EAU 2023: Debate: High-Risk BRCA Mutated Case with N0 M0 at Conventional Imaging and Multiple cN1 at PSMA: What to Do?

(UroToday.com) The 2023 EAU annual meeting included a session discussing clinically meaningful questions in the management of advanced, hormone-sensitive prostate cancer, featuring a debate of treatment of high-risk BRCA mutated prostate cancer with N0 M0 at conventional imaging and multiple cN1 at PSMA.

Case Presentation

Dr. Martina Maggi started with a case presentation of a 49 year old men with no relevant comorbidities, but a brother with prostate cancer and a sister with a history of BRCA positive breast cancer. He presented with a PSA of 45 ng/mL and his digital rectal exam demonstrated bilateral cT3 prostate cancer. In December 2022, he underwent a multiparametric MRI that showed a PI-RADS 5 lesion in the entire prostate gland and a left obturator lymph node measuring 7 mm:


He subsequently underwent a random systematic biopsy that showed prostate adenocarcinoma, ISUP grade group 2 (Gleason 3+4) in 11/14 positive cores. A full body CT scan and bone scan were negative. In January 2023, he underwent re-review of his prostate biopsy that showed ISUP grade group 3 (Gleason 4+3) in 11/14 positive cores, and intraductal carcinoma in 2/14 cores. Subsequent germline testing showed that he was BRCA2 positive. Finally, he underwent a 68Ga-PSMA PET/CT that showed positive lesions in the internal left iliac lymph node, bilateral obturator lymph nodes, and left common iliac lymph nodes.

Surgery with Extended Pelvic Lymph Node Dissection

The position of surgery with extended pelvic lymph node dissection was taken by Dr. Jochen Walz who notes that the EAU guidelines have several important recommendations for locally advanced disease:

  1. Offer radical prostatectomy to selected patients with locally-advanced prostate cancer as part of multimodal therapy (Strength rating: Strong)
  2. Perform an extended pelvic lymph node dissection prior to radical prostatectomy in locally advanced prostate cancer (Strength rating: Strong)

Dr. Walz notes that the Local Treatment of Metastatic Prostate Cancer (LoMP) Registry has published on the utility of cytoreductive radical prostatectomy in the treatment of newly diagnosed low-volume metastatic prostate cancer.1 In this assessment, 109 patients with low volume newly diagnosed prostate cancer were identified, including 48 men that underwent cytoreductive prostatectomy, 26 prostate radiotherapy, and 35 that had no local therapy. Dr. Walz notes that based on this study, perhaps surgery is associated with avoidance of local complications: 2-year local event free survival was 92% for cytoreductive prostatectomy, 77% for prostate radiotherapy, and 60% for no local therapy:

cumulative comparison graph.jpgAdditionally, the 2-year OS was 93% for cytoreductive prostatectomy, 100% for prostate radiotherapy, and 69% for no local therapy. The cytoreductive prostatectomy and prostate radiotherapy groups had better OS compared to no local therapy and there was no significant difference between cytoreductive prostatectomy and prostate radiotherapy:

cumulative survival.jpg

Dr. Walz emphasized that based on multiple studies, PSMA PET/CT is not particularly adept to lymph node staging with sensitivity of ~40%. From a surgical perspective, there is tremendous staging efficacy with super extended templates: 97% of patients are correctly staged and 99% of positive nodes are removed. In the Brazilian phase 3 clinical trial assessing extended versus limited pelvic lymph node dissection during radical prostatectomy for intermediate- and high-risk prostate cancer, patients with preoperative biopsy ISUP grade groups 3-5 who were allocated to extended pelvic lymph node dissection had better biochemical recurrence free survival (HR 0.33, 95% CI 0.14-0.74, interaction p = 0.007).2

With regards to treatment of localized disease in BRCA mutated patients, Castor et al. evaluated the response of BRCA carriers to conventional treatments for localized prostate cancer following radical prostatectomy or external-beam radiation therapy.This study identified 67 BRCA carriers and 1,235 noncarriers and at 3, 5, and 10 years after treatment, 97%, 94%, and 84% of noncarriers and 90%, 72%, and 50% of carriers were free from metastasis (p < 0.001):

BRCA graphs.jpg

The 3-, 5- and 10-year cancer specific survival rates were significantly better in the noncarrier cohort (99%, 97%, and 85%, respectively) than in carriers (96%, 76%, and 61%, respectively; p < 0.001):

BRCA graphs 2.jpg

Dr. Walz concluded his portion of the debate with the following take-home messages:

  • Local treatment should not be abandoned
  • The patient has the choice
  • Each option has inherent advantages and disadvantages
  • It remains to be fully established if BRCA mutated patients are better (or worse) candidates for surgery

Radiotherapy with Systemic Treatment

The position of radiotherapy with systemic treatment was taken by Dr. Pierre Blanchard who notes that according to the MSKCC nomogram for probability of biochemical control, this patient has a 15-year prostate cancer survival of 42% and only a 6% 5-year and 4% 10-year progression free probability after radical prostatectomy. Additionally, he notes that multimodal therapy leads to additional multimodal toxicity.

