Open here the Newsletter

The phase 3 study KEYNOTE-045 randomly assigned patients whose urothelial cancer had recurred or progressed after platinum-based chemotherapy, to either pembrolizumab (n=272) or the investigator’s choice of paclitaxel, docetaxel, or vinflunine chemotherapy (n=270).

Now the 22.5 months of follow-up data confirmed a significantly longer survival in patients with advanced urothelial cancer who receive the checkpoint inhibitor pembrolizumab after initial chemotherapy, compared to an alternative chemotherapy regimen. Pembrolizumab resulted in an approximately 3 month advantage in overall survival (OS compared to that of a second-line of chemotherapy (median 10.3 months vs. 7.4 months), with a further improvement in the hazard ratio [HR] from 0.73 to 0.70 (P = 0.0003) since the interim analysis.

The progression-free survival was not superior with pembrolizumab: median progression-free survival (PFS) was not significantly different (2.1 months for pembrolizumab vs 3.3; HR, 0.96; P = 0.32).

Quality of life (QOL), measured at week 15 and reported earlier this year, showed better results in the pembrolizumab arm.

Bernard Escudier, Institut Gustave Roussy, Villejuif, France presented the results of the phase III, randomised, open-label CheckMate-214 study evaluating the combination of nivolumab and ipilimumab compared to sunitinib in patients with previously untreated advanced or metastatic RCC.

Patients with measurable clear-cell metastatic RCC, Karnofsky performance score ≥70, and available tumour tissue were stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score and by region, and randomised to receive nivolumab and ipilimumab combination or VEGFR-inhibitor sunitinib.
The 550 patients in the combination arm were treated with nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab at 3 mg/kg every 2 weeks and 546 patients received sunitinib at 50 mg once daily for 4 weeks and 2 weeks off in 6-week cycles.

Co-primary endpoints of CheckMate-214 were ORR, PFS per independent committee and overall survival (OS) in the cohort of patients at intermediate or poor-risk. Efficacy was also evaluated according to IMDC risk group and baseline tumour PD-L1 expression.

Intermediate/poor risk patients
ORR in intermediate/poor risk patients was 41.6% for the nivolumab/ipilimumab combination compared to 26.5% for sunitinib (p < 0.0001) with 9.4% of patients receiving combination therapy achieving complete response (CR) compared to 1.2% of patients on sunitinib.
Median duration of response (DoR) was not reached (95% confidence interval [CI] 21.82, NR) versus 18.2 months with sunitinib (95% CI 14.82, NR).
Median PFS was 11.6 months for the nivolumab and ipilimumab combination versus 8.4 months with sunitinib, hazard ratio [HR] 0.82 (p = 0.03).

Favourable risk patients
In patients at favourable risk, both the ORR and PFS were higher with sunitinib over combination; in this cohort, ORR was 29% with nivolumab/ipilimumab versus 52% with sunitinib (p = 0.0002) and median PFS was 15.3 (95% CI 9.7, 20.3) months versus 25.1 (95% CI 20.9, NR) months, respectively, HR 2.17 (95% CI 1.46, 3.22; p < 0.0001).

In the overall composite of patients at any risk, no significant difference between treatments was demonstrated in ORR (p = 0.0191) or PFS (p = 0.819).

Any grade drug-related adverse events (AEs) occurred in 509 (93%) of patients in the nivolumab/ipilimumab cohort and in 521 (97%) of patients receiving sunitinib. With the combination, 54% of patients had a grade 3 to 4 AE, and with sunitinib 63% of patients had a grade 3 to 5 AE.

Discontinuation due to an AE was reported for 22% of combination patients and 12% of sunitinib patients. Of the 159 deaths that occurred in the combination cohort, seven (1%) were considered drug-related, whereas 4 (1%) of the 202 deaths occurring in the sunitinib cohort were considered drug related.

This is the first phase III trial investigating (combination) immunotherapy nivolumab plus ipilimumab versus (standard) sunitinib TKI as first-line treatment in mRCC. CheckMate-214 phase III trial support the use of combined nivolumab plus ipilimumab as a first-line treatment for patients with intermediate/poor risk mRCC, particularly those patients with tumour PD-L1 expression ≥1%. CheckMate-214 does not support the use of nivolumab/ipilimumab in good risk mRCC patients.

