(UroToday.com) The 2024 American Urological Association (AUA) annual meeting held in San Antonio, TX was host to the Society of Urologic Oncology (SUO) session Dr. Martin Gleave was invited to deliver the Whitmore lecture during this year's SUO session at AUA. His presentation focused on optimizing outcomes in high-risk localized prostate cancer.
Dr. Gleave initiated his presentation by sharing a treatment dilemma posed by urologist Dr. Willet Whitmore: “If treatment for cure is necessary, is it possible? If possible, is it necessary?” This question underscores the long-standing challenge of over-treating low-risk prostate cancer (PCa) while simultaneously under-treating advanced cases (both localized and metastatic). Dr. Gleave emphasized the importance of aiming for a cure when feasible but also prioritizing control and chronicity when necessary.
He highlighted numerous advancements in the diagnosis and treatment of PCa, including early detection facilitated by PSA and MRI, enhanced risk stratification methods utilizing factors such as volume, Gleason pattern, PSA, and biomarkers. Dr. Gleave also pointed out improvements in treatment techniques such as surgery and radiotherapy. Additionally, he discussed the emergence of multimodal therapy integration, encompassing image-guided early salvage therapy, metastasis-directed therapies, and neoadjuvant strategies involving androgen receptor pathway inhibitors (ARPI).
Dr. Gleave delved into the optimal treatment approach for high-risk localized prostate cancer, emphasizing the importance of achieving optimal local control while minimizing treatment-related morbidity through the judicious use of multimodal therapy. He cited evidence from multiple trials indicating that external beam radiation therapy (EBRT) to the prostate combined with androgen deprivation therapy (ADT) improves overall survival. However, he noted that radical prostatectomy (RP) and EBRT + ADT have shown similar outcomes thus far.
Data from randomized controlled trials: SWOG 1802 (NCT03678025) and SPCG-15 (NCT02102477) is eagerly awaited. However, there is propensity adjusted studies comparing RP vs RT, and he mentioned that 13 out of 14 studies favored RP over radiation. However, he acknowledges there is significant systematic bias in unmeasured confounding variables and theoretically with RT there is more and longer use of ADT which is associated with cardiovascular adverse events and, second malignancies with RT.
Furthermore, Dr. Gleave presented data comparing the incidence of secondary malignancies in PCa patients following brachytherapy or RP. With a median follow-up of 14 years, the absolute risk of secondary malignancy at 20 years was 9.8% after brachytherapy vs. 4.2% after RP (p<0.0001), with a corresponding increase in death from secondary malignancies (p=0.0039).
The discussion transitioned to the integration of multimodal therapy for biochemical recurrence (BCR). Dr. Gleave outlined three key considerations: i) the impact of BCR on oncological outcomes, ii) the choice between adjuvant versus salvage radiotherapy and image-guided salvage therapies, and iii) the timing, schedule (continuous or intermittent), and intensification (such as ARPI or doublets) of ADT. While evidence suggests that systemic therapy and salvage radiotherapy confer an overall survival (OS) benefit, the same quality data is lacking for metastasis directed therapy.
He presented the results of the SABR-COMET Phase II trial and shared a case study of one of his patients who participated in this trial. In this study, 99 patients with 1-5 metastases (oligometastatic disease) and a controlled primary tumor were randomized to standard of care with or without stereotactic body radiation therapy (SBRT) to all metastatic sites. The 5-year overall survival (OS) favored SBRT (p=0.006). This trial underscores the potential benefits of integrating metastasis-directed therapy (MDT) into standard systemic therapy.
Dr. Gleave also discussed the findings of the recently published EMBARK trial, a phase 3 randomized controlled trial evaluating enzalutamide versus placebo plus androgen deprivation therapy (ADT), and enzalutamide monotherapy for high-risk biochemical recurrence (BCR) prostate cancer (PCa). The study demonstrated that initiating androgen receptor pathway inhibitor (ARPI) doublets earlier in high-risk BCR PCa significantly prolonged disease control and OS (p<0.0142).(4) He presented a timeline illustrating the gradual stage migration of ARPI therapy, initially starting in second-line metastatic castration-resistant PCa (mCRPC) and now extending to M0 BCR and even locally advanced M0 disease.
Dr. Gleave shifted toward the neoadjuvant surgical studies. He discussed how the first neoadjuvant trials pre-surgery compared 0 vs 3m months and 3 vs. 8 months neoadjuvant therapy in the 1990s. These trials failed to show a benefit for neoadjuvant ADT, there was a similar BCR, low pathologic complete response (pCR) <8%, however, there was a 50% reduction in positive margin rates. He highlighted these studies had not selected for high-risk patients, were underpowered, and measured the wrong endpoints. He highlighted the results of the CUOG study published by himself in 2001. They compared 3 vs 8 months of ADT before RP. They found no significant differences in OS, biochemical progression-free survival and disease specific survival.
