Heterogeneity of Radiological Progression Patterns and Association with Outcomes in Patients with Metastatic Prostate Cancer

Radiological endpoints are commonly utilized in therapeutic clinical trials of metastatic disease, serving as objective criteria in analyzing the response to treatment and partially substituting overall survival (OS) in evaluating the benefits to patients. According to the current standard of Prostate Cancer Working Group Criteria (PCWG) guidelines and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, progressive disease is determined by the enlargement of target lesions, unequivocal progression of nontarget lesions, appearance of new lesions, and two or more validated new lesions on bone scan.

However, the heterogeneity of different radiological progression patterns in radiographic progression-free survival (rPFS) and post progression survival (PPS) remains unclear. In this research, we found that patients with multicategory radiological progression patterns had similar rPFS but significantly shorter PPS than those experiencing single-category progression patterns. In addition, we extensively characterized the proportions of various radiological progression patterns in patients with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC), as well as their associations with rPFS and PPS.¹

In both patients with metastatic hormone sensitive prostate cancer (mHSPC) and metastatic castration resistant prostate cancer (mCRPC), the most common radiological progression pattern was the identification of validated new lesions on bone scans. Notably, mCRPC patients displayed a higher incidence of enlargement in target lesions compared to mHSPC patients, while a greater proportion of new lesions was observed in mHSPC patients. These findings suggest that the composition of radiological progression patterns after treatment is associated with the stage of prostate cancer (mHSPC or mCRPC). Therefore, a personalized approach to treatment and monitoring should be considered, taking into account the patient's stage of disease. For example, in patients with mCRPC, it may be beneficial to focus more on monitoring the growth of existing lesions, while in patients with mHSPC, periodic scans of unaffected organs at baseline should be considered.

Our study also revealed that the four single-category progression patterns have different radiographic progression-free survival (rPFS), regardless of whether the patient has mHSPC or mCRPC. Furthermore, there are differences in prostate-specific survival (PPS) at the mCRPC stage. When bone metastasis progression is used as a reference, a significant proportion of target lesions and prognostic variations were observed in both mHSPC and mCRPC patients. This indicates that the majority of nonbone metastatic target lesions in mHSPC patients may respond positively to first-line therapy, with a small proportion exhibiting rapid progression and a moderate outcome with subsequent therapy. Conversely, target lesions in mCRPC patients appear to demonstrate improved rPFS and PPS compared to bone progression.

Nowadays, an increasing number of clinical trials are utilizing PFS instead of OS as the primary study endpoint as a means of validating the effectiveness of drugs quickly. Of these, rPFS has become the mainstream choice due to its higher consistency with OS. Susan Halabi et al. showed a high correlation between rPFS and OS in men with mHSPC. At the patient level, Kendall's tau was 0.83 (95% CI, 0.82 to 0.84; Table 2) for rPFS and OS. From weighted linear model (WLR), R² between 3-year rPFS and 5-year OS rates and 3-year cPFS rates was 0.62 (95% CI, 0.29 to 0.89)^[2]. A fair correlation between rPFS and OS was also found in other mCRPC prospective randomized controlled trials (R² = 0.58, 95% CI 0.32–0.82)^[3]. Our study clearly shows that different progression patterns associated with different rPFS and their impact on PPS are varied. The confounding of rPFS composition can affect the interpretation of rPFS as a homogenous endpoint in different clinical trials. Therefore, the information provided in this study is of great value for the design of future studies. This finding may also partly explain the occurrence of patients with rPFS but no OS benefits in some recent clinical trials (eg, ACIS). In clinical trials, if the progression diseases in the experimental group are mostly multicategory progression patterns, while those in the control group are mostly single-category progression patterns, even if the experimental group has more extended rPFS, patients may not necessarily have an OS benefit. Hence, the pattern of radiological progression is a crucial reference standard for risk stratification, prognosis estimation, and treatment choice in patients with prostate cancer progression.

Written by: Xudong Ni,¹ Junlong Wu,¹ Jian Pan,¹ Xiaomeng Li,¹ Bangwei Fang,¹ Yu Wei,¹ Dingwei Ye,¹ Fei Liang,² Yao Zhu³

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Genitourinary Cancer Institute, Shanghai, China.
Department of Biostatistics, Zhongshan Hospital, Fudan University, Shanghai, China; Clinical Research Unit, Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Genitourinary Cancer Institute, Shanghai, China.

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