EAU 2021

Meeting: European Association of Urology - 2021 Virtual Meetings

Date: July 8-12, 2021

Session: Game Changing Session 4

Presentation Title: Discussant: Phase 3 KEYNOTE-564 Study

 The Game Changing session at the European Association of Urology’s 2021 virtual annual meeting included a discussion by Dr. Alberto Breda of the important phase 3 KEYNOTE-564 clinical trial. Dr. Breda notes that based on several failed TKI trials, the EAU guidelines do not recommend adjuvant therapy (sorafenib, pazopanib, everolimus, girentuximab, axitinib, or sunitinib) for high-risk RCC given a lack of survival benefit. Data from Zisman et al. [1] notes that the natural history of intermediate-high risk RCC is a 55%-80% 5-year DFS rate on the basis of UCLA Integrated Staging System risk categorization:

Looking at the Kaplan-Meier curve for disease-free survival in KEYNOTE-564, Dr. Breda notes that the benefit starts at 12 weeks and is maintained for up to two years. Beyond two years, and specifically at three years, the benefit is less clear for pembrolizumab:

Dr. Breda highlighted that for the first time M1 no evidence of disease (defined as no evidence of disease after primary tumor + soft tissue metastases completely resected <=1 year from nephrectomy) was assessed as a specific subgroup in the Forest plot analysis. In KEYNOTE-564, M1 NED patients (29 patients in each arm of the trial) had a significant benefit favoring pembrolizumab (HR 0.29, 95% CI 0.12-0.69).

Although there is much excitement regarding the DFS benefit of pembrolizumab from the KEYNOTE-564 trial, Dr. Breda notes that to truly make an impact, we must see an overall survival. For context and by way of caution, we previously saw that sunitinib in the S-TRAC trial had a significant DFS benefit (HR 0.76, 95% CI 0.59-0.98), but this did not translate into a survival benefit (HR 1.014, 95% CI 0.716-1.435) [2]. Dr. Breda is cautiously optimistic that we will eventually see an OS benefit in the KEYNOTE-564 trial, although it may take 4-5 years of follow-up to see this benefit. Encouraging data from the melanoma literature has recently shown an OS benefit for adjuvant pembrolizumab for stage III melanoma, but after 10 years of follow-up.

With regards to adverse events, Dr. Breda notes that in the S-TRAC trial 28.1% of patients in the sunitinib arm discontinued treatment secondary to adverse events. In the KEYNOTE-564 trial, a non-insignificant 18.9% of patients receiving pembrolizumab had grade 3-5 adverse events and 17.6% of patients had treatment-related adverse events leading to treatment discontinuation. As we have historically seen, patients (and likely physicians) are less likely to accept/tolerate side effects/adverse events of adjuvant treatment, specifically when the control arm is placebo and there is a yet to be proven survival benefit.

Dr. Breda concluded his discussant presentation of the KEYNOTE-564 trial with the following take home messages:

• Additional follow-up is needed to assess the impact on overall survival despite adjuvant pembrolizumab post nephrectomy/metastasectomy positively impacting DFS
• Subset analysis by stage, grade and clinical parameters are needed to understand the benefit for the target population and sub-groups
• Safety results were acceptable with an expected immune-mediated adverse event profile

References:

1. Zisman A, Pantuck AJ, Wieder J, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol. 2002 Dec 1;20(23):4559-4566.
2. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 2016;375(23):2246-2254.

Presented By: Alberto Breda, Autonomous University of Barcelona, Barcelona, Spain

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 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.

(UroToday.com) At the metastatic prostate cancer session at the European Association of Urology 2021 annual meeting, Dr. Giuseppe Fallara discussed the impact of time on treatment with abiraterone or enzalutamide among men with metastatic castration resistant prostate cancer (mCRPC). To date, there are little real-world data on the time of treatment with abiraterone and enzalutamide in men with mCRPC. The objective of this study was to assess time on treatment with abiraterone and enzalutamide from population-based data and to compare it with that reported in randomized control trials. 

