The ecosystem of therapy in genitourinary (GU) cancers is evolving and progressing, with emerging data continuing to shape clinical treatment regimens. Here we will highlight 4 key abstracts presented at the ASCO (American Society of Clinical Oncology) 2023 Annual Meeting, which may impact management of patients with advanced prostate cancer and testicular cancer (seminoma).

Table. Key Points From 2023 American Society of Clinical Oncology Highlights of Genitourinary Cancer: Prostate and Testicular Cancer

Abstract LBA5000, discussing local therapy in metastatic prostate cancer, reports the PEACE-1 trial, which compared standard of care (SOC) therapy alone or with abiraterone, radiotherapy, or abiraterone+radiotherapy.¹ This is a multicenter, open-label, randomized, phase 3 study that required patients to have de novo castration-sensitive prostate cancer (mCSPC) with >1 bone lesion and investigated coprimary end points of radiographic progression-free survival (rPFS) and overall survival (OS). Enrolled patients were well balanced between arms, with about 43% of patients with low-volume disease (LVD). In patients with LVD, patients randomized to SOC+abiraterone+radiotherapy had improved rPFS compared to SOC+abiraterone (HR = 0.65), without improvement in OS (HR = 0.98). There was no difference in rPFS between patients receiving SOC vs SOC+radiotherapy. The investigators reported significant improvement in time to serious GU events in patients with LVD receiving radiotherapy.

These results are important, given recent data regarding local treatment of mCSPC. In 2018, the HORRAD trial established the benefit of radiotherapy on PSA progression but did not reveal improvement in OS between androgen deprivation therapy (ADT) vs ADT+radiotherapy.² However, this trial did not provide data on volume of disease. Similarly, the STAMPEDE trial (Arm H) demonstrated benefit of radiotherapy in failure-free survival but no difference in OS in the general population.³ However, subgroup analysis of patients with low metastatic disease burden revealed a significant difference in both failure-free and OS. Most recently, the phase 2 OMPCa-Shanghai trial reported significantly higher rates of rPFS and OS in patients with oligometastatic prostate cancer receiving ADT+local treatment (surgery or radiotherapy) compared to ADT alone, though the majority of participants underwent surgery as local therapy.⁴

In summary, the data suggest that prostate radiotherapy with intensified systemic treatment may improve rPFS and reduce serious GU events in patients with LVD. However, this is without detectable impact on OS in PEACE-1 and HORRAD, but with improvement in STAMPEDE (Arm H) and OMPCa-Shanghai. An additional trial, SWOG1802, will be important to help answer this question, which is enrolling patients with mCSPC, randomized to systemic therapy with or without local treatment, with primary end point of OS. Results are eagerly anticipated to further inform management of patients with LVD mCSPC.

Abstracts 5004 and 5005 reported utilization of poly-(ADP-ribose) polymerase (PARP) combination therapy in patients with mCRPC. Aberrations in DNA repair genes are common in mCRPC, leading to recent approvals of PARP inhibitors (PARPi) for biomarker-positive mCRPC. Additionally, it is suggested that PARPi may increase activity of novel hormonal agents (NHAs), and NHAs may increase susceptibility to PARPi. The PROPEL trial demonstrated superior rPFS with olaparib/niraparib+abiraterone vs placebo+abiraterone in all-comer, first-line mCRPC patients, but the MAGNITUDE trial showed benefit only in patients with homologous recombination repair (HRR) mutations (ie, biomarker-positive patients).^5,6 The TALAPRO-2 trial, comparing talazoparib+enzalutamide or placebo+enzalutamide, reported similar benefit in rPFS in the overall population. Abstract 5004 reports the results from the TALAPRO-2 HRR+ cohort (n=399).⁷ In HRR-deficient tumors, talazoparib+enzalutamide demonstrated improved rPFS (HR = 0.45) and a favorable trend toward improved OS (HR = 0.69), though OS data are yet to mature. Abstract 5004 reinforces that PARPi+NHA combinations are active in mCRPC, with a more robust benefit in HRR-deficient patients. However, an important limitation of these studies is that only a minority of patients received NHAs before development of castration resistance. Management of mCSPC has progressed to include early administration of NHAs and prior to development of castration resistance, which may limit the direct applicability of these results. While this limitation is a consideration, it is encouraging to see CRPC treatment options continuing to progress and include precision medicine approaches.

Abstract 5005 reports LuPARP, a phase 1 trial of ¹⁷⁷Lu—prostate-specific membrane antigen (PSMA)—617+olaparib in mCRPC patients.^{8 177}Lu-PSMA-617 delivers radiation to PSMA+ tumors, causing predominantly single-strand breaks over more lethal double-strand breaks. PARP is essential in repairing these single-strand breaks, mediating the primary (∼25%) and acquired (∼100%) resistance to ¹⁷⁷Lu-PSMA-617 in mCRPC patients. The combination of ¹⁷⁷Lu-PSMA-617 with PARPi is suggested to leverage the DNA-damaging and immune modulating effects of radioligand therapy, which is supported by preclinical and clinical studies, such as ¹⁷⁷Lu-DOTATATE.⁹ The LuPARP trial enrolled 48 patients, with primary objectives of identifying dose-limiting toxicities and recommended phase 2 dose, and secondary objectives of toxicity, rPFS, and PSA response rate. Of the patients, 67% received prior NHA and 38% had RECIST-measurable disease at enrollment. Safety analysis was highly favorable, with no dose-limiting toxicities. Of the patients, 65% achieved 50% decline in PSA response (75% of patients with higher-dose treatment). Overall, this trial reports encouraging safety and early efficacy data. Dose expansion and larger trials will be important in establishing further efficacy. Notably, this abstract also reported interesting correlative analysis, demonstrating heterogeneity in circulating tumor cells, despite requiring PSMA—positron emission tomography—avid disease, underscoring the importance of translational research efforts to understand the biology of the tumor microenvironment and how this affects clinical outcomes.

Abstract 5008 reported the role of primary retroperitoneal lymph node dissection (RPLND) in stage IIA-IIC seminomas (SWENOTECA/COTRIMS trial).¹⁰ Current treatment for stage 2 seminoma includes radiotherapy/chemotherapy. Cure rates are exceptionally high, though late mortality effects materialize at 20+ years, including emergence of secondary cancers. This study enrolled 94 patients from 5 centers, with either relapsed CS (clinical stage) 1 or primary CS2A/B, who underwent RPLND. The overall recurrence rate was 9.6% with all but 1 in the first year following RPLND. Overall, this trial demonstrates that RPLND is a treatment option with low morbidity and mortality in patients with clinically low-volume retroperitoneal disease, which is consistent with a recent phase 2 trial of RPLND,¹¹ reporting 22% recurrence rate and low complication rates. Additional follow-up, including patient reported-outcomes, will be useful to ensure no additional safety signals.

In conclusion, these abstracts highlight exciting new data in GU oncology, with particular implications in treatment of advanced prostate cancer and seminoma-type testicular cancer. Key discoveries are summarized in the Table.