ORAL: Genitourinary Cancer—Prostate, Testicular, And Penile Cancer

This session discusses the management of genitourinary cancer through the findings of various studies.

Prostate Irradiation in Men with De Novo, Low-Volume and mCSPC: Results of PEACE-1 trial

Late-breaking results from the phase III of abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1) trial, a multicenter, open-label, randomized, phase 3 study with a 2 × 2 factorial design, evaluating prostate irradiation in men with de novo, low-volume, metastatic castrate-sensitive prostate cancer (mCSPC) was discussed. Landscape of the management of patients presenting with de Novo metastatic castration sensitive prostate cancer has been evolving very rapidly in the last 10 years. Ten years ago, we would propose ADT alone. Nowadays there are combinations of systemic therapy which have proven effective for those patients. In PEACE-1, the accrual time of PEACE-1 exactly matches this evolving landscape. PEACE-1 randomized some 1,200 patients from 2013 to 2018 with these characteristics in four arms in what is called a factorial two times two design. The co-primary endpoints for each question were rPFS and OS. The standard of care (SOC) was ADT alone or ADT plus docetaxel (Doce) at investigator’s discretion until 2017, then accrual was restricted to men receiving ADT+Doce. RT (74 Gy/37 fractions) was delivered after Doce completion when applicable. SOC included continuous ADT, with or without Doce at 75 mg/m² every 3 weeks for 6 cycles. AAP, 1000 mg/day with prednisone 10 mg/day was given to men randomized to the AAP arms until disease progression or intolerance. The median follow-up of this series is 73 months. From the study findings it was concluded that combining prostate radiotherapy with intensified systemic treatment (abiraterone +/- docetaxel) was associated with improved radiographic progression-free survival (Rpfs) and Castrate-resistant prostate cancer (CRPC) free-survivals in men with low volume, de novo mCSPC. With a median follow-up of 6.1 years, 303 Rpfs and 214 OS events were recorded for the low-volume population. When compared individually to SOC, rPFS was improved by SOC+AAP+RT (median 7.5 years (99.9%CI: 4.0-NR); HR=0.49, [0.28-0.87], p<0.0001) and borderline improved by SOC+AAP (median 4.4 years (95% CI: 2.5-7.6); HR=0.74, [0.44-1.26], p=0.066). To date, it does not appear that prostate radiotherapy improves overall survival (OS) in such men, albeit with minimal added toxicity. For OS the predefined threshold for a statistical interaction was not reached (p=0.11). OS was not improved by RT: median OS was 6.9 years (95.1%CI: 5.9-7.5) without RT vs 7.5 (6.0-NR) with RT (HR=0.97 [0.74-1.27], p=0.81). Median OS was 7.1 years in the SOC arm and not yet reached in the SOC+AAP+RT arm. Interestingly, it appears that the addition of radiotherapy in this setting is associated with improvements in the rates of serious genitourinary events, irrespective of the metastatic burden. Combining prostate radiotherapy with intensified systemic treatment, abiraterone with or without docetaxel, improves radiographic progression-free survival and castration-resistant prostate cancer free survival in men with low burden de novo metastatic castration-sensitive prostate cancer without a minimal added toxicity. There is no detectable impact on prostate radiotherapy on overall survival. PEACE-1 also establish a role for radiotherapy in the prevention of serious GU events. And this is irrespective of the metastatic burden of patients. a triplet of ADT, abiraterone, and prostate radiotherapy should be considered a standard of care in men with de novo low burden metastatic castration prostate cancer.

AI-Derived Digital Pathology Biomarker Predicts Benefit of Long-Term ADT with Radiotherapy in Localized High-Risk Prostate Cancer