(UroToday.com) The treatment for metastatic hormone-sensitive prostate cancer plenary session at the European Association of Urology 2021 virtual annual meeting included a presentation by Dr. Karim Fizazi on personalized medicine for mHSPC. Dr. Fizazi notes that the concept of giving the right treatment to the right patient is mostly based on molecular analyses.

(UroToday.com) At the metastatic prostate cancer session at the European Association of Urology 2021 annual meeting, Dr. Miguel Aliaga discussed the impact of prior local therapy on survival in metastatic castration-resistant prostate cancer (mCRPC). The role of prior local therapy on the outcomes of men with metastatic prostate cancer is a subject of growing interest. Retrospective studies have suggested an improved survival in metastatic hormone-sensitive prostate cancer (mHSPC) patients who underwent prior local therapy with radical prostatectomy or radiation therapy. The effect of prior local therapy in newly diagnosed mCRPC patients and its prognostic significance remains unknown. The objective of this study was to evaluate the incidence and prognostic significance of prior local therapy with radical prostatectomy or radiotherapy on overall survival (OS) in chemo-naïve mCRPC patients treated with abiraterone acetate/placebo + prednisone.

This study was a retrospective analysis of chemotherapy-naïve mCRPC patients from the COU-AA-302 trial¹. Patients were categorized based on prior local therapy (radical prostatectomy or radiotherapy). Kaplan-Meier method was used to estimate OS, biochemical progression-free survival, and radiographic progression-free survival. Cox proportional hazards regression model was used to test the association of prior local therapy with OS, biochemical progression-free survival, and radiographic progression-free survival.

Of 1,088 patients included in the study, 469 (43.1%) were M0, 277 (25.5%) were M1, and 337 (31%) were metastasis at diagnosis. The Median time from prostate cancer diagnosis to randomization was 80 months for M0 patients and 28 months for M1 patients. There were 408 (87%) M0 patients that underwent prior local therapy, including 196 (41.8%) that had prostatectomy and 323 (68.9%) that underwent radiotherapy. Prior local therapy was associated with a significant benefit in OS (33.5 versus 25.4 months; HR: 0.61; p=0.001):

and a radiographic progression-free survival benefit (11.7 versus 8.3 months; HR: 0.71; p=0.015):

There was no biochemical progression-free survival benefit observed. Radical prostatectomy but not radiotherapy (HR 0.91; p=0.404) was associated with improved OS:

The improvement in OS based on prior local therapy (HR 0.66, 95% CI 0.47-0.94) was maintained in a multivariable prognostic model.

Dr. Aliaga concluded his presentation with the following take-home messages:

• Men with metastatic castration-resistant prostate cancer who underwent prior local therapy had improved OS when compared to men with no prior local therapy
• This survival benefit is consistent with previous reports on the hormone-sensitive setting 

Presented By: Miguel Rodrigo Aliaga, Hospital General Universitario, Dept. of Urology, Castellon, Spain

Co-Authors: Lorente Estellés D.², Garau Perelló C.¹, Sánchez Llopis A.¹, Bosquet Sanz M.¹, Di Capua Sacoto C.³, Villamón Fort R.³, Blasco Maspons J.A.⁴, Alonso Coscojuela M.⁴, Sánchez Hernández A.²

¹Hospital General Universitario, Dept. of Urology, Castellon, Spain, ²Hospital Provincial, Dept. of Urology, Castellon, Spain, ³Hospital La Plana, Dept. of Urology, Vila-real, Spain, ⁴Hospital Comarcal Vinaroz, Dept. of Urology, Vinaroz, Spain

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 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.

References:

1. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148.

