Metastatic Prostate Cancer
Promise in Treatment Personalization for Advanced Prostate Cancer
The availability of targeted therapies is beginning to allow for personalized treatment in advanced prostate cancer. Several abstracts related to molecular/genomic testing and targeting were presented at the 2021 Genitourinary Cancers Symposium.
Our featured expert, E. David Crawford, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD, and Dr Crawford ’s perspectives on these emerging data are presented here.
Professor of Urology
“There were a number of interesting presentations that, by themselves, stood out. And, collectively, this work is going to have a major impact on the direction we take in our approach to advanced prostate cancer.”
Identifying actionable genomic alterations and the subsequent development of targeted therapies have paved the way for personalized treatments in advanced prostate cancer. The first abstract in this section describes the impact of Decipher (Decipher Biosciences, Inc), a 22-gene, tissue-based genomic classifier, on treatment decisions. Decipher helps to determine the risk of metastasis post radical prostatectomy, and we can use this information to selectively administer radiation therapy in men with high-risk features for disease progression.
In abstract 15, Morgan and colleagues reported results from G-MINOR, the first prospective randomized trial that evaluated the effects of genomic classifier results on adjuvant treatment decisions in approximately 350 men. Patients and providers were randomized to the genomic classifier or the usual care group, and, while Decipher scores were obtained in all patients, the usual care arm was blinded to the results. The investigators reported that 10.9% of patients in the genetic classifier arm received adjuvant treatment 18 months post radical prostatectomy compared with 7.3% of patients in the usual care arm. This study is groundbreaking, as it is the first to demonstrate that genetic classifier test results impact treatment decisions, but we need additional data to understand how it affects patient outcomes.
The next abstract in this section addressed the potential need for introducing novel therapies earlier in the disease course. As prostate cancer progresses, the tumor may undergo changes that result in genetic heterogeneity, leading to a decreased response to chemotherapy and hormonal therapy. Therefore, there may be value in initiating novel treatments earlier instead of waiting until patients progress on first- or second-line treatments. In abstract TPS180, Azad et al announced the design of UpFrontPSMA, a randomized, phase 2, multicenter study conducted in Australia that will evaluate the effects of sequential 177Lu‐PSMA-617 (Lu-PSMA) with docetaxel vs docetaxel alone in 140 men with metastatic hormone-naive prostate cancer. The primary end point is undetectable prostate-specific antigen (≤0.2 ng/mL) at 12 months. This is an exciting concept. The minimal success in the past with docetaxel and targeted therapies might be reason for skepticism; however, I applaud this group for investigating the effects of 2 treatments with different mechanisms of action before hormonal therapy to discover whether this combination can change the course of the disease. Moreover, patients enrolled in this study will receive a whole body scan every 12 weeks, which will provide additional information on disease progression.
Abstract 25 evaluated the concordance between tissue biopsies and plasma circulating tumor DNA (ctDNA). Genomic profiling using next-generation sequencing of ctDNA from plasma is a minimally invasive method to identify targetable genomic alterations. Tukachinsky and colleagues presented the accuracy of ctDNA compared with tissue biopsies to identify BRCA1/2 mutations in men with advanced prostate cancer. After evaluating plasma from approximately 3300 men with advanced prostate cancer (about half of whom had metastatic castration-resistant prostate cancer [mCRPC]) and genomic profiles in approximately 2000 metastatic prostate cancer biopsies, concordance was evaluated in 837 men with both tissue and plasma next-generation sequencing assays. The investigators discovered a similar detection rate of BRCA1/2 mutations with ctDNA and tissue biopsy (8.8% vs 8.6%). This is the most extensive study to date to demonstrate that ctDNA may be an effective method to detect BRCA1/2 mutations in patients with mCRPC and could be an invaluable supplement to tissue-based biopsy.
The last abstract in this section focused on PTEN loss as a prognostic marker in prostate cancer. Previously reported results from the phase 3 IPATential150 trial showed that patients who had tumors with PTEN loss and received ipatasertib plus abiraterone as first-line treatment for mCRPC had a significant reduction in disease worsening or death compared with placebo plus abiraterone. In abstract 13, de Bono et al tested tumor cells for PTEN loss (predefined as ≥50% of tumor cells with no specific cytoplasmic immunohistochemistry staining) and discovered that ipatasertib plus abiraterone was not associated with improved radiographic progression-free survival in patients without PTEN loss. However, it is important to note that more than 90% of tumor cells were archival; therefore, since prostate cancer is a dynamic disease, the initial biopsy may not reflect the existing tumor characteristics. To tie in the findings from abstract 25, ctDNA could be used as a minimally invasive method to identify current tumor characteristics. Nevertheless, this was an interesting study that illustrated that tumors with PTEN loss were more likely to respond to treatment with ipatasertib plus abiraterone, and this is another step toward personalized treatment in advanced prostate cancer. Individually, these are small steps, but, in aggregate, when you put it all together, it is a much bigger step forward.
In conclusion, there were a number of interesting presentations at the 2021 Genitourinary Cancers Symposium that, by themselves, stood out. And, collectively, this work is going to have a major impact on the direction we take in our approach to advanced prostate cancer.
Azad A, Dhiantravan N, Emmett L, et al. UpFrontPSMA: a randomized phase II study of sequential 177Lu-PSMA617 and docetaxel versus docetaxel in metastatic hormone-naïve prostate cancer (mHNPC) [abstract TPS180]. Abstract presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021.
de Bono JS, Bracarda S, Sternberg CN, et al. IPATential150: phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC) [abstract LBA4]. Abstract presented at: ESMO Virtual Congress 2020; September 19-21, 2020.
de Bono JS, De Giorgi U, Rodrigues DN, et al. Randomized phase II study evaluating Akt blockade with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN loss. Clin Cancer Res. 2019;25(3):928-936. doi:10.1158/1078-0432.CCR-18-0981
de Bono JS, Sweeney C, Bracarda S, et al. PI3K/AKT pathway biomarkers analysis from the phase III IPATential150 trial of ipatasertib plus abiraterone in metastatic castration-resistant prostate cancer [abstract 13]. Abstract presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021.
Jairath NK, Dal Pra A, Vince R Jr, et al. A systematic review of the evidence for the Decipher genomic classifier in prostate cancer. Eur Urol. 2021;79(3):374-383. doi:10.1016/j.eururo.2020.11.021
Morgan TM, Okoth LA, Spratt DE, et al. Prospective randomized trial of gene expression classifier utility following radical prostatectomy (G-MINOR) [abstract 15]. Abstract presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021.
Tukachinsky H, Madison R, Chung J, et al. Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer to identify targetable BRCA alterations and AR resistance mechanisms [abstract 25]. Abstract presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021.
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