Association Between Pseudoprogression and Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer Treated with XTANDI®

January 10th, 2020
SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of prostate cancer were diagnosed in 2019 and 31,620 men died of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation, anti-androgen agents, which include, ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide), ERLEADA® (Apalutamide) and NUBEQA® (Darolutamide). Approximately 10-20% of patients with advanced prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis (mCRPC). Among those patients without metastases at CRPC diagnosis, 33% are likely to develop metastases within two years. The estimated mean survival of patients with CRPC is 9-36 months.
The skeletal system is the most common site for distant metastases among patients with prostate cancer and over 80% of patients with advanced prostate cancer develop bone metastases, which are osteoblastic (or sclerotic), characterized by deposition of new bone. Bone scan is the most common and cost effective modality for the diagnosis of bone metastases and Technetium (Tc) 99m-labeled methylene diphosphonate is the most widely used bone scanning agent. Bone scans are commonly used to both diagnose and monitor disease progression in the bone, among patients with advanced prostate cancer, with a sensitivity ranging from 60-90% but with lower specificity. Bone scan however is more sensitive and specific than plain films and CT scans, whereas MRI is superior in evaluating vertebral metastases. Bone scan provides information on osteoblastic activity and skeletal vascularity, with preferential uptake at sites of active bone formation, reflecting the metabolic reaction of bone to the disease activity, regardless of whether it is neoplastic, traumatic or inflammatory. It is for these reasons it has been well known that bone scans can be misleading in determining whether a patient with bone metastases is benefiting from a treatment, particularly endocrine therapy. The Prostate Cancer Working Group (PCWG) recommended that the assessment of disease progression in bone in the absence of other signs of progression, requires that new lesions detected on the first post-treatment scan be confirmed with the documentation of additional new lesions on the next follow-up scan, in the absence of other signs of disease progression. This is because the new lesions detected on the first post-treatment scan may either reflect true progression or can be the result of bone healing known as pseudoprogression (also known as bone scan flare) that can be misinterpreted as treatment failure, and lead to the premature discontinuation of an effective therapy. Even though the occurrence of pseudoprogression is well documented, its association with clinical outcomes in large prospective studies has not been evaluated.
The authors therefore conducted a post hoc retrospective analysis of the PREVAIL (A Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer) and AFFIRM (Safety and Efficacy Study of MDV3100 in Patients With Castration-Resistant Prostate Cancer Who Have Been Previously Treated With Docetaxel-based Chemotherapy) studies to determine the association between new unconfirmed lesions detected on a follow up bone scan, and clinical outcomes in XTANDI® (Enzalutamide)-treated men with mCRPC. The PREVAIL and AFFIRM trials were both designed in accordance with the PCWG guidelines. This analysis included 643 patients from the PREVAIL study who had not received Docetaxel and 404 men from the AFFIRM study who had previously received Docetaxel. Eligible patients had stable disease or response to therapy based on non-bone disease criteria, including assessment of PSA and soft-tissue disease response. Pseudoprogression was defined as detection of one or more lesions on a first post-treatment bone scan (at week 9 in PREVAIL or 13 in AFFIRM) or a second bone scan (at week 17 in PREVAIL or 25 in AFFIRM), without subsequent new lesions detected at later assessments. The authors evaluated the association of the new lesions detected on the first and second bone scans, with radiographic Progression Free Survival (rPFS), Overall Survival (OS), PSA decline, Objective Response in soft tissue, and Quality of Life.
In the PREVAIL study, new unconfirmed bone lesions were detected on bone scans in 27.5% of Docetaxel-naive patients. The rPFS, OS and time to PSA progression among these patients was similar to those without new lesions, suggesting pseudoprogression. In the AFFIRM study, new, unconfirmed lesions were detected in 18.1% of Docetaxel-treated patients and the rPFS, and time to PSA progression among these patients was similar to those without new lesions on bone scans. However, the OS was significantly worse among these patients, compared with those without new lesions on bone scan, suggesting true disease progression. Most lesions were detected on the first follow up bone scan and investigators were unable to identify any pretreatment factor associated with the development of new, unconfirmed lesions in patients responding to XTANDI®, in either clinical setting.
It was concluded that new unconfirmed lesions detected on follow up bone scans within the first 4 months of treatment initiation may represent pseudoprogression in men with mCRPC and are indicative of a favorable treatment response to XTANDI®. However, new unconfirmed bone lesions in men with mCRPC who were previously treated with Docetaxel may reflect disease heterogeneity and true progression with associated worse Overall Survival. Treatment discontinuation can be considered in this patient group, taking into consideration other disease manifestations such as changes in PSA level, finding on soft tissue imaging, symptoms, and patient preferences. These findings reinforce the importance of functional imaging for diagnosing bone metastases. Association Between New Unconfirmed Bone Lesions and Outcomes in Men With Metastatic Castration-Resistant Prostate Cancer Treated With Enzalutamide: Secondary Analysis of the PREVAIL and AFFIRM Randomized Clinical Trials. Armstrong AJ, Al-Adhami M, Lin P, et al. JAMA Oncol. 2019 Dec 12. doi: 10.1001/jamaoncol.2019.4636. [Epub ahead of print]