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ASCO 2023 Genitourinary Cancers Update with Dr Zhang

Presentation by Dr Tian Zhang, UT Southwestern


At the Total Health 2023 ASCO Review held in Napa Valley, California, Dr Tian Zhang, MD, MHS, from UT Southwestern presented updates the genitourinary cancers from the 2023 American Society for Clinical Oncology (ASCO) Annual Meeting, including her top abstracts each for prostate, kidney, and bladder cancers.



Prostate Cancer

 

The PEACE-1 trial was a large, randomized, phase III trial that examined the use of abiraterone acetate, in addition to the current standard of care (SOC), in men with newly occurring (de novo) low-volume metastatic, castration-sensitive prostate cancer (mCSPC). Abiraterone is an oral systemic treatment that suppresses the production of androgens including testosterone, and thereby inhibits its growth-promoting effects in prostate cancer.  The results presented at ASCO 2023 reported on the use of Abiraterone + SOC + radiotherapy (RT) as compared with SOC + RT alone, with the co-primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS).  The results for the “low volume” population (defined as fewer that 4 bone metastases, and no visceral metastases) show that RT improved rPFS when added to abiraterone and SOC, but not when added to SOC alone.  Dr Tian noted that the results suggest that “consolidative” local disease control using RT to the prostate, when added to systemic treatment with abiraterone, was beneficial for outcomes in men with low volume CSPC.  While OS was also improved with the triple regimen of SOC + RT + Abiraterone, Dr Tian noted the results were not statistically significant, and will require longer follow up.  The time to serious genitourinary events like obstruction (i.e., adverse events occurring as a result of the primary prostate tumor) was also longer with the triple regimen, as was the time to development of castration resistance, particularly in the low volume disease population, suggesting again that RT is beneficial for outcomes when used in combination with effective systemic treatment.

 

In the TALAPRO-2 trial, the use of enzalutamide (an oral nonsteroidal antiandrogen medication) in combination with talazoparib (a PARP inhibitor drug) was examined in patients with metastatic, castration-resistant prostate cancer (mCRPC), specifically in the subset of patients who had homologous recombination repair (HRR) mutations. These two classes of drugs in combination (i.e., an androgen receptor inhibitor, plus a PARP inhibitor) are believed to act cooperatively to promote cancer cell killing in mCRPC with HRR gene alterations.  Patients were randomized to the talazoparib/enzalutamide combination, or to placebo + enzalutamide in this randomized, placebo-controlled phase III trial, and the primary endpoint was rPFS.  The analysis presented at ASCO 2023 was limited to the HRR mutant (HRRm) patients (n=399), of which about 1/3 were BRCA2 mutated, ~25% were ATM mutant, and ~20% were CDK12 mutant.  In this population, the rPFS was significantly improved for the combination treatment versus placebo, with a hazard ratio [HR] of 0.45 (P<0.0001).  Notably, in subgroup analysis, there was a consistent improvement in rPFS with the combination therapy across all relevant subgroups (e.g., Gleason score, disease stage, prior treatment), but the benefit was most prominent for patients in the BRCA1/2 mutated group.

 

Bladder Cancer

 

The EV-103 trial was a phase 1b/2 long-term outcome study for patients treated with enfortumab-vedotin, an antibody-drug conjugate (ADC) type therapy, in combination with pembrolizumab, an immunotherapy treatment, for first line (1L) therapy in patients with locally advanced or metastatic urothelial carcinoma (la/mUPC) who were not candidates for cisplatin-based therapy (i.e., ‘cisplatin-ineligible’).  Among the 45 patients in the la/mUC study cohort, approximately one third had upper tract disease and most (84%) had visceral metastases.  The results showed an objective response rate (ORR) of 73.3% in a population of patients with mostly visceral metastases, and Dr Tian noted that ORRs such as this are not often seen in such a patient population.  She also noted the “promising” result of 41% of the patients being progression free at 24 months, and the median OS exceeding 2 years, at 26.1 months. She noted the primary adverse events associated with the combination, which included rashes, peripheral neuropathy, and pruritis, as well as hyperglycemia, which can necessitate holding the dose of enfortumab vedotin for patients at glucose levels over 250 mg/dL.

 

In the phase III THOR trial, erdafitinib, a fibroblast growth factor receptor (FGFR)-directed therapy was compared with chemotherapy in patients with advanced or metastatic UC who had FGFR gene alterations (FGFRalt).  The primary endpoint of the trial was overall survival, and between 66 and 74% of patients in the study had received two lines of prior therapy, either with chemotherapy alone or in combination with immunotherapy. The results showed a significant improvement in OS with erdafitinib versus the investigator’s choice of chemotherapy, with a median OS of 12.1 versus 7.8 months in the respective groups, and a relative reduction of 36% in the risk of death with erdafitinib versus chemotherapy (HR=0.64; P=0.005).  The relative risk of progression or death was also significantly improved by 42% with erdafitinib versus chemotherapy (HR=0.58; P=0.0002), with a median progression free survival (PFS) of 5.6 and 2.7 months, respectively.  ORR was also significantly improved, at 45.5% versus 11.5% in this highly refractory patient population (P<0.001).  Hyperphosphatemia, diarrhea, skin and nail disorders, as well as ophthalmologic conditions such as serous retinopathy were more commonly observed with erdafitinib treatment.  Owing to the efficacy of erdafitinib in this setting, Dr Tian emphasized that all patients with bladder cancer should undergo genomic testing to see if they are candidates for erdafitinib treatment.