Androgen deprivation therapy (ADT) improves survival and reduces risk of metastasis in men with high-risk localized prostate cancer (PC) receiving radiotherapy (RT). Predictive biomarkers are needed to guide ADT duration to maximize benefits and minimize risks. The current standard of care or at least a current standard of care for men with high-risk prostate cancer is radiation and long-term ADT concurrently and adjuvantly for two to three years. Current clinical and genomic tools have strong prognostic value for the identification of men at risk for distant metastases and death from prostate cancer, but lack predictive utility to guide the duration of ADT. And the hypothesized that AI tools using digital pathology could inform this clinical decision. The results of a pooled analysis of multiple phase III NRG/RTOG trials were presented, it aimed at developing and subsequently validating an AI-derived digital pathology-based biomarker to predict the benefit of long-term ADT addition to radiotherapy in men with localized, high-risk prostate cancer. ArteraAI long-term ADT predictive biomarker was trained on NRG/RTOG phase III studies across thousands of patients using digital pathology tools to machine-learn the AI algorithms important in predicting the benefits of distant metastases prediction with long-term ADT. The artificial intelligence (AI)-derived clinical and histopathological predictive biomarker was trained on RTOG 9408, 9413, 9902, 9910, and 0521 to predict differential benefit of LTADT on distant metastasis (DM). After the AI biomarker was locked, it was validated on RTOG 9202, which randomized men to RT + STADT (4 mo) vs LTADT (28 mo). The AI-derived biomarker was trained on 2,641 men (median follow-up of 9.8 years, IQR [8.2, 11.5]) and validated on 1,192 men from RTOG 9202 (median follow-up of 17.2 years, IQR [9.1, 19.6]), where 80% had at least one high/very high (H/VH) risk feature (cT3-4, Gleason 8-10, PSA > 20, or primary Gleason pattern 5). A significant biomarker-treatment interaction was observed (p = 0.04), in which AI-biomarker (+) men (n = 785, 66%) had reduced DM with LTADT (sHR 0.55, 95% CI 0.41-0.73, p < 0.001), but no benefit was observed (sHR 1.06, 95% CI 0.61-1.84, p = 0.84) for AI-biomarker (-) men (n = 407, 34%). The 10-year DM rate difference between RT + LTADT vs RT + STADT was 13% in AI-biomarker (+) men vs 2% in AI-biomarker (-) men. It was concluded that they have trained and validated the first predictive biomarker to guide ADT duration in locally advanced prostate cancer with validation in a completed phase III randomized trial of radiotherapy plus short- versus long-term ADT. The ArteraAI long-term ADT predictive model was successfully developed using prostate biopsy histopathology image data and standard clinical variables. Approximately 1/3 of men with high-risk prostate cancer could safely avoid long-term ADT based on similar rates of distant metastasis and death with distant metastasis outcomes with short-term ADT. Overall, AI-derived digital pathology biomarker predicts benefit of long-term ADT with radiotherapy in localized high-risk prostate cancer.

Prognostic Impact of PSA Nadir (N) ≥0.1 ng/mL Within 6 Months After Completion of Radiotherapy for Localized Prostate Cancer

Radiotherapy plus androgen deprivation therapy (ADT) is a standard of care in treatment of intermediate- and high-risk localized PCa. The results of an individual patient data meta-analysis of randomized trial from the (Intermediate Clinical Endpoints in Cancer of the Prostate) ICECaP collaboration was presented evaluating the prognostic impact of a PSA nadir ≥0.1 ng/mL within 6 months of completion of radiotherapy for localized prostate cancer. 10,415 pts from 16 RCTs were included: 2629 (25%) allocated to RT, 6033 (58%) to RT+stADT, and 1753 (17%) to RT+ltADT. Median follow-up was 10.1years (yrs). 2339 (98%), 4756 (84%) and 1258 (77%) of patients allocated to RT, RT+stADT and RT+ltADT respectively achieved a PSAn ≥0.1ng/mL within 6m after RT completion It was highlighted that this is the largest assessment of the impact of PSA 6 months after radiotherapy completion in patients receiving radiotherapy or radiotherapy plus ADT for localized prostate cancer. It was demonstrated that a 6-month PSA level ≥0.1 ng/ml was associated with significantly worse 5-year metastasis-free survival (MFS), 10-year overall survival (OS), and 10-year prostate cancer-specific mortality (PCSM), on univariable analysis, in all three treatment groups (radiotherapy alone, radiotherapy plus short-term ADT (3-6 months), and radiotherapy plus long-term ADT (24-36 months)). These results demonstrated that a 6-month PSA level ≥0.1 ng/ml following radiotherapy completion is strongly prognostic for MFS, PCSM, and OS in patients receiving radiotherapy either alone or in combination with ADT. These findings have important implications for trial design with patients having a PSA level ≥0.1 ng/ml potential candidates for treatment escalation, whereas those with a level <0.1 ng/ml may be candidates for treatment de-escalation.