(UroToday.com) The treatment for metastatic hormone-sensitive prostate cancer plenary session at the European Association of Urology 2021 annual meeting included a presentation by Dr. Alberto Briganti discussing surgery for local treatment to the primary +/- to the lymph nodes. Dr. Briganti notes that we must acknowledge that (i) there are no prospective randomized trials available assessing surgery in oligometastatic prostate cancer, (ii) surgery has been tested in retrospective/prospective registries only (with possible patient selection biases), (iii) there is no standardized post-radical prostatectomy treatments or use of metastasis directed therapies, and (iv) it is not yet clear if the results obtained by radiotherapy can also be applied to a radical prostatectomy series. As such, there is a low level of evidence for surgery in this disease space, but it is still practiced.

The EAU 2021 guidelines give a strong recommendation to offer ADT combined with prostate radiotherapy (using the doses from the STAMPEDE trial) to patients whose first presentation is M1 disease and who have low volume of disease by CHAARTED criteria. Dr. Briganti notes that based on these statements, there is indirect support for the fact that the outcome of radiotherapy cannot be extrapolated to surgery due to the lack of evidence.

Over the last decade, there have been several population-based studies assessing the outcomes of radical prostatectomy in the setting of oligometastatic disease. Generally, the 5-year survival data in these population-level studies ranges from 55% to 70%: 

Without question, there are limitations to interpreting the data from these population studies, including:

• There is no information on the number and location of metastases
• There is no data on comorbidity profile, type of systemic therapies, as well as baseline hematological and/or biochemical blood values that represent established predictors of survival in metastatic prostate cancer
• There is no standardized use of peri-operative treatments
• There is no data on functional outcomes
• There are significant patient selection biases

Additionally, there are institutional series that have presented data in this disease space, generally with 2-year OS rates of 77%-89% and 5-year OS rates of 78%-80%:

Similar to the population-level studies, there are limitations with institutional series:

• These are retrospective series with inherent selection biases
• There is no standardized use of peri-operative treatments
• There are different definitions used for oligo-metastatic disease
• There is limited follow-up among these patients

In these patients with metastatic disease, should we be also targeting the lymph nodes? Data from the SEER database suggests that 199 of 330 patients (60.3%) treated with radical prostatectomy underwent lymph node dissection¹. In this series, there was a significantly improved 5-year cancer-specific survival rate for those that received pelvic lymph node dissection in adjusted analyses (HR: 0.52, 95% CI 0.31-0.87; p=0.01):

In the institutional series, the most common complications from radical prostatectomy include lymphocele (8.5%-13%), transfusion (7.9%-14%), and DVT (7%-13%), whereas urinary continence rates did not vary substantially from non-metastatic radical prostatectomy series’. In Dr. Briganti’s opinion, the following patients are the optimal candidates for surgery:

• Low volume disease according to CHAARTED criteria/1-3 bone metastases
• Men with cN0 disease
• Gleason grade group 3-4 (versus 5)
• Patients with lower PSA (< 60 ng/mL according to a population-based series)
• Patients responding to neoadjuvant ADT

As follows is a list of the ongoing randomized controlled trials assessing surgery in the context of metastatic prostate cancer:

Dr. Briganti concluded his presentation by emphasizing that when considering surgery for patients with metastatic disease, this decision must be made in the context of good patient selection in experienced hands. However, cytoreductive radical prostatectomy should primarily be considered as an option for men with oligometastatic prostate cancer within the setting of a clinical trial. 

Presented By: Alberto Briganti, MD, Ph.D., Urological Research Institute, IBCAS San Raffaele Scientific Institute, Milan, Italy

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 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.

References:

1. Mazzonee, Priesser F, Nazzani S, et al. The effect of lymph node dissection in metastatic prostate cancer patients treated with radical prostatectomy: A contemporary analysis of survival and early post-operative outcomes. Eur Urol Oncol. 2019 Sep;2(5):541-548.