 

Kidney Cancer

 

The Phase III CONTACT-03 study was conducted in patients with advanced or metastatic renal cell carcinoma (RCC) who had evidence of radiologic progression either during or after immune checkpoint inhibitor (ICI) therapy.  Patients in the trial were randomized to treatment with atezolizumab, an ICI, in combination with cabozantinib, a tyrosine kinase inhibitor (TKI) type therapy, or cabozantinib alone with the primary efficacy endpoints of PFS and OS.  Most of the patients in the trial (>77%) had “clear cell” type kidney cancer without sarcomatoid features, and a smaller proportion (~11%) had non clear cell disease.  The results of the trial were negative, with no significant difference between the groups in PFS (median PFS 10.6 vs. 10.8 months; P=0.784), and there was also no significant difference in OS (HR=0.94; P=0.690).  Results for response rate were also disappointing, with few complete responses, and an ORR of ~40% for patients treated in either arm.  Dr Zhang further noted the safety results which showed a higher incidence of grade 3/4 adverse events with the combination versus cabozantinib monotherapy, suggesting that cabozantinib monotherapy, the current standard of care, is adequate treatment and efficacy is not improved with the addition of an ICI type therapy.

 

The first of two additional trials in RCC which Dr Zhang reviewed was the CAN-I trial, a Phase II trial for non-clear cell kidney cancer which explored the triple regimen of cabozantinib with two immunotherapies, nivolumab and ipilimumab.  Results for the first 40 patients in the trial showed an ORR of ~18% with most of these responses occurring the patients with papillary-type disease as compared to patients with chromophore-type disease.  Disease control rate for this regimen (including partial response, and stable disease) was 76% overall.  With regard to toxicity of the regimen, she noted that hepatotoxicity limits the use of the triple regimen in this patient population and dose adjustments will be needed.  The second trial examined the use of another kinase inhibitor drug, Lenvatinib, in combination with the immunotherapy pembrolizumab in a Phase II, single cohort study of patients with non-clear cell RCC.  This study showed ORRs of 54% and 28% for the papillary and chromophore histologic subtypes, with some complete responses seen in the papillary group.

Quick Summary: ASCO 2023 Genitourinary Updates

Updates in Prostate Cancer:

  • PEACE-1 Trial: Radiotherapy improves outcomes when added to effective systemic therapy (abiraterone acetate) and current standard of care treatment in men with metastatic, castration-sensitive prostate cancer.

  • TALAPRO-2 Trial: Use of enzalutamide (antiandrogen) in combination with a PARP inhibitor (talazoparib) improves radiographic progression free survival in men with metastatic castration-resistant prostate cancer and homologous recombination repair (HRR) mutations.

 

Updates in Bladder Cancer:

  • EV-103 Trial: Enfortumab-vedotin, an antibody-drug conjugate, in combination with pembrolizumab immunotherapy shows promising efficacy in patients with locally advanced or metastatic urothelial carcinoma who are cisplatin-ineligible.

  • THOR Trial: Erdafitinib, a fibroblast growth factor receptor directed therapy, improves survival over chemotherapy in patients with advanced/metastatic urothelial carcinoma and FGFR gene alterations.

 

Updates in Kidney Cancer:

  • CONTACT-03 Trial: Atezolizumab, an immunotherapy, in combination with cabozantinib, a tyrosine kinase inhibitor, did not improve outcomes over cabozantinib alone in patients with advanced or metastatic renal cell carcinoma and progression either during or after immune checkpoint inhibitor therapy.

  • CAN-I Trial: Triple regimen of cabozantinib with two immunotherapies, nivolumab and ipilimumab, shows responses for selected histologic subtypes of renal cell carcinoma.

  • Lenvatinib + Pembrolizumab: Combination treatment shows responses for selected histologic subtypes of renal cell carcinoma.

Speaker Disclosure Information: Dr Zhang reports the following disclosures for this presentation: PI/research funding: Novartis, Merck, Regeneron, Mirati Therapeutics, Janssen, Astra Zeneca, Pfizer, Astellas, Eli Lilly, Tempus; Advisory Board: Merck, Exelixis, Sanofi-Aventis, Janssen, Astra Zeneca, Pfizer, Amgen, BMS, Pharmacyclics, SeaGen, QED Therapeutics, Eisai, Aveo, Eli Lilly, Bayer; Consultant: Pfizer, MJH Associates, Vaniam, Aptitude Health, PeerView, Aravive, Caris.

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