Highlights from the 2017 Genitourinary Cancer Symposium (ASCO-GU), Orlando, Florida, USA
Germ cell tumors
Unfortunately, one in five men with an advanced germ cell tumor who undergo primary chemotherapy for metastatic disease will experience a recurrence. In this situation, high-dose salvage chemotherapy is an option. A phase II study from Toulouse revealed interesting insights on carboplatin dosing in TI-CE high-dose therapy (paclitaxel 200 mg/m2 on day 1 plus ifosfamide 2 g/m2 on days 2–4, every 2 weeks, followed by carboplatin area under the curve (AUC) 24 mg.min/mL on days 1–3 plus etoposide 400 mg/m2 on days 1–3, every 3 weeks, in combination with stem cell reinfusion) . The objective was to optimize the dose of carboplatin and reach the AUC of 24 mg.min/mL carboplatin by therapeutic drug monitoring. The primary endpoint was complete response (CR) and a historic cohort served as the control group.
A total of 101 patients with a median age for 34 years were included between March 2009 and November 2015. Patients had two (26%) or more (15%) chemotherapy lines before inclusion, and about one-third had liver metastasis. Seventy-nine patients were eligible for data retrieval within this intention-to-treat population, and mainly gastrointestinal toxicity grade 3–4 (32%) was prevalent. One patient died due to sepsis. Optimizing the carboplatin dose, a CR was achieved in 35 of 79 patients (44.3%). Twenty-five percent reached tumor marker-negative partial remission. Median progression-free survival (PFS) was 12.3 months, with a reported medial overall survival (OS) of 33.9 months following a 51-month follow-up period. The authors conclude by recommending performing therapeutic drug monitoring to optimize the carboplatin dose in the treatment of advanced metastatic germ cell tumors.
Penile cancer is a rare disease with relatively sparse evidence with regards to novel treatment options for advanced metastatic disease. At this year’s ASCO-GU, the results of a one-arm, phase II study of dacomitinib, an irreversible pan-HER-tyrosine kinase inhibitor, in metastatic penile cancer were presented . Twenty-eight male patients with metastatic tumors, with a median age of 63.5 years, were treated with dacomitinib (45 mg/day) for a median of 2.2 months (range: 1.9–2.9 months). Response was observed in 32.1% of patients, with one patient (3.6%) achieving CR. Stable disease was observed in 46.4% of patients with 60.7% tumor shrinkage. OS for the whole group was 13.7 months, with a six-month rate of 82.4% and twelve-month rate of 54.9%. Treatment-associated adverse events were less than with standard chemotherapy. Interestingly, OS was better than historically-reported outcomes with combination chemotherapy. Preliminary data on molecular alterations linked to clinical benefit are being observed. Tissue samples from 23 patients were analyzed post dacomitinib treatment and, interestingly, telomerase reverse transcriptase (TERT) mutations (60%) were found only in responders. Mutations were found in 47% of non-responders compared to 25% of responders. HRAS and BRAF mutations were common in non-responders suggesting an association with eGFR resistance.
A breakthrough year for the treatment of metastatic renal cell carcinoma (mRCC), 2016 delivered major advances that will shape the scene over the coming years. Data from the CheckMate 025 trial , the first randomized trial examining immunotherapy for patients with mRCC, set the benchmark for OS in patients. Additionally, the METEOR trial  demonstrated cabozantinib, a new, multi-targeted tyrosine-kinase inhibitor, to be effective in improving OS and PFS.
While most studies were riding on the tidal wave of novel checkpoint inhibitors in renal malignancies, Dr. Choueiri from Boston (MA, USA) presented interesting data on the application of a potent MET inhibitor, savolitinib, in patients with advanced papillary renal cell carcinoma (PRCC) . Therapy-naïve and pre-treated patients with a relatively rare subtype of PRCC with good Eastern Cooperative Oncology Group performance status were treated with savolitinib (600 mg/day until progression). The primary endpoint was ORR, with PFS and duration of response as secondary endpoints. Out of 109 patients, eight had a partial remission, 43 had stable disease, and 48 had progressive disease. Interestingly, MET-positive patients had a median PFS of 6.2 months compared to 1.4 months in MET-negative patients.
According to data from the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry , active surveillance (AS) is considered to be a safe option in the intermediate term for carefully selected patients who present with small renal masses (SRMs) less than 4.0 cm in diameter. A prospective study, the DISSRM registry was opened in 2009 and included patients who had an SRM of no more than 4.0 cm in size and a clinical stage of T1a. Interestingly, patients in the registry chose for themselves whether to undergo AS or primary intervention following counseling. All patients in the AS group underwent axial imaging (computed tomography or magnetic resonance imaging) at enrollment, and follow-up imaging every six to 12 months was requested. Intervention was recommended upon evidence of progression, defined as a growth rate of more than 0.5 cm/year, a tumor diameter greater than 4.0 cm, or metastatic disease. A total of 615 patients were included in the analysis, approximately evenly split between primary intervention (298 patients, 48.5%) and AS (317 patients, 51.5%). The cancer-specific survival was very similar after 7 years: 100% with AS and 98.9% with primary intervention (P = 0.3). However, OS was significantly worse with AS than with primary intervention (62.8 vs. 85.1%, respectively; P = 0.001), which was likely biased by the older age and poorer health of patients in the AS group. In summary, the data presented underscores AS an option especially in elderly or comorbid patients who are willing to undergo axial imaging on a regular basis.