Outcomes in mCSPC Patients Receiving Firstline Treatment Stratified by BRCA Status

Up to 30% of all advanced prostate cancer might present pathogenic alterations in DNA repair genes. Homologous recombination DNA repair is the most commonly altered in prostate cancer. Importantly, BRCA1 and 2 gene alterations, and maybe defects in other HR genes, could be really good predictors of PARP inhibitor benefit. CAPTURE study, which has three different cohorts. This is result of initial results of cohort one, which focused in metastatic CRPC. Cohort one was built from prospective well-annotated data from five different prospective cohorts within our PROCURE biomarker study network that has been running since 2013. The results of an analysis evaluating the association between presence of somatic/germline homologous recombination repair (HRR) gene alterations and outcomes in mCRPC patients receiving 1st line treatment, stratified by BRCA mutational status was presented. It was shown that both germline and somatic BRCA1/2 alterations are associated with shorter rPFS, progression-free survival 2 (PFS2) and OS in mCRPC patients treated with either an androgen receptor signaling inhibitor or taxanes in the first-line setting. BRCA1/2 alterations are associated with worse mCRPC outcomes compared to other HRR alterations. The poor outcomes were not related to a less frequent exposure to active mCRPC treatments. Exploratory analysis in the BRCA1/2 subgroup, although limited, suggested that no significant differences were observed in rPFS, PFS2, and OS between those treated with taxanes versus novel hormone therapies, germline versus somatic, bi-allelic versus mono-allelic, or BRCA2 versus BRCA1 mutations. These findings further support the importance of screening germline and somatic BRCA1/2 alterations for a more precise patient-centered approach.

Updated Results of TALAPRO-2 Phase 3 Study

Updated results of TALAPRO-2, which is a phase 3 randomized clinical trial evaluating talazoparib + enzalutamide versus placebo + enzalutamide as 1st line treatment for mCRPC patients harboring homologous recombination repair (HRR) gene alterations showed that talazoparib plus enzalutamide resulted in a statistically significant and clinically meaningful improvement in rPFS by blinded independent central review (BICR), compared to placebo plus enzalutamide. The rPFS benefit was greater for patients with BRCA alteration (HR: 0.20, 95% CI: 0.11 – 0.36, p <0.0001) compared to those with non-BRCA alterations (HR: 0.68, 95% CI: 0.46 – 1.02, p=0.06). Although OS data remains immature, there appears to be a favorable trend towards improved survival for patients with HRR gene alterations (HR: 0.69, 95% CI: 0.46 – 1.03, p=0.068). No new safety signals were identified, with treatment-emergent anemia the most common grade 3-4 TEAE. Time to definitive clinically meaningful deterioration in global health status/quality of life was significantly prolonged with talazoparib plus enzalutamide versus placebo plus enzalutamide. Talazoparib in combination with enzalutamide, if approved, has the potential to become a first-line treatment option for patients with mCRPC and HRR gene alterations.

LuPARP: Phase 1 Trial of 177Lu-PSMA-617 and Olaparib in Patients with mCRPC

The results of LuPARP, a phase 1 trial of 177Lu-PSMA-617 plus olaparib in mCRPC patients showed that 177Lu-PSMA-617 in combination with olaparib has a promising activity and was well-tolerated. In the overall cohort (i.e., Cohorts 1 to 9), the prostate-specific antigen (PSA)50 and PSA90 response rates were 66% and 44%, respectively. The objective response rate was 78%. No dose limiting toxicities were reported. Three patients had a treatment break due to a deep response.