Karim Fizazi, Institut Gustave Roussy, Villejuif, France, presented the results of the LATITUDE Trial (Abstract LBA3).

Rationale
Despite androgen-deprivation therapy, the adrenal glands and prostate cancer cells continue making small amounts of androgens. Abiraterone inhibits production of testosterone throughout the body by blocking an enzyme that converts other hormones to testosterone. The U.S. Food and Drug Administration previously approved abiraterone for patients with metastatic prostate cancer that worsened despite androgen-deprivation therapy. Addition of abiraterone acetate (Zytiga) plus prednisone to standard hormonal therapy for men newly diagnosed with high-risk, metastatic prostate cancer lowers the chance of death by 38%.

About the study
LATITUDE is a multinational, randomized placebo-controlled phase III clinical trial of men with newly diagnosed, high-risk metastatic prostate cancer who had not previously received androgen-deprivation therapy. All patients had at least two of three risk factors: Gleason score of 8 or more, 3 or more bone metastases, or 3 or more visceral metastases.

The patients were randomly assigned to receive androgen-deprivation therapy plus abiraterone and prednisone or androgen-deprivation therapy plus placebo. Corticosteroid prednisone is routinely given with abiraterone to manage certain side effects of abiraterone, such as low potassium or high blood pressure.

Key Findings

Conclusion
In the phase III clinical trial LATITUDE of 1,200 men with newly diagnosed, high-risk metastatic prostate cancer who had not previously received androgen-deprivation therapy, abiraterone more than doubled the median time until the cancer worsened, from 14.8 months to 33 months.

Nick James, University of Birmingham, UK, presented the latest data at the 2017 ASCO Annual Meeting (Abstract LBA5003).

The STAMPEDE clinical trial of nearly 2,000 men shows that adding abiraterone acetate (Zytiga) to a standard initial treatment regimen for high-risk, advanced prostate cancer lowers the relative risk of death by 37%. The 3-year survival rate was 76% with standard therapy alone vs 83% with standard therapy plus abiraterone.

About the Study

STAMPEDE is an ongoing multiarm, multistage randomized clinical trial conducted in the United Kingdom and Switzerland. The current analysis compared standard therapy with standard therapy plus abiraterone in men with high-risk prostate cancer who were starting androgen-deprivation therapy. The men had either locally advanced or metastatic cancer, and all were commencing long-term standard androgen-deprivation therapy for the first time. The standard therapy consisted of androgen-deprivation therapy for at least 2 years; men with locally advanced cancer (48% of all patients) could also receive radiation therapy in addition to androgen-deprivation therapy. A novel approach to the clinical trial design meant this comparison recruited patients much more quickly than most academic-led trials, and STAMPEDE will report randomized data from at least 10 comparisons over 2 decades.

Key Findings

• At a median follow-up of 40 months, 262 deaths had occurred in the standard therapy group and 184 deaths had occurred in the abiraterone group.
• The 3-year overall survival rate was 83% in the abiraterone group vs 76% in the standard therapy group.
• Abiraterone lowered the relative chance of treatment failure (measured by worsening scans or symptoms, or elevated prostate-specific antigen level) by 71% compared with standard therapy. The effects were consistent across the different subgroups of people enrolled in the trial.

Overall, side effects were similar between the two groups. Severe side effects were more common in the abiraterone group, occurring in 41% of patients compared with 29% of patients in the standard therapy group. The main side effects occurring more frequently with abiraterone were cardiovascular problems such as high blood pressure; there were also more liver problems with abiraterone. There were two treatment-related deaths in the abiraterone group and one in the standard therapy group.

Location:             Room Madrid, North Hall (Level 1)

Date:                    Saturday, 25^th March

Time:                    11:30 – 11:55 am

Title:                     Circulating tumour cells in prostate cancer: A marker?  )

Speaker :              Susanne Osanto

We cordially invite you to attend this session.

During the EAU 2017 in London, there is a scheduled EUOG meeting on Sunday, from 13.00 – 14.00 pm. We will launch the URANUS study (UTUC). If you are interested in attending this meeting, please send an email to EUOG@lumc.nl for more information or registering.