Based on published data, the American Society of Clinical Oncology Clinical Practice Guideline Endorsement includes recommendations on prostate-specific antigen (PSA) testing and other examinations, discussion of novel radiological and genomic testing, and recommendations on when to shift toward active therapy . Patients with a Gleason score less than or equal to six are candidates, as are, in some circumstances, patients with low-volume, intermediate-risk disease (Gleason score 3+4 = 7a).
In more advanced disease, Shipley et al.  presented the ten-year results from the RTOG9601 trial demonstrating the positive prognostic value of adding anti-androgen therapy (ATT) to radiation therapy (RT) in males with prostate cancer who require salvage RT following radical prostatectomy. In this placebo-controlled, phase III trial, males with higher pathologic Gleason scores, higher entry values of PSA failure, or positive surgical margins were most likely to benefit by the addition of peripheral androgen blockade (bicalutamide) to salvage RT. A total of 760 patients from the United States and Canada following radical prostatectomy who were treated in the trial from 1998 to 2003 were followed for a median of 13.0 years. At 10 years, 82% of patients randomly assigned to RT plus AAT were alive, compared to significantly fewer (78%) assigned to RT plus placebo, translating to a 23% reduced risk of death (hazard ratio: 0.77, 95% confidence interval: 0.59–0.99; P = 0.040). The number needed to treat to save one patient dying from prostate cancer was 12.
In localized bladder cancer, there is increasing discussion on patients’ quality of life with regards to urinary diversion following radical cystectomy (RC). A significant number of patients suffer from changes in their bowel habits and defecation following RC. Hupe and colleges  presented their cross-sectional study evaluating long-term bowel issues in a large cohort of patients with the help of an issue-tailored questionnaire. A total of 431 patients were evaluated following RC for symptoms such as diarrhea, constipation, urge to defecate, sensation of incomplete defecation, uncontrolled stool loss, and flatulence, and the impact on quality of life. A total of 324 patients were followed for 1 year or more, and 43% of these reported current bowel disorders, 40% reported life restriction, and 60% reported dissatisfaction. The most frequently reported bowel symptom was flatulence (49%), followed by diarrhea (30%) and the sensation of incomplete defecation (23%). Importantly, the observation that the highest prevalence rate of diarrhea is reported in 3 years after surgery mandates consulting patients on what side effects to expect.
The recent approval of checkpoint inhibitors for the treatment of metastatic urothelial carcinoma (mUC) has the potential to change the standard of care for advanced bladder cancer. New data from the IMvigor 210 trial for patients with mUC for whom prior treatment with platinum-based chemotherapy has failed, the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab yielded an overall response rate (ORR) of 26% and median OS of 11.4 months in patients, with the highest levels of PD-L1 expression on immune cells . All patients received 1,200 mg of atezolizumab intravenously every 3 weeks until loss of clinical benefit. Based on independent review according to RECIST (version 1.1) , the ORR reached 15% in the total cohort and the highest response rates were observed in patients with higher PD-L1 status. For example, ORRs reached 26%, 10%, and 8% in patients with IC2/3, IC1, and IC0 disease, respectively.
Taken together, this year’s ASCO-GU proceeds with the motion in finally including molecular factors aside important clinical variables into decision making of urologic malignancies.
- Chevreau C, Massard C, Flechon A, et al. Phase II trial of TI-CE high dose chemotherapy (HDCT) with drug monitoring for individual carboplatin dosing in patients with relapsed advanced germ cell tumors: A multicentric prospective GETUG trial. J Clin Oncol 2017;35(suppl 6S):abstract 401. Full-text link
- Raggi D, Necchi A, Giannatempo P, et al. Pan-HER tyrosine-kinase inhibitors (TKI) dacomitinib and afatinib in penile squamous cell carcinoma (PSCC): Results from an ongoing open-label, single-group, phase 2 trial of dacomitinib in chemonaive patients (pts). J Clin Oncol 2016;34(suppl 2S):abstract 483. Full-text link
- Choueiri TK, Plimack ER, Arkenau H-T, et al. A single-arm biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer (PRCC). J Clin Oncol 2017;35(suppl 6S):abstract 436. Full-text link
- Alam R, Patel HD, Riffon MF, et al. Intermediate-term outcomes from the DISSRM registry: A prospective analysis of active surveillance in patients with small renal masses. J Clin Oncol 2017. 35(suppl 6S):abstract 430. Full-text link
- Shipley WU, Pugh SL, Lukka HR, et al. NRG Oncology/RTOG 9601, a phase III trial in prostate cancer patients: Anti-androgen therapy (AAT) with bicalutamide during and after salvage radiation therapy (RT) following radical prostatectomy (RP) and an elevated PSA. J Clin Oncol 2016.34(suppl 2S):abstract 3. Full-text link
- Hupe MC, Vahlensieck W, Hennig MJ, et al. Cross-sectional evaluation of long-term bowel issues after radical cystectomy. J Clin Oncol 2017;35(suppl 6S):abstract 318. Full-text link
- Hoffman-Censits JH, Grivas P, Van Der Heijden MS, et al. IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC). J Clin Oncol 2016;34(suppl 2S):abstract 355. Full-text link
- Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803–1813. Full-text link
- Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016;17(7):917–927. Full-text link
- Resnick MJ, Lacchetti C, Bergman J, et al. Prostate cancer survivorship care guideline: American Society of Clinical Oncology Clinical Practice Guideline endorsement. J Clin Oncol 2015;33(9):1078–1085. Full-text-link
- Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228–247.