257 patients who received androgen receptor– axis–targeted drugs did not undergo a confirmatory bone scan [19]. Thus, in this study, we attempted to assess the performance rate of confirmatory bone scans for the new bone lesions and their survival outcomes in enzalutamide-treated mCRPC using multicenter real-world data. The novelty of this study is that we provided clinical evidence bolstered by a multicenter setting with regard to the clinical impact of confirmatory bone scans in enzalutamide-treated mCRPC, which is strikingly underperformed.

Essentially, we found no clinicopathological differences between patients with or without confirmatory bone scans, indicating that a confirmatory bone scan is somewhat randomly performed in a multicenter (14 tertiary centers) real-world setting. Nevertheless, performance of a confirmatory bone scan significantly extended the enzalutamide maintenance duration by approximately 8 months, which ultimately led to prolonged OS, rPFS, and time to PSA progression. On the other hand, the pseudoprogression group showed similar oncological outcomes to the stable disease group, in agreement with the PREVAIL and AFFIRM results. We next compared the incidence of unconfirmed bone lesions with the previous post-hoc analysis of the PREVAIL and AFFIRM data [13]. The new bone lesions were observed in 17.7% (92/520) of all patients in this study, which was comparable to the frequencies in previous trials. In subgroup analyses, pre-chemotherapy and post-chemotherapy settings showed a similar prevalence, i.e., 17.1% (41/240) and 17.9% (50/280), respectively. Through analysis of the multicenter-based real-world data, we revealed that only about 44.6% of patients underwent confirmatory bone scans when clinicians encountered the newly developed bone lesions. This indicates that, although the PCWG3 guidelines emphasize the clinical importance of the bone flare phenomenon and the necessity of a confirmatory bone scan, the confirmatory bone scan performance rate remains far from expected in real clinical practice.

Our patient cohort harbored different clinical characteristics from those in the AFFIRM and PREVAIL trials. First, for the pre-chemotherapy group, compared with the PREVAIL trial, the incidence of bone metastasis only group was higher (69.9% vs. 39.9%), and the ratio of the International Society of Urological Pathology (ISUP) grade group (GG) ≥ 4 was also markedly higher (76.9% vs. 50.6%). The group using two or more types of prior ADT accounted for 62.9%, which was almost triple of that (21.4%) in the PREVAIL trial, indicating that our cohort showed more aggressive mCRPC with a higher disease burden. In fact, this trend was similar to the distribution in an East Asian subpopulation shown in the post-hoc analysis results of the PREVAIL study [20]. Compared with the overall study population, a higher percentage of East Asian patients had a Gleason score ≥ 8 and a greater percentage had bone disease (East Asian vs. overall: 80% vs. 50.6%), suggesting a higher disease burden [20]. Additionally, this study was timely, given the current trend of increasingly advanced stages and an aggressive PCa, as well as increasing prevalence of bone-metastatic mCRPC [21-23]. This shift has been primarily driven by increased diagnosis of high-grade disease [24]. The same trend was observed in the post-chemotherapy group. Patients with ISUP GG 4-5 were 80.2% in our cohort, which was more than one and a half times that in the AFFIRM trial (50.4%).

In our comparison of OS between those with and those without new bone lesions, the former group showed significantly shorter survival than the pre-docetaxel (30.9 vs. 63.1 months, p < 0.001) and post-docetaxel (21.4 vs. 37.9 months, p < 0.001) values. This was in stark contrast to the results of previous studies (PREVAIL and AFFIRM), which consistently performed confirmatory bone scans. In short, the AFFIRM trial showed shortened OS, but no difference in rPFS in men with unconfirmed bone lesions, while the PREVAIL trial did not show differences in any oncological outcome, regardless of whether newly developed unconfirmed bone lesions were present. Approximately 40% of patients who underwent confirmatory bone scans revealed that the lesions represented pseudoprogression. This emphasizes that patients with new bone lesions who have not undergone confirmatory bone scans (55.4%) should be strongly recommended to undergo confirmatory bone scans to categorize their oncological risk appropriately and decide whether enzalutamide treatment should be maintained or switched to the next sequential drug. Our results may raise awareness of these new bone lesions among the community healthcare network and convey the necessity of a confirmatory bone scan when these lesions are encountered. At present, men who are likely to develop pseudoprogression rather than true progression cannot be identified prospectively, and thus, all patients with mCRPC who are receiving enzalutamide should be carefully observed for this phenomenon.

This study had some limitations. The first is the retrospective nature of the analysis, possibly because of inherent patient selection biases. A second limitation is the relatively small number of patients with pseudoprogressive lesions compared to the PREVAIL and AFFIRM trials. The third limitation is the lack of information on accompanying bone pain related to bone metastasis, which could have provided a more accurate clinical context. Fourth, this study did not suggest any useful clinical biomarkers for predicting pseudoprogression. Although the pre-enzalutamide laboratory test revealed that hemoglobin (11.7±1.6 [true progression] vs. 12.9±1.0 [pseudoprogression], p=0.008) was significantly different and lactate dehydrogenase (333±249 vs. 112±103, p=0.076) and alkaline phosphatase (305±454 vs. 129±62, p=0.072) demonstrated borderline significance, no sequential laboratory data could be obtained. Improved functional imaging, such as prostate-specific membrane antigen positron emission tomography–computed tomography [25], or automated bone scan index [19] may provide useful information for equivocal lesions that cannot be fully discriminated with confirmatory bone scans.

In our multicenter study using real-world data of enzalutamide-treated mCRPC, a confirmatory bone scan was not performed in a considerable number of patients showing new bone lesions in their early scan (< 6 months after treatment), contrary to the recommended guidelines. The performance of a confirmatory bone scan itself may be associated with prolonged OS in chemotherapy-naïve or post-chemotherapy subpopulations. Pseudoprogression occurred in approximately 40% of patients who underwent a confirmatory bone scan, and their OS was not different from that of men responding to treatment without new bone lesions. Based on these findings, we suggest that premature discontinuation of enzalutamide without a confirmatory bone scan should be discouraged to improve oncological outcomes.

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