Practice-changing data
The ASCO Genitourinary Cancers Symposium presentations delivered several advances including a multitude of practice-changing phase III clinical trials. An important practice changing trial was the EV304 (KEYNOTE B-15) phase III trial which evaluated neoadjuvant enfortumab vedotin (EV) + pembrolizumab in the perioperative setting for cisplatin eligible muscle invasive bladder cancer (MIBC). Previously, the EV + pembrolizumab regimen has been reported to improve outcomes in cisplatin-ineligible MIBC in the EV303 (KEYNOTE-905) clinical trial, which led to FDA approval. Now, the phase III EV304 trial demonstrated an improvement in event-free survival (EFS, HR 0.53, p<.0001), overall survival (OS, HR of 0.65, p=0.0029), and pathological complete response (pCR 55.8% versus 32.5%) with EV + pembrolizumab versus gemcitabine-cisplatin (GC) in cisplatin-eligible disease. While the combination of GC + durvalumab was also recently approved in this cisplatin-eligible setting, the more robust improvement in outcomes (EFS and OS HRs were 0.68 and 0.75 in NIAGARA, which compared GC-durvalumab vs GC) makes it probable that EV + pembrolizumab will become the preferred perioperative systemic therapy for cisplatin-eligible MIBC patients undergoing radical cystectomy. Thus, EV + pembrolizumab will likely become the preferred perioperative systemic therapy for MIBC regardless of cisplatin eligibility.
In the setting of clear cell renal cell carcinoma (ccRCC), a couple of phase III clinical trials incorporating belzutifan, a hypoxia inducible factor (HIF)-2α inhibitor, improved outcomes and are expected to be practice-changing. The LITESPARK-011 trial demonstrated longer progression-free survival (PFS, HR=0.70, p=0.00007), higher objective response rate (ORR 52.6% versus 39.6%), longer duration of response (DOR, median 23.0 versus 12.3 months), and a trend toward prolonged OS with belzutifan + lenvatinib versus cabozantinib following prior immune-checkpoint inhibitor-based therapy. In this post immune checkpoint inhibitor setting there are other options available, including the combination of lenvatinib + everolimus and tivozanib and the choice between all these options will involve individualized decision-making based on the efficacy and toxicities. The LITESPARK-022 trial demonstrated an improvement in disease-free survival (DFS) with adjuvant belzutifan + pembrolizumab versus placebo + pembrolizumab alone (HR 0.72, p = 0.0003), despite higher grade ≥3 toxicities especially anemia and hypoxia. The secondary endpoint of OS is not mature.
Potentially practice-changing data
The PEACE-III trial, a randomized, open-label, multicenter phase III trial evaluating the addition of radium-223 to enzalutamide in metastatic castration resistant prostate cancer (mCRPC) with bone metastases, was updated at this ASCO symposium. The combination of enzalutamide and 6 cycles of radium 223 shows a significant improvement in OS (HR 0.76, p-value = 0.0096) with median OS improving from 32.6 → 38.2 months with the combination therapy. An improvement in radiographic progression free survival (rPFS) was also confirmed (HR 0.71, 95% CI 0.57-0.89), with the median rPFS improving from 16.4 → 19.2 months. The relevance of this finding in the current study has been questioned since most of the study population includes mCRPC patients who progressed after therapy with androgen deprivation therapy (ADT) or ADT + chemotherapy but not exposed to androgen receptor pathway inhibitors (ARPIs). However, the improvement in survival supports its inclusion as an option for mCRPC.
Further analysis of the IMvigor011 phase III trial showed that postoperative tumor-informed circulating tumor (ct)-DNA (Signatera®) guided atezolizumab administration up to 1 year after surgery with or without neoadjuvant cisplatin-based chemotherapy improved both PFS and OS. However, the relevance of this result in the setting of perioperative chemo-immunotherapy or EV + pembrolizumab is unclear. Higher ctDNA concentrations and early ctDNA positivity were associated with worse outcomes, and ctDNA clearance was associated with improved outcomes. Interestingly, ~22% of patients in the placebo arm demonstrated low quantitative ctDNA levels and cleared ctDNA without treatment, which was associated with favorable outcomes, although ~40% of patients who converted to a negative ctDNA eventually did develop recurrence. This phenomenon may be attributable to fluctuations around the assay detection threshold and suggests that repeat testing may be prudent before initiating therapy to assess the trajectory at least in those with low initial ctDNA levels.