Long Term Follow-up Analysis of Plasma miR371 Expression to Detect Early Relapse in Patients with Testicular Germ Cell Tumors

Long-term follow-up analysis of plasma miR371 expression to detect early relapse in patients with clinical stage I testicular germ cell tumors on surveillance was discussed. It was highlighted that miR371 has high specificity, negative and positive predictive values (NPV, PPV) in detecting germ cell tumor at an early stage with a follow-up longer than the expected median time of relapse. Sensitivity appears to be more dependent on tumor burden and histology than specificity and PPV. In the baseline post-orchiectomy false negative patients, miR371 became detectable during the follow-up prior to / or at the time of relapse with a median time of relapse anticipation of 3 months. More sensitive methodologies to detect extremely low circulating miR371 copies are under development and could improve the sensitivity of the test also in patients with subclinical tumor.

Molecular Drivers of Organotropism and Cisplatin Resistance in Germ Cell Tumors

Molecular drivers of organotropism and cisplatin resistance in germ cell tumors was discussed. It was highlighted that there are no molecular alterations associated with site of metastasis: KIT mutations are more prevalent in primary tumors and TP53 mutations more prevalent in metastases. No recurrent alterations were associated with platinum-resistance. In chemotherapy-naïve tumors, significantly lower platinum sensitivity scores were associated with platinum-resistant alterations. Limitations of this study include the small sample size and lack of clinical follow-up.

Primary RPLND in Seminoma Stage IIA-IIC ≤3cm: Combined Results of the SWENOTECA (Swedish Norwegian Testicular Cancer Group) and Cologne

Combined results of the SWENOTECA (Swedish Norwegian Testicular Cancer Group) and Cologne experience of primary retroperitoneal lymph node dissection (RPLND) in seminoma stage IIA-IIC ≤3 cm tumors was discussed. This study included 94 patients operated from May 2018 to November 2022, and the number of operations per site varied from 4 to 28. The median age of patients at the time of RPLND was 41.8 years (range 21-79) and median follow-up since RPLND was 21 months (range 4-61). Twenty-six patients (28%) were operated on with robotic laparoscopic technique. 10 patients (10.6%) had a Clavien-Dindo postoperative complication > 2, and 23 of the patients were given adjuvant oncological treatment after RPLND, most of them one course of BEP chemotherapy. The histology from RPLND showed seminoma in 83 patients, benign/necrosis in eight patients, vital non-seminomatous germ cell tumor in one patient, teratoma only in one patient, and lymphoma in one patient. The mean number of resected nodes was 19, and mean number of positive nodes was 1.5. The patients have been followed for a median 18 months (range 2-59), of which nine patients (9.6 %) have had recurrences, all but one in the first year after RPLND. Hence it was concluded that these early results of primary RPLND of seminomas IIA-IIB ≤ 3 cm are promising and can be performed at experienced centers. Longer follow-up is required to ensure this as a safe treatment option, but currently the risk of late morbidity and mortality is minimal.

Video No: S03. American Society of Clinical Oncology (ASCO) 2023 Conference, 2nd -6th June, Chicago

ORAL: Genitourinary Cancer—Kidney and Bladder

Efficacy and safety of atezolizumab plus cabozantinib vs cabozantinib alone after progression with prior immune checkpoint inhibitor treatment in metastatic renal cell carcinoma: Phase III CONTACT-03 study

Toni K Choueiri

ICIs represent a cornerstone of cancer therapy and inhibitors of PD-L-1 and PD-1 are approved across multiple cancer types. In mRCC, prospective evidence supports the use of VEGFR-TKIs, including cabozantinib, in patients previously treated with ICI-based regimens. An emerging practice in treatment of mRCC and other cancers is the rechallenge of PD-L-1 or PD-1 inhibitors after initial progression. To rigorously assess this practice, CONTACT-03 was conducted, a phase III study comparing the efficacy of atezolizumab plus cabozantinib vs cabozantinib alone in the post-ICI setting in patients with mRCC. Of 522 pts randomized to atezo + cabo (n=263) or cabo (n=259), 55% and 51% had most recent ICI in the 1L setting and 10% and 11% had sarcomatoid RCC, respectively. The addition of atezolizumab to cabozantinib did not result in improved clinical outcomes in patients with mRCC who progressed on or after prior ICI treatment. The subgroup analysis did not identify a subset of patients who may benefit from atezolizumab plus cabozantinib, No PFS or OS benefit was observed with atezo + cabo vs cabo. ORR was 41% in both arms; DOR was 12.7 (95% CI: 10.5, 17.4) mo with atezo + cabo and 14.8 (95% CI: 11.3, 20.0) mo with cabo. The increased toxicity was observed with the combination, although no specific safety signal was identified. These data highlight the importance of randomized, prospective assessment of re-challenge with checkpoint inhibitors in RCC and other tumor types.