Dr. Blanchard noted that common iliac nodes are staged as oligometastatic M1a for prostate cancer. As such, Chopade et al. assessed whether outcomes of pelvic node-positive (cN1) differ from common iliac node-positive (common iliac-M1a) prostate cancer after curative treatment with radical whole pelvic radiation therapy and long-term ADT. Among 130 patients analyzed, 87 had cN1 and 43 had common iliac-M1a stage disease.4 After a median follow up of 61 months, biochemical failure rates in the 2 groups was similar: cN1 24.1%; common iliac-M1a 25.6%, p = 0.86. In addition, the 5-year biochemical failure-free (cN1 77.4%; common iliac-M1a 70.4%, p = 0.43), distant metastasis-free (cN1 86.9%; common iliac-M1a 79.4%, p = 0.23), and overall (cN1 92.6%; common iliac-M1a 90.1% p = 0.80) survival were similar in the two groups.

In the STAMPEDE arm of high-risk localized prostate cancer treated with either abiraterone or enzalutamide, there was a consistent effect with ARPI regardless of metastatic burden.5 Local radiotherapy (74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. There were 1,974 patients randomized and over a median follow-up of 72 months (IQR 60–84), metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR NE–NE) than in the control groups (not reached, 97–NE; HR 0.53, 95% CI 0.44–0.64). The 6-year metastasis-free survival was 82% (95% CI 79–85) in the combination-therapy group and 69% (66–72) in the control group:


Dr. Blanchard highlighted that BRCA2 heterozygosity leads to a moderate increase in radiosensitivity. With regards to genetics and excess radiation risk, Dr. Blanchard highlighted several key points:

  1. Mutations that lead to rare radiation sensitivity syndromes are typically obvious before adulthood. Thus, mutations identified in genetic screening are not likely to be previously undetected indicators of severe radiation sensitivity
  2. Significant germline mutations in DNA repair genes, such as BRCA1 or BRCA2 increase lifetime cancer risk, but most do not increase radiation-induced cancers or radiation toxicity
  3. For most patients, radiation toxicity is not predicted well by any single genetic variant. Tests that incorporate broad genomic information, or polygenic tests, do not yet exist and are likely needed to identify patients with increased radiation-induced toxicity risks

Dr. Blanchard concluded his portion of the debate in favor of radiotherapy with the following take home messages:

  • It is almost certain that upfront surgery will require post-op radiotherapy (larger volumes and higher toxicity)
  • There is an unproven benefit of upfront surgery in very high risk patients
  • Current evidence supports safety and efficacy of radiotherapy in BRCA mutation carriers
  • Intensified systemic therapy is key in addition to radiotherapy as these patients are likely already metastatic

Presented by: Martina Maggi, MD, Sapienza Rome University, Policlinico Umberto I Hospital, Rome, Italy

Debater 1: Jochen Walz, Institut Paoli Calmettes Cancer Center, Marseille, France

Debater 2: Pierre Blanchard, Gustave-Roussy, Villejuif, 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 2023 European Association of Urology (EAU) Annual Meeting, Milan, IT, Fri, Mar 10 – Mon, Mar 13, 2023.


  1. Lumen N, De Bleser E, Buelens S, et al. The role of cytoreductive radical prostatectomy in the treatment of newly diagnosed low-volume metastatic prostate cancer. Results from the Local Treatment of Metastatic Prostate Cancer (LoMP) Registry. Eur Urol Open Sci. 2021 Jun 5;29:68-76.
  2. Lestinig JFP, Guglielmetti GB, Trinh QD, et al. Extended versus limited pelvic lymph node dissection during radical prostatectomy for intermediate- and high-risk prostate cancer: Early oncological outcomes from a randomized phase 3 trial. Eur Urol. 2021 May;79(5):595-604.
  3. Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localized prostate cancer. Eur Urol. 2015 Aug;68(2):186-193.
  4. Chopade P, Maitre P, David S, et al. Common Iliac Node-Positive Prostate Cancer Treated with Curative Radiation Therapy: N1 or M1a? Int J Radiat Oncol Biol Phys. 2022 Nov 15;114(4):711-717.
  5. Attard G, Murphy L, Clarke NW, et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: A meta-analysis of primary results from two randomized controlled phase 3 trials of the STAMPEDE platform protocol. Lancet 2022 Jan 29;399(10323):447-460.