(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 (nmCRPC), and a presentation by Dr. Pierre Blanchard discussing treatment of the primary or local relapse in this disease space. Dr. Blanchard notes that based on previous APCCC reports, several important statements were made: “a combined total of 86% of panelists voted for consideration of salvage radiation therapy over systemic therapy in either most (54%) or selected (32%) patients with local recurrence, despite a lack of data supporting such an approach.” Furthermore, “these gaps raise questions about the role of local treatment (prostate and/or pelvis) in nmCRPC, especially when next-generation imaging confirms the presence of disease in the pelvis.”
Next generation imaging suggests that nmCRPC may not exist given that this advanced imaging is leading to stage migration. 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:
Dr. Blanchard then presented two case summaries. The first patient was born in 1950, had mHSPC diagnosed in 2004, and treated with ADT, followed by referral for M0 CRPC in 2015 at which point in time he was included in the PROSPER trial. In 2018, he had PSA progression (15 ng/mL) with a choline PET showing only fixation of the prostate. In July 2018, he underwent EBRT to the prostate only, with PSA controlled (nadir 0.4 ng/mL) until February 2022 (PSA 2.5 ng/mL) when PSMA PET/CT shows only prostate hyperfixation.
The second case was of a male born in 1946 who had EBRT for Gleason 6 prostate cancer (PSA 9.6, T3 on MRI) in 2002. In 2011, he had a local relapse of Gleason 8 (3+5) prostate cancer treated with ADT. In 2018, he was referred to Dr. Blanchard at which time an MRI showed local relapse on the entire right lobe of the prostate (T3aN0). A PSMA PET/CT subsequently showed 3 intraprostatic nodules (N0M0), and he was treated with repeat EBRT, with no reported side effects, with an IPSS of 6/35 and only minor proctitis on rectoscopy.
Goals of care for local treatment in nmCRPC include delaying change in systemic therapy, avoiding/palliating local symptoms, and with limited/no toxicity. Open questions that remain include:
- Sensitivity of imaging
- Impact of local treatment on disease course
- Impact of previous radiotherapy on local treatment options
- Biomarkers for patient selection
There are several modalities of radiotherapy that have been assessed in retrospective studies in this disease space:
- Palliative local radiotherapy – palliation of symptoms in ~75% of patients, treated with an EBRT dose of >= 40 Gy with low toxicity
- Full dose prostate radiotherapy – radiotherapy after CRPC (median time to CRPC: 10 months)
- Prostate SBRT in CRPC – SBRT 36-48 in 6-8 fractions, with all patients receiving docetaxel, and replication as needed
- Salvage brachytherapy – in the Gustave Roussy experience, salvage brachytherapy is for PET/CT (choline or PSMA) detected lesions, isolated M0, biopsy proven local relapse
- Progression directed therapy – 78% experience PSA decline and clinical outcomes improve with metastasis-directed therapy over systemic therapy alone. When comparing patients that received metastasis-directed therapy versus those that did not, there was improvement in:2 (i) PSA failure: 9.7 vs 4.2 months (p = 0.066); (ii) time to next intervention: 14.9 vs 8.8 (p = 0.025); (iii) distant metastasis free survival: 12.7 vs 8.9 months (p = 0.05)
Ongoing randomized trials for ARSI +/- metastasis directed therapy for M1 (novel imaging) CRPC are as follows:
However, there are several limitations of these trials, including small trials, PSA based endpoints (vs MFS/OS for ARSI), and these studies are mostly single center cohorts.
Dr. Blanchard concluded his presentation discussing treatment of the primary or local relapse in nmCRPC with the following take-home messages:
- What do we know:
- There is very little evidence to support progression directed therapy (to prostate or metastases)
- What is the impact of PSMA PET/CT (stage migration): does M0 CRPC still exist?
- Retrospective data show feasibility (low toxicity) and potential for efficacy, with delays in time to next systemic treatment by 12-18 months
- What can we do:
- Retrospective analyses to be conducted in large nmCRPC trials
- Support current progression directed therapy trials and develop larger “real-world” trials
- In clinical practice:
- ARSI is standard of care in nmCRPC with rapid PSA doubling time (MFS and OS benefit)
- In favor of progression directed therapy: low risk of side effects, PSA response to progression directed therapy offers rapid insight into efficacy, with the possibility to retreat (with progression directed therapy or systemic therapy) at next relapse
- Progression directed therapy should be discussed in patients with slower PSA doubling time, those with oligometastatic disease on next-generation imaging, and especially when frail/risk of toxicity is expected from next systemic therapy
- Ideally on clinical trials
Presented by: Pierre Blanchard, Radiation Oncology and Biostatistics, Gustave Roussy Cancer Center, Villeuf, France
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.
- 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.
- Deek MP, Taparra K, Phillips R, et al. Metastasis-directed therapy prolongs efficacy of systemic therapy and improves clinical outcomes in oligoprogressive castration-resistant prostate cancer. Eur Urol Oncol. 2020 Jun 11 [Epub ahead of print].