Pembrolizumab plus axitinib versus Sunitinib as first line therapy for advanced clear cell renal cell carcinoma: 5-year analysis of KEYNOTE-426 

Brian I Rini

Pembrolizumab plus axitinib significantly improved the efficacy outcomes vs sunitinib for patients with untreated advanced clear cell RCC in the first interim analysis of the phase 3 KEYNOTE-426 study. A continued benefit was observed with pembrolizumab plus axitinib versus sunitinib. Of 861 enrolled patients (pts), 432 were assigned to pembro + axi and 429 to sun. Long term results after a median follow up of 67 months demonstrated improved OS, PFS and ORR by Pembrolizumab plus axitinib versus sunitinib for patients with previously untreated clear cell RCC. Efficacy for the ITT population and IMDC risk subgroups are shown in table. For pembro + axi vs sun, the 60-mo OS rates were 41.9% vs 37.1%, and the 60-mo PFS rates were 18.3% vs 7.3%. A substantial percentage of patients completed 35 cycles of pembrolizumab with good long-term outcomes. These data continued to support pembrolizumab plus axitinib as a standard of care for patients with previously untreated advanced clear cell RCC.

Final prespecified OS analysis of CLEAR: 4-year follow up of lenvatinib plus pembrolizumab versus Sunitinib in patients with advanced renal cell carcinoma

Thomas E Hutson

In the phase 3, open-label CLEAR study, the efficacy and safety of lenvatinib pluspembrolizumab and Len+Eve vs sunitinib was compared in patients with advanced clear cell RCC. Len+ Pembro significantly improved PFS, OS and ORR vs sunitinib. PFS benefit of L+P vs S was maintained (HR, 95% CI; 0.47, 0.38–0.57). PFS favored L+P vs S across MSKCC risk groups (HR, 95% CI; fav: 0.46, 0.32–0.67; int: 0.51, 0.40–0.65; poor: 0.18, 0.08–0.42). The final prespecified OS analysis of Len+ pembro vs sunitinib with a median follow up of 4 years was done. Len+ pembro continued to demonstrate clinically meaningful and durable benefit vs sunitinib in the first line treatment of patients with advanced RCC. No new safety signals were identified, adverse events were managed with dose modifications as necessary.

Combination therapies come of age in kidney cancer

David A Braun

CLEAR study showed that Len+ pembro continued to demonstrate clinically meaningful and durable benefit vs sunitinib in the first line treatment of patients with advanced RCC. KEYNOTE-426 supported pembrolizumab plus axitinib as a standard of care for patients with previously untreated advanced clear cell RCC. However, these updated results did not change the practice but they did re-affirm it for IMDC intermediate/poor risk and there is a need for additional investigation. CONTACT-03 was conducted comparing the efficacy of atezolizumab plus cabozantinib vs cabozantinib alone in the post-ICI setting in patients with mRCC. The addition of atezolizumab to cabozantinib did not result in improved clinical outcomes in patients with mRCC who progressed on or after prior ICI treatment. It changed the practice as Anti PD-L-1 should not be used after progression on prior PD-L-1 because of more toxicity and potential to compromise dosing of TKI. There should be more trial conducted to optimize the clinical outcomes and the novel targets should aim for cure.

