(UroToday.com) The 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Hybrid Meeting included a session on the management of non-metastatic castrate-resistant prostate cancer (CRPC), and a presentation by Dr. Eleni Efstathiou discussing an overview of treatment options in this disease space. Dr. Efstathiou started her presentation by noting that the CRPC definition “threshold” is such that when a patient has castrate serum testosterone levels (<50 ng/dL or 1.7 mmol/L) they have either biochemical progression (3 consecutive rises of PSA with PSA >2 ng/mL) and are deemed nmCRPC, or they have radiologic progression (appearance of >=2 bone lesions on bone scan or enlargement of soft issues lesion) and are deemed mCRPC:
Dr. Efstathiou notes that progression to CRPC is essentially the admission of failure to cure, thus it is important to optimize treatment prior to nmCRPC, particularly when there is an opportunity to cure in the localized setting and an opportunity to salvage in the biochemical recurrence setting. There are several strategies available in the nmCRPC disease space, including (a) interrogation of the (i) disease / (ii) patient, (b) systemic therapy options, (c) local treatment options (covered in another talk in this session), and (d) monitoring tools.
With regards to interrogation of the disease, the advent of advanced imaging has certainly changed how we may think about nmCRPC. Fendler and colleagues1 retrospectively characterized cancer burden in 200 high-risk patients with nmCRPC using PSMA-PET. Of note, PSMA-PET was positive in 196 of 200 patients, including 44% with pelvic disease, 24% with local prostate bed recurrence, and 55% with M1 disease despite negative conventional imaging:
PSA ≥ 5.5 ng/mL, locoregional nodal involvement determined by pathology (pN1), prior primary radiation, and prior salvage radiotherapy independently predicted M1 disease (all p < 0.05).
When interrogating the patient status, it is important to consider long-term exposure to ADT + advanced age + other comorbidities. This assessment should account for metabolic syndrome, bone health (musculoskeletal decline), cardiovascular risk, fatigue, and emotional impact. For systemic therapy options, we have excellent level one data suggesting an MFS benefit for apalutamide (SPARTAN)2, enzalutamide (PROSPER)3, and darolutamide (ARAMIS)4 for patients with nmCRPC. Although there are subtle nuances to these three clinical trials, the trial designs are very similar:
With further follow-up, all three of these clinical trials also showed an overall survival benefit for the intervention arm.5-7 As such, there has been tremendous reproducibility across these trials for both MFS and OS:8
Furthermore, a pooled meta-analysis reinforces the OS benefit with a fixed and random effects model HR of 0.74 (95% CI 0.65-0.83). A comparison of safety across these trials also demonstrates consistency:
Dr. Efstathiou notes that with total adverse events there is very little difference between the trials, however for grade 3-4 fatigue, falls and hypertension, there may be a benefit to darolutamide:
For monitoring tools, Dr. Efstathiou mentioned that PSA may be one of our best biomarkers. Highlighting work that she is a part of that is currently under review, there was an association with PSA decline in the PROSPER trial and MFS stratified by PSA decline subgroups.
Dr. Efstathiou concluded her presentation noting that in order to maximize the “therapeutic index” we need to dose our “therapeutic strategy” towards the most efficacious and least toxic regimen for each specific patient:
Presented by: Eleni Efstathiou, Houston Methodist Hospital, Houston, TX
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Annual Hybrid Meeting, Lugano, Switzerland, Thurs, Apr 28 – Sat, Apr 30, 2022.
References:
- Fendler WP, Weber M, Iravani A, et al. Prostate-Specific Membrane Antigen Ligand Positron Emission Tomography in Men with Nonmetastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2019 Dec 15;25(24):7448-7454.
- Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018;378(15):1408-1418.
- Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018 Jun 28;378(26):2465-2474.
- Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246.
- Smith MR, Saad F, Chowdhury S, et al. Apalutamide and Overall Survival in Prostate Cancer. Eur Urol. 2021 Jan;79(1):150-158.
- Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Jun 4;382(23):2197-2206.
- Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020 Sep 10;383(11):1040-1049.
- Rodriguez-Vida A, Rodriguez-Alonso A, Useros-Rodriguez E, et al. Impact of new systemic therapies in overall survival in non-metastatic castration resistant prostate cancer: Systematic review and meta-analysis.