In this context, the RETAIN-2 Phase II trial presented outcomes including data for Signatera® in patients with cT2-T3N0 MIBC undergoing dose-dense MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) + nivolumab neoadjuvant therapy and proceeding to omission of radical cystectomy if harboring ERCC2, RB1 or ATM alterations and achieving clinical complete remission (cCR). However, while this approach is promising and Signatera® positivity and dynamics was prognostic, it remains investigational and requires validation in randomized trials.
Practice-informing/affirming data
POSEIDON, a large individual patient-level meta-analysis of 6 phase III trials totaling 6057 patients assessing ADT use and duration with post-operative radiotherapy for PSA-recurrent prostate cancer, revealed that only patients with a post-operative PSA > 0.5 ng/mL may benefit from ADT. For most patients, short-term ADT appeared sufficient for 4-6 months. The major limitation of the study was that the value of long-term ADT may be overlooked by the fact that 70% of patients in the long-term ADT cohort were on RTOG 9601, which used bicalutamide monotherapy and would currently be considered suboptimal. Moreover, in the real world, decisions are based not only on the absolute PSA value, but also on the life expectancy of patients, PSA doubling time, Gleason score, prior pathologic stage, and the Decipher® score in selected patients.
CYTOSHRINK, a randomized Phase II trial evaluated cytoreductive stereotactic body radiotherapy (SBRT) to ipilimumab + nivolumab for advanced ccRCC. Unfortunately, the primary endpoint of 12-month PFS was not met. The value of cytoreductive nephrectomy also remains unproven. Better support for the ongoing U.S. Intergroup PROBE Phase III clinical trial is necessary, which is evaluating the role of delayed cytoreductive nephrectomy in patients starting immune checkpoint inhibitor-based therapy with clinical benefit 9-12 weeks after starting therapy.
Conclusion
Thus, ASCO Genitourinary Cancers Symposium successfully delivered multiple advances in the field of GU malignancies. Transformative advances will come with better knowledge of tumor biology and discovery of biomarkers to enable precision medicine. Accrual to clinical trials should be considered a preferred standard of care to expedite advances.
Guru P. Sonpavde, MD is the Director of Genitourinary (GU) Oncology and Phase I Research as well as the Christopher K. Glanz Chair for Bladder Cancer Research at the AdventHealth Cancer Institute, and Professor of Medicine at the University of Central Florida, Orlando, Florida, USA. Previously, he was Bladder Cancer Director at the Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School from 2017-2022, GU Oncology Director and Associate Professor of Medicine at the University of Alabama at Birmingham from 2012 to 2017 and practiced from 2004 to 2012 at Texas Oncology, a US Oncology affiliate. His focus is drug development (including early development Phase I clinical trials and later Phase II/III trials) evaluating novel and emerging classes of treatments across solid tumors and clinical/translational research to cure GU cancers with a focus on bladder cancer.
Dr. Sonpavde has received grants from Bayer, Sumitomo Pharma, and Blue Earth Diagnostics. He has received consulting fees or honorarium from EMD Serono, BMS, Merck, Seattle Genetics, Astellas, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, Eli Lilly, Loxo Oncology, Vial, Aktis, Daiichi-Sankyo, GSK, Syapse, Merck, Servier, Ellipses, and Biosite Research. He has received support for travel from BMS, Astellas, and Merck. He has received payment for lectures from Seagen, Gilead, Natera, Exelixis, Janssen, Astellas, Bayer, Aveo, Pfizer, Merck, and Astrazeneca. Dr. Sonpavde's spouse is or has been employed by Myriad and Exact Sciences.
Collage by Joe Lee