Overall survival by response to first line induction treatment with atezolizumab+ platinum/gemcitabine vs placebo + plt/gem in patients with metastatic urothelial carcinoma: updated data from IMvigor130 OS final analysis

Enrique grande

The standard of care for first line treatment of mUC is platform-based chemotherapy and for patients without PD, maintenance CPI treatment is a new therapeutic option. IMvigor130 was a randomized phase 3 study that investigated the combination of atezolizumab and chemotherapy as first line treatment for mUC. The updated analysis of OS by response to induction plt/gem treatment with atezolizumab vs placebo based on the final OS analysis from IMvigor130 showed that initial responses did not seem to impact OS outcomes. Similar to prior exploratory analysis, cisplatin-treated patients appeared to derive a greater benefit with atezolizumab than did carboplatin-treated patients. OS improvements favoring Arm A vs C appeared greater for pts treated with cis than with carbo. In the cis subgroup, OS rates at 36 mo were 47% (Arm A) and 34% (Arm C) for pts who achieved at least SD during induction. For the patients without PD during induction, those with PD-L-1 IC2/3 tumors appeared to have greater OS benefit with atezolizumab than those with PD-L-1 IC0/1 tumors. A limitation of the data is the exploratory nature of this retrospective analysis and the sma; sample sizes in the subgroup analysis.

Erdafitinib versus erdafitinib plus cetrelimab for patients with metastatic urothelial carcinoma and fibroblast growth factor receptor alterations: final results from the phase 2 NORSE study

Arlene Siefker-Radtke

Erdafitinib is an oral selective pan-FGFR tyrosine kinase inhibitor granted accelerated approval to treat FGFR-altered advanced or mUC. In the final data from the NORSE study, both erdafitinib monotherapy and erdafitinibplus cetrelimab demonstrated clinically meaningful activity in patients with newly diagnosed mUC with FGFR alterations who were ineligible for cisplatin-based therapy. Median follow-up time was 14.2 months (mo). ORR for ERDA+CET was 54.5% with 6 (13.6%) CRs and 12 mo OS 68%. 11/24 responders were ongoing. ORR for ERDA was 44.2% with 1 CR and 12 mo OS 56%. 9/19 responders were ongoing. 4 pts in each arm were PD-L1 positive. 3/4 (75%) PD-L1 positive pts responded to ERDA+CET vs 0 for ERDA. The ORR and observed durable CRs in the erdafitinib + cetrelimab arm support further study of the combination. The safety profile was consistent with the known profile of these drugs, with no additive toxicity observed for the combination. These results support the use of erdafitinib in mUC with FGFR alterations.

Study EV-103 dose escalation/Cohort A: long term outcome of Enfortumab Vedotin + Pembrolizumab in first line cisplatin-ineligible locally advanced or metastatic urothelial carcinoma (la/mUC) with nearly 4 years of follow up

Shilpa Gupta

Despite gem-carbo as first line treatment for cisplatin-ineligible patients with Ia/mUC, significant need remains as Avelumab maintenance is only indicated in patients who do not progress after platinum-based chemotherapy and PD-1/L1 inhibitor monotherapy is indicated in only selected patients. Enfortumab Vedotin(EV) + Pembrolizumab(P) received US accelerated approval in cisplatin-ineligible patients based on data from EV-103 which demonstrated that this combination has rapid, durable responses and a manageable safety profile in patients with previously untreated Ia/mUC. After a median follow up of 47 months, updated results of EV-103 dose escalation cohort A showed that EV+P demonstrated clinically meaningful efficacy with a high confirmed ORR, durable responses and a median survival exceeding 2 years. The safety profile was manageable with no new safety concerns observed with 4 years follow up. The benefit of EV+P will be further assessed via the phase 3 EV-3-2 trial in a broader first line platinum-eligible patient population.

Potpourri of Options in First line Urothelial Cancer: Are we ready to select? 

Maria T Bourion

The diverse population, different drug options and biomarkers allowed combination therapy trials in the first line setting of mUC, however, cross-trials comparisons must be avoided. Chemotherapy plus immunotherapy in the first line is a failed strategy and Avelumab maintenance is the standard of care. NORSE reports on targeted therapy +/- immunotherapy in FGFRa with high single agent activity, not FDA approved and the follow up approach is unclear. EV+ pembrolizumab received FDA accelerated approval in cisplatin-ineligible patients and phase 1b/2 Cohort A with 4-year data showed low rate of progressive disease, however, we need to wait for Phase III data, toxicity and cost.

Video No: T05. American Society of Clinical Oncology (ASCO) 2023 Conference, 2nd-6th June, Chicago