(UroToday.com) The treatment for metastatic hormone-sensitive prostate cancer plenary session at the European Association of Urology (EAU) 2021 annual meeting included a presentation by Dr. Noel Clarke discussing systemic treatments and how to choose the right treatment for the right patient.

(UroToday.com) The treatment for metastatic hormone-sensitive prostate cancer plenary session at the European Association of Urology (EAU) 2021 annual meeting included a presentation by Dr. Piet Ost discussing radiation therapy for local treatment to the primary +/- to the lymph nodes.

(UroToday.com) Dr. Giorgio Gandaglia discussed the identification of the best candidates for PSMA PET/CT among those experiencing a biochemical recurrence after radical prostatectomy at the European Association of Urology (EAU) 2021 annual meeting’s detection of recurrence and salvage treatment options after primary treatment of prostate cancer session. Although PSMA PET/CT is recommended in the biochemical recurrence setting after radical prostatectomy, its impact on clinical management is unclear. This is particularly true when considering prostate cancer patients at low risk of metastases who could be managed with salvage radiotherapy alone. The objective of this study was to assess when PSMA PET/CT could be safely avoided or postponed.

(UroToday.com) The European Association of Urology 2021 Annual Meeting included a joint session of the EAU and the Advanced Prostate Cancer Consensus Conference and a discussion regarding current gaps in the evidence, specifically adjuvant versus early salvage radiotherapy. Participants in this discussion included Drs. Derya Tilki, Gert De Meerleer, Alberto Bossi, and Arnulf Stenzl.

Dr. Tilki started by presented the case of a 67-year-old male who underwent a TRUS biopsy that demonstrated high-risk prostate cancer: Gleason 5+4 in 12 out of 12 cores positive for prostate adenocarcinoma. His PSA was 12 ng/ml, his DRE was 40 grams and he was cT2c. His mpMRI was suggestive of T3b prostate cancer, his family history was negative for malignancy and he had no relevant medications or comorbidities. Dr. Tilki notes that in view of the evidence of the randomized, multi-center proPSMA trial¹, replacing bone scan and abdominopelvic CT with more sensitive imaging modalities may be a consideration in patients with high-risk prostate cancer undergoing initial staging. In the proPSMA trial, PSMA PET/CT had a 27% greater accuracy than that of conventional imaging (92% versus 65%). Also of note for this patient is the significance of Gleason Group 5 prostate cancer. Dr. Tilki states that at diagnosis, patients with primary Gleason 5 disease have a PSA recurrence rate of approximately 55% at 5 years after primary therapy, and this failure rate is likely in great part secondary to micrometastases given the negative conventional imaging at diagnosis. Ultimately, this patient underwent robotic radical prostatectomy and extended lymphadenectomy, with pathologic pT3b, Gleason 5+4, pN0 (0/22), tumor volume 37 mL. The surgical margin was positive with multiple contacts on both sides with contact up to 8 mm of Gleason 4 and 5. The next step in management according to Dr. Tilki is “adjuvant or early salvage radiation, with or without ADT”?

Dr. Gert De Meerleer then discussed potential arguments for adjuvant radiotherapy post-prostatectomy. Based on the RAVES, RADICALS-RT trials, and the GETUG-AFU 17 trial, the ARTISTIC collaboration was a preplanned, prospective effort to undertake a meta-analysis of each of the three trials comparing adjuvant and early salvage radiotherapy². Across the three trials, a total of 1,074 men were randomized to adjuvant radiotherapy and 1,077 to an early salvage strategy. Despite some differences in patient population and study design, the findings of the three trials were remarkably similar: there was no significant improvement in biochemical event-free survival for patients receiving adjuvant radiotherapy (hazard ratio 1.12, 95% confidence interval 0.88 to 1.42). Further, among patients randomized to an early salvage strategy, 395 (37%) have thus far commenced salvage radiotherapy and the remainder have been spared therapy.

