ASCO 2023 RECAP Highlights of Genitourinary Cancer: Prostate and Testicular Cancer
By: Caroline S. Jansen, PhD, Emory University School of Medicine, Atlanta, Georgia, Winship Cancer Institute of Emory University, Atlanta, Georgia; Mehmet Asim Bilen, MD, Emory University School of Medicine, Atlanta, Georgia, Winship Cancer Institute of Emory University, Atlanta, Georgia | Posted on: 25 Oct 2023
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 No.||Trial name||Trial arms||Key findings||Implications for practice|
|LBA5000||PEACE-1||SOC, SOC+abiraterone, SOC+radiotherapy, SOC+abiraterone+ radiotherapy||Improved rPFS, time to serious GU events for SOC+abiraterone+ radiotherapy arm compared to SOC+abiraterone in low-volume mCSPC. No difference in OS||Radiotherapy with intensified systemic therapy appears to improve rPFS and prevent serious GU events in men with low-volume mCSPC|
|5004||TALAPRO-2||Talazoparib+enzalutamide, placebo+enzalutamide||Improved rPFS for talazoparib+ enzalutamide arm (HR = 0.45) in HRR-deficient mCRPC||PARPi+NHA combinations are active in mCRPC, with a more robust benefit in HRR-deficient patients|
|5005||LuPARP||177Lu-PSMA-617+olaparib||No DLTs, 1 treatment-related SAE (febrile neutropenia), no grade 4 AEs reported. Of patients 65% achieved PSA50 response (75% at higher doses)||Encouraging safety and early efficacy data, future study will determine efficacy of this combination|
|5008||SWENOTECA /COTRIMS||RPLND in patients with relapsed CS1 or primary CS2A/B||Overall recurrence rate 22%, median survival 10.2 mo. Low risk of mortality/morbidity.||RPLND is a treatment option with low morbidity and mortality in patients with clinically low-volume retroperitoneal disease|
|Abbreviations: AE, adverse event; CS, clinical stage; DLT, dose-limiting toxicity; GU, genitourinary; HR, hazard ratio; HRR, homologous recombination repair; mCSPC, metastatic castration-sensitive prostate cancer; NHA, novel hormonal agent; OS, overall survival; PARPi, poly-(ADP-ribose) polymerase inhibitor; PSA50, 50% decline in PSA; PSMA, prostate-specific membrane antigen; rPFS, radiographic progression-free survival; RPLND, retroperitoneal lymph node dissection; SAE, severe adverse event; SOC, standard of care.|
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 177Lu-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.
- Bossi A, Foulon S, Maldonado X, et al. Prostate irradiation in men with de novo, low-volume, metastatic, castration-sensitive prostate cancer (mCSPC): results of PEACE-1, a phase 3 randomized trial with a 2x2 design. J Clin Oncol. 2023;41(17_suppl):LBA5000.
- Boevé LMS, Hulshof MCCM, Vis AN, et al. Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: data from the HORRAD trial. Eur Urol. 2019;75(3):410-418.
- Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366.
- Dai B, Zhang S, Wan FN, et al. Combination of androgen deprivation therapy with radical local therapy versus androgen deprivation therapy alone for newly diagnosed oligometastatic prostate cancer: a phase II randomized controlled trial. Eur Urol Oncol. 2022;5(5):519-525.
- Saad F, Armstrong AJ, Thiery-Vuillemin A, et al. PROpel: phase III trial of olaparib (Ola) and abiraterone (Abi) versus placebo (Pbo) and Abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2022;40(6_suppl):11.
- Chi KN, Rathkopf DE, Smith MR, et al. Phase 3 MAGNITUDE study: first results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2022;40(6_suppl):12.
- Fizazi K, Azad A, Matsubara N, et al. TALAPRO-2: phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations. J Clin Oncol . 2023;41(16_suppl):5004.
- Sandhu S, Joshua AM, Emmett L, et al. LuPARP: phase 1 trial of 177Lu-PSMA-617 and olaparib in patients with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(16_suppl):5005.
- Cullinane C, Waldeck K, Kirby L, et al. Enhancing the anti-tumour activity of 177Lu-DOTA-octreotate radionuclide therapy in somatostatin receptor-2 expressing tumour models by targeting PARP. Sci Rep. 2020;10(1):10196.
- Tachibana I, Alabd A, Tong Y, et al. Primary retroperitoneal lymph node dissection for stage II seminoma: is surgery the new path forward?. J Clin Oncol. 2023;41(23):3930-3938.
- Daneshmand S, Cary C, Masterson T, et al. Surgery in early metastatic seminoma: a phase II trial of retroperitoneal lymph node dissection for testicular seminoma with limited retroperitoneal lymphadenopathy. J Clin Oncol. 2023;41(16):3009-3018.