1. Pachynski, Russell K. MD

Article Content

The 2016 ASCO Annual Meeting brought several exciting updates with regards to the management of genitourinary (GU) malignancies. While key data and recent FDA approvals for atezolizumab, cabozantinib, and nivolumab in GU tumors had previously been announced, there were a number of important updates as well as other studies presented at this year's meeting.

genitourinary malign... - Click to enlarge in new windowgenitourinary malignancies. genitourinary malignancies

Prostate Cancer

On the radiation front in prostate cancer, the results of the OCOG/TROG PROFIT (Prostate Fractionated Irradiation Trial) study (Abstract 5003) were shown.


This is the third non-inferiority trial (RTOG 0415, CHHiP trials being the other two) to show that a hypofractionation schedule is non-inferior to conventional fractionation radiation. Here, men with intermediate risk prostate cancer were randomized to a hypofractionated course (60Gy in 20 fractions over 4 weeks) versus conventional course (78Gy in 39 fractions over 8 weeks). The primary endpoint was biochemical-clinical failure (BCF).


With a median follow up of 6 years, the BCF event rate at 5 years in both arms was 21 percent, with a hazard ratio of 0.96-supporting non-inferiority of clinical outcomes. Importantly, late (>6 months) toxicity favored the hypofractionation schedule. This trial now solidly supports a shortened course of radiotherapy as a standard of care option for men with low to intermediate prostate cancer, with no impact on efficacy and a trend toward improved tolerability.


In the adjuvant setting, results from the Scandinavian Prostate Cancer Group 12 trial were presented (Abstract 5001). Here, post-prostatectomy men with high-risk features (i.e., pT2 with a positive margin of GS 4+3 or higher, pT3b >GS 3+4, any lymph node positive disease with >GS 3+4) were randomized to receive adjuvant docetaxel (75 mg/m2 x 6 cycles) or surveillance.


With a median follow-up of almost 5 years, there was no overall difference (p=0.078) in the primary endpoint of biochemical disease free survival (BDFS; PSA >0.5 ng/mL). However, on Kaplan-Meier analysis, the chemotherapy group curve crossed over the surveillance one at an early time point, then remained parallel-suggesting a negative impact of chemotherapy on disease progression. Additionally, there were twice as many deaths in the chemotherapy group compared to surveillance. This suggests there may be an adverse impact of docetaxel on the disease at an early time point post-prostatectomy, and does not support the use of adjuvant chemotherapy in this setting.


This is an interesting departure from other trials (i.e., STAMPEDE, CHAARTED, GETUG-15) in the advanced disease setting showing a benefit of earlier chemotherapy, and further studies are warranted to investigate this prior to any routine use in practice.


Bladder Cancer

In the non-prostate realm, updated data was presented for atezolizumab in bladder cancer. Efficacy results from the IMvigor 210 trial (Abstract 4515) showed continued, late responses in several patients with a median of now 17.5 months of follow-up.


Overall, 71 percent of responses were ongoing, with 86 percent of complete responses ongoing. Impressively, there were five patients with an initial partial response who later converted to complete responses, as well as two patients converting to partial responses from stable disease. In this cohort, there was correlation seen between PD-L1 staining and median overall survival, with an almost doubling in the PD-L1 "2/3" vs "0/1" staining groups.


In the cisplatin-ineligible arm of this trial with a follow-up of 14.4 months, complete response rates of 6-8 percent were seen across all PD-L1 subgroups, including those with "negative" staining (ie <1% by IHC). The majority of these (75%) were ongoing, with a median overall survival in this cohort of 14.8 months, which compares favorably to frontline carboplatin-based chemotherapy in these patients. Favorable safety and tolerability of atezolizumab in all patients was again shown as well.


These studies continue to support the establishment of atezolizumab as the new standard of care in second-line metastatic bladder cancer. Outcomes of the ongoing IMvigor211 phase III study comparing atezolizumab to chemotherapy (NCT02302807) in this setting are eagerly anticipated.


Renal Cell Carcinoma

Updates from two recently approved drugs for renal cell carcinoma (RCC) were presented.


First, a key secondary endpoint from the METEOR trial comparing cabozantinib and everolimus was reported. Cabozantinib was recently FDA-approved for second line treatment of metastatic RCC (mRCC) on the basis of improvement in PFS. At the meeting, updated overall survival results were shown (Abstract 4506). In the trial, patients were randomized to receive either cabozantinib 60 mg or everolimus 10 mg once daily.


At almost 30 months of follow-up, median overall survival for cabozantinib was 21.4 months compared to 16.5 months for the everolimus group. Importantly, the beneficial impact of cabozantinib on survival crossed all risk groups, and included patients with both bone only and bone + visceral metastases as well. The choice of prior TKI had no impact on cabozantinib survival outcomes, also supporting the broad benefit of this agent to patients with mRCC.


Lastly, intriguing clinical outcomes from RCC patients treated on the CheckMate 025 trial, comparing nivolumab to everolimus, were presented (Abstract 4509). In this trial, previously treated advanced or metastatic RCC patients were randomized to receive nivolumab 3 mg/kg IV every 2 weeks or everolimus 10 mg PO daily.


Patients were treated beyond first progression by RECIST 1.1 if they were found to have a "clinical benefit" and acceptable side-effect profile by the investigators. Of the 140 patients treated beyond progression with >=4 weeks of nivolumab, 14 percent were found to have >=30 percent tumor burden reduction compared with time of first progression.


The median overall survival for the entire group treated beyond progression was 28.1 months, compared to 15.0 months in those patients not treated beyond progression. While encouraging given the sometimes delayed/late responses seen with immunotherapies, these data should be interpreted with caution due to selection bias introduced by the investigators during the trial. However, such encouraging results certainly warrant additional trials to assess optimal treatment strategies with nivolumab.


RUSSELL K. PACHYNSKI, MD, is an Assistant Professor in the Department of Medicine, Washington University School of Medicine, St. Louis, Mo.

Russell K. Pachynski... - Click to enlarge in new windowRussell K. Pachynski, MD. Russell K. Pachynski, MD