 When discussing adjuvant versus salvage radiotherapy it is important to discuss side effects of treatment, which tend to be worse (specifically for cystitis and hematuria) for patients receiving adjuvant radiotherapy:

Last month, Tilki and colleagues³ published data evaluating the impact of adjuvant versus early salvage radiotherapy on all-cause mortality risk in men with adverse pathology defined as positive pelvic lymph nodes or pathologic Gleason score 8-10 prostate cancer and disease extending beyond the prostate (pT3/4). Over a median follow-up of 8.16 (IQR 6.00-12.10) years, of the 26,118 men in the study cohort, 2,104 (8.06%) died, of which 539 (25.62%) were from prostate cancer. After excluding men with a persistent PSA, adjuvant compared with early salvage radiotherapy was associated with a significantly lower all-cause mortality risk among men with adverse pathology at radical prostatectomy when men with pN1 prostate cancer were excluded (HR 0.33, 95% CI 0.13-0.85; p = 0.02):

or when pN1 men were included (HR 0.66, 95% CI 0.44-0.99. p = 0.04):

Dr. Bossi then discussed the utility and arguments for early salvage radiotherapy. Dr. Bossi emphasized that in a patient with the pathology report as the aforementioned patient discussed by Dr. Tilki, the two most important questions are (i) what is the risk of a rising PSA? And (ii) what is the risk of death secondary to prostate cancer? Based on available nomograms we know that the risk of rising PSA at 2 years is 54%, at 5 years is 75%, and at 10 years is 86%. The risk of dying of prostate cancer at 15 years is estimated at 20%.

Dr. Bossi notes that the best evidence-based medicine for early salvage therapy is from the aforementioned ARTISTIC meta-analysis [2] that showed no difference between early salvage and adjuvant radiotherapy (HR 1.12, 95% CI 0.88-1.42). However, the potential absolute difference of 1% at 5-years favors early salvage radiotherapy. Even in high-risk patients (CAPRA-S risk group high; RAVES high risk), Vale and colleagues showed that there was no difference between adjuvant and early-salvage radiotherapy:

Further arguments for the role of early salvage radiotherapy rather than adjuvant radiotherapy is the 2x greater incidence of cystitis and 10x greater incidence of hematuria for adjuvant compared to an early salvage radiotherapy approach.

Dr. Bossi concluded his presentation discussing early salvage radiotherapy with the following take-home messages:

• Adjuvant radiotherapy will reduce the probability of a subsequent rise of the PSA
• But, there is no clear “randomized’ evidence that men will live longer or that the risk of developing metastasis is reduced
• Furthermore, there is a price to pay with adjuvant radiotherapy, given there is more urinary toxicity in the short and long-term
• Salvage radiotherapy should be rapidly administered if a rise in the PSA is detected during follow-up

Dr. Stenzl then provided a brief summary of this discussion noting that the recent publications of the RAVES, RADICALS, and GETUG-AFU 17 trials, in addition to the ARTISTIC collaborative meta-analysis, have certainly tipped the favor towards early salvage radiotherapy given the similar efficacy, low/no risk of overtreatment, and decreased side-effects of adjuvant treatment. In his practice, even with high-risk men in which he may consider adjuvant radiotherapy; he is still inclined to wait up until 6 months post-radical prostatectomy in order to allow the patient to fully heal from their operation and perhaps decrease the risk of functional side effects of treatment.

Presented By: Derya Tilki, MD, Martini-Klinik Prostate Cancer Center, Hamburg, Germany; Gert De Meerleer, MD, Ph.D., University Hospitals Leuven, Leuven, Belgium; Alberto Bossi, MD, Gustave Roussy Institute, Villejuif, France; Arnulf Stenzl, MD, University of Tubingen Hospital, Tubingen, Germany

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 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.