He delved into the utilization of ARPI doublets for neoadjuvant therapy prior to radical prostatectomy (RP) and highlighted the PROTEUS trial, a phase III randomized controlled trial (RCT) assessing 6 months of neoadjuvant plus 6 months of adjuvant luteinizing hormone-releasing hormone agonist (LHRHa) therapy with or without apalutamide. This trial is evaluating metastasis-free survival as the primary endpoint, and results are eagerly awaited.
Dr. Gleave then discussed the PUNCH neoadjuvant trial, comparing surgery alone versus neoadjuvant androgen deprivation therapy (ADT) plus docetaxel doublet. This study revealed that neoadjuvant ADT plus docetaxel led to improved freedom from PSA failure (p=0.02) and freedom from treatment failure (p<0.001). However, as of yet, no improvements in overall survival (OS) have been observed. Furthermore, the study explored the molecular characteristics of prostate cancer undergoing neoadjuvant therapy with docetaxel. They observed a higher mutation frequency of TP53 in the docetaxel-ADT arm compared to the control, along with down-regulation of androgen receptor (AR) target genes like KLK3 and increased expression of AR-V7.
He emphasized the significance of precision medicine in prostate cancer (PCa) today, underscoring the necessity of genomic and imaging biomarkers to direct therapy effectively. In the following slide, he illustrated various therapy targets in PCa, with each study demonstrating improvement when treating patients guided by genomic markers, immunohistochemistry (IHC), or imaging.
The rationale for biomarker-driven neoadjuvant strategies in high-risk PCa lies in that genomic sequencing enables the matching of targeted agents to distinct molecular aberrations. However, most defects arise in a small proportion of patients (10-20%) hampering clinical testing with multiple single-agent, single-arm phase II studies. He mentioned why it is important to have as an outcome pCR. He presented the design of his hallmark trial: the GUNS: Genomic umbrella neoadjuvant study in high-risk PCa. This study had four subprotocols and with the option of adding new ones as they become available., They aimed to investigate mechanisms of treatment resistance, and lineage plasticity in relation to genotypes.
He showed the reported genomic alterations in 83 GUNS pre-treatment tumors. They observed FOXA1 mutations in 25%, SPOP in 13%, He noted the rate of FOXA1 mutations was higher in GUNS than in previous localized PCa cohorts. 18/83 (22%) of pre-treatment tumours had a biologically relevant FOXA1 mutation. Only 4% of patients were found to have TP53 and PTEN alterations
He moved on to explain how clustering by transcriptomic gene set enrichment scores aligns with ETS and SPOP (They tend to cluster together) this suggests that these two genotypes have the largest consequence on the transcriptome.
Preliminary data from the GUNS trial regarding pathologic responses revealed 2 cases of complete pathological response (pCR). One patient exhibited Gleason Grade 5 (GG5) in 6-10 cores, with a PSA level of 20. The other had 3 cores of GG4 and FOXA1 (SP1a). Among eight patients with maximal reduction diameter (MRD), defined as the largest residual focus being less than 3mm, five harbored SP1 mutations (FOXA1, SPOP, FOXA1, No mutations in two), as well as SP2b and SP4 mutations. Dr. Gleave presented four cases of patients who demonstrated MRD, comparing histopathologic findings before and after radical prostatectomy (RP). Notably, FOXA1 mutations were observed in three of the patients who were pCR/MRD responders.
He also mentioned they found some outlier responders of interest. These patients exhibited mutations in MSH2 with High Tumor Mutational Burden (TMB), BRCA2, TMPRSSS2, and POLE (high TMB). One of these outlier responders had pre-treatment MSH2 with high TMB, and post-neoadjuvant treatment with ARPI+ Atezolizumab resulted in a massive increase in Neuroendocrine Prostate Cancer (NEPC) signature gene sets.
The GUNS trial was designed with an adaptive protocol, and two subprotocols have been added thus far. One target treatment for SP5 (lineage plasticity), TP35, RB with Tazmetostat (EZH2), an epigenetic regulator of B-cell identity in the germinal center. The other subprotocol targets SP.6a and SP.6b with Capivasertib, which aims to target oncogenic signaling driven by PIK3CA, AKT1, and/or PTEN alterations.
Dr. Gleave concluded his talk by revisiting the initial premise: cure is possible when it's necessary. For high-risk prostate cancer, he emphasized the importance of early detection, appropriate risk stratification, and the integration of adequate multimodal therapy.
Presented by: Martin Gleave, CM, MD, FRCSC, FACS at University of British Columbia and the Vancouver Prostate Centre.
Written by: Julian Chavarriaga, MD – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @chavarriagaj on Twitter during the 2024 American Urological Association (AUA) Annual Meeting, San Antonio, TX, Fri, May 3 – Mon, May 6, 2024.
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