References:

1. Hofman MS, Lawrentschuk N, Francis, RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): A prospective, randomized, multicentre study. Lancet 2020 Apr 11;395(10231):1208-1216.
2. Vale CL, Fisher D, Kneebone A, et al. Adjuvant or early salvage radiotherapy for the treatment of localized and locally advanced prostate cancer: A prospectively planned systematic review and meta-analysis of aggregate data. Lancet 2020 Oct 31;396(10260):1422-1431.
3. Tilki D, Chen MH, Wu J, et al. Adjuvant versus early salvage radiation therapy for men at high risk for recurrence following radical prostatectomy for prostate cancer and the risk of death. J Clin Oncol. 2021 Jul 10;39(20):2284-2293.

(UroToday.com) The European Association of Urology (EAU) 2021 Virtual Meeting included a joint session of the EAU and the Advanced Prostate Cancer Consensus Conference and a discussion regarding current gaps in the evidence, specifically optimal management of cN1 patients. Participants in this discussion included Drs. Ricardo Mestre, Alberto Briganti, Piet Ost, Karim Fizazi, and Peter Albers.

(UroToday.com) Dr. Henk Luiting discussed the utility of histological confirmation for intraprostatic recurrences on PSMA PET/CT after prostate whole gland radiotherapy at the European Association of Urology (EAU) 2021 annual meeting’s detection of recurrence and salvage treatment options after primary treatment of prostate cancer session. Patients with an intraprostatic recurrence after radiotherapy can be considered for salvage therapy, however, the EAU guidelines recommend obtaining histological confirmation before salvage therapy. This recommendation, however, does not consider the diagnostic accuracy of PSMA PET/CT. In current daily clinical practice, the need to obtain histological confirmation is often deemed unnecessary as a result of the recognized high specificity of PSMA PET/CT, which currently is the modality of choice for detecting recurrences. The objective of this study was to evaluate the biopsy outcomes in patients with an intraprostatic recurrence on PSMA PET/CT after prostate whole gland radiotherapy.

(UroToday.com) Dr. Christoph Wurnschimmel discussed long-term validation on the impact of PSMA-PET on metastasis-free survival (MFS) in a large salvage radiotherapy cohort at the European Association of Urology (EAU) 2021 annual meeting’s detection of recurrence and salvage treatment options after primary treatment of prostate cancer session. Earlier studies focusing on the impact of PSMA-PET imaging for treatment planning prior to salvage radiotherapy for PSA recurrence after radical prostatectomy suggested a high response rate in PSMA negative findings as opposed to PSMA positive findings. However, most available literature either only reported short-term follow-up or did not address long-term MFS. The objective of this study was to provide a large and contemporary report that provides 5-year MFS rates after salvage radiotherapy by PSMA PET results.

(UroToday.com) The controversies in onco-urology joint session of the ESOU, ERUS, ESMO, and ESTRO societies included a debate around whether we should perform PSMA PET/CT in the initial staging of prostate cancer.

(UroToday.com) It is now well established that PSMA PET/CT is more sensitive than conventional imaging. As such, PET/CT scan might lead to the identification of nodal metastases (e.g., cN1) in prostate cancer (PCa) patients considered for radical prostatectomy (RP). However, there are no data addressing the performance characteristics and prognostic value of a positive PET/CT in the nodes for the identification of men more likely to recur.

(UroToday.com) In PROSPER (NCT02003924),¹ a multinational, double-blind, randomized Phase 3 study that examined enzalutamide (ENZA) in men with nmCRPC continuing androgen deprivation therapy, ENZA significantly improved metastasis-free survival versus placebo (PBO).

(UroToday.com) Dr. Laurence Albiges discussed the evolving landscape of first-line systemic treatment in metastatic renal cell carcinoma (mRCC) at the European Association of Urology’s (EAU) 2021 annual meeting’s controversies in onco-urology session. Dr. Albiges started by highlighting the new guidelines adapted from the EAU and ESMO guidelines for RCC, using the IMDC risk classification to select treatment options. A summary of the adapted guidelines are as follows: