Background

Loss-of-function alterations in HRR genes are associated with response to PARP inhibition. PROfound (NCT02987543) is a randomized, open-label, Phase III trial evaluating efficacy and safety of olaparib (ola) vs enzalutamide (enza) or abiraterone (abi) in patients (pts) with mCRPC with alterations in any of 15 predefined genes with a direct or indirect role in HRR whose disease had progressed on prior new hormonal agent (NHA) therapy.

Methods

Qualifying tumor tissue HRR alterations were centrally and prospectively identified using an investigational next-generation sequencing test (Foundation Medicine, Inc). Cohort A included pts with alterations in BRCA1, BRCA2 or ATM; Cohort B pts with any 1 of 12 other HRR alterations (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L). Pts were randomized (2:1) to ola (300 mg bid) or physician’s choice (pcNHA) of enza (160 mg/d) or abi (1000 mg/d + prednisone 5 mg bid). Primary endpoint was radiographic progression-free survival (rPFS) in Cohort A, assessed by blinded independent central review (BICR) and analyzed via stratified log-rank test. Crossover to ola was allowed after BICR progression.

Results

4425 men were screened; 245 randomized to Cohort A, 142 to Cohort B (65.6% had prior taxane). Efficacy is shown in the table. Most common adverse events (AEs) were anemia (46.5 v 15.4%), nausea (41.4 v 19.2%), decreased appetite (30.1 v 17.7%) and fatigue/asthenia (41.0 v 32.3%) for ola vs pcNHA; 18.0 and 8.5% of pts, respectively, discontinued due to AE.

Table: LBA8 Efficacy summary*

Conclusions

In pts with mCRPC and HRR alterations with prior NHA treatment, ola improved rPFS and ORR vs pcNHA, with a favorable trend for OS despite crossover. Safety was generally consistent with the known profile of ola. PROfound is the first positive Phase III biomarker-selected study evaluating a targeted treatment in pts with mCRPC.

Clinical trial identification

NCT02987543.

Editorial acknowledgement

Sarah Bulman, PhD, from Mudskipper Business Ltd, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD).

Legal entity responsible for the study

AstraZeneca and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.

Funding

AstraZeneca and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.

Disclosure

M. Hussain: Honoraria (self), Lectures: Sanofi/Genzyme (women in Pca); Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Lectures: Genentech; Honoraria (self), Lectures: Research to Practice; Honoraria (self), Lectures: Aptitude Health; Honoraria (self), Lectures: Epics (covering 2019 GU ASCO; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer. J. Mateo: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Sanofi. K. Fizazi: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AAA; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Curevac; Honoraria (self), Advisory / Consultancy: Essa; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Orion; Honoraria (self), Advisory / Consultancy: Sanofi. F. Saad: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas. N. Shore: Advisory / Consultancy, Research grant / Funding (self): Amgen; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): BMS; Advisory / Consultancy, Research grant / Funding (self): Dendreon; Advisory / Consultancy, Research grant / Funding (self): Ferring; Advisory / Consultancy, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Merck & Co.; Advisory / Consultancy, Research grant / Funding (self): MDx Health; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Sanofi; Advisory / Consultancy, Research grant / Funding (self): Tolmar. K. Chi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. O. Sartor: Advisory / Consultancy: Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Inc., Constellation, Dendreon, EMD Serono, Endocyte, Hinova, Johnson & Johnson, Myovant, Pfizer, Progenics, Sanofi; Research grant / Funding (institution): AstraZeneca, Bayer, Constellation, Dendreon, Endocyte, Innocrin, Invitae, Johnson & Johnson, Merck, Progenics, Roche, Sanofi, Sotio; Officer / Board of Directors, Co-chairman of GU Committee: NRG; Advisory / Consultancy, Consultant on Board of Scientific Counsellors: NCI; Speaker Bureau / Expert testimony: Sanofi; Non-remunerated activity/ies, Data safety monitoring: AstraZeneca, J&J, Pfizer, Myovant. N. Agarwal: Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Argos; Advisory / Consultancy: BMS; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Ely Lilly; Advisory / Consultancy: Foundation One; Advisory / Consultancy: Genentech; Advisory / Consultancy: Janssen; Advisory / Consultancy: Merck; Advisory / Consultancy: Medivation; Advisory / Consultancy: Novartis; Advisory / Consultancy: Nektar; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Pharmacyclics; Research grant / Funding (institution): AstraZeneca, Bavarian Nordic, BMS, Calithera, Celldex, Eisai, Exelixis, Genentech, GSK, Immunomedics, Janssen, Medivation, Merck, New link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Sanofi Takeda, Tracon, Bayer, Clovis, EMD Serono, Ely Lilly, Janssen. D. Olmos: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Speaker Bureau / Expert testimony: Sanofi-Aventis; Research grant / Funding (institution): Medivation/Pfizer; Research grant / Funding (institution): Tokai; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Genentech; Officer / Board of Directors, Directors Board Committee member: EORTC; Non-remunerated activity/ies: BioOncoTech & Tokai. A. Thiery-Vuillemin: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy: Astellas Pharma. P. Twardowski: Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: BMS. N. Mehra: Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi. C. Goessl: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Kang: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Burgents: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. W. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Kohlmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C. Adelman: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. de Bono: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: GSK; Licensing / Royalties, X Rewards to Inventors with royalties paid to institution, no personal income, and a patent PARP inhibitors and DNA repair defects with royalties paid to institution, no personal income: Abiraterone; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Genmab; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Orion Pharma; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Qiagen; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Taiho Pharma; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Vertex.

Background

PARACHUTE, a phase IV, prospective, observational study of treatment patterns and outcomes planned to describe the clinical effectiveness and safety of pazopanib in patients (pts) with advanced or mRCC who are naïve to VEGF-TKI therapy in the real-life setting from Asia Pacific, North Africa, and the Middle East countries where data from the registration trials are lacking.

Methods

Eligible pts were ≥18 years with advanced or mRCC and clinical decision to initiate pazopanib treatment or had already started new treatment with pazopanib within 15 days prior to study entry and naïve to any prior anti-VEGF therapy. Primary endpoint was the proportion of patients remaining progression free at 12 months (mo). The secondary endpoints were ORR, PFS, safety and tolerability, and relative dose intensity (RDI).

Results

Between Jun 2017 and Dec 2018, 200 pts were enrolled from 15 countries in Asia, North Africa and Middle East. A total of 101 pts with a median age of 62 y (range, 32.0-95.0) were included in this interim analysis. Majority of the pts were Asian (63%) followed by Caucasian (36%). Clear cell was the main (82%) histologic type. At data cut-off (May 2, 2019) of 12 mo observation period, 29 pts completed the observational period and 72 discontinued the study. Only 57% of pts had the starting dose at 800mg. Median RDI was 79% with 52% pts received under <85%. 25 of 92 evaluable pts (27%) remained progression-free and median PFS was 4 mo (95% CI, 3.02-6.54). The best overall response per RECIST 1.1 is CR (2%), PR (18%) and SD (41%). 74% pts experienced ≥1 treatment related adverse event (TRAE) and 11% of pts discontinued due to TRAE. Most frequent (>10%) TRAEs include diarrhoea (27%), palmar-plantar erythrodysaesthesia syndrome (12%) and hypertension (15%).

Conclusions

The interim results of the PARACHUTE study support the use of pazopanib in pts with advanced or mRCC who are naïve to VEGF-TKI therapy. Safety profile is consistent with the previously reported pivotal and realworld evidence studies. The efficacy data are still immature due to limited number of pts and the short follow-up duration.

Editorial acknowledgement

Anuradha Bandaru, Novartis Healthcare Pvt Ltd (Hyderabad, India).

Legal entity responsible for the study

Novartis.

Funding

Has not received any funding.

Disclosure

R. Kanesvaran: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer, Novartis, MSD, BMS, Ipsen, Eisai, J&J, Astellas, Amgen, Mundipharma, Sanofi, Roche, AZ. P. Danchaivijitr: Advisory / Consultancy: MSD and Pfizer. B. Karabulut: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Serono, Bayer, Pfizer, Novartis, MSD, BMS, J&J, Astellas, Amgen, Sanofi, Roche. Y.F. Wong: Advisory / Consultancy: Merck and Roche. K. Slimane: Full / Part-time employment: Novartis. M. Erman: Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer, Novartis, BMS, Astellas, Roche, AstraZeneca, Boehringer Ingelheim, Nobel, Gen Pharma, MSD, Pierre Fabre, Amgen, Takeda, Mustafa Nevzat Pharma, Teva.

Background

While decreased renal function is a well-known risk factor of kidney cancer (KC), association of proteinuria with KC is unclear. In this large cohort study, we evaluated the risk of KC according to glomerular filtration rate (GFR) and dipstick proteinuria, as well as the joint effects between the two.

Methods

A total of 9,809,366 participants who participated in the nationwide health screening program in 2009 and did not have history of any cancer were included. The impact of GFR, dipstick proteinuria, and interactive associations of the two factors on the development of KC were analyzed.

Results

During the median follow-up of 7.3 years, 10,634 participants developed KC (overall incidence rate: 14.9 per 100,000 person-years). Subjects with low GFR (<60 mL/min/1.73 m2) had a higher incidence of KC (adjusted hazard ratio [aHR] 1.26, 95% CI 1.18-1.34) than those with a high GFR (≥ 60). When GFR of 60-90 was considered the reference group, KC risk was higher in low GFR groups: GFR <30 (aHR 1.21) and GFR 30-60 group (aHR 1.27), while there was no decreased risk in higher GFR groups (GFR >90 or ≥ 120). A clear dose-response relationship was also found with the degree of dipstick proteinuria; compared to the no proteinuria group, even the trace group had an elevated risk of KC (aHR 1.20) and the risk increased more than double in the 4+ proteinuria group (aHR 2.15). Analyses of joint effects of GFR and dipstick proteinuria showed that in the no proteinuria group, the increased incidence of KC was less evident with decreasing GFR, whereas in the proteinuria group, there was marked increase in KC incidence along with decreasing GFR. The association between smoking and KC was more evident in low GFR groups (GFR <30 and GFR 30-60) (P-interaction <0.001), while there were no interactions between smoking and proteinuria. Clinically significant association was not found between body mass index and GFR/proteinuria.

Conclusions

Low GFR and proteinuria were associated with future KC development, possibly in synergistic manner. Smoking had a more profound effect when GFR was lower. Further research is warranted to develop strategies to reduce cancer risk in the chronic kidney disease population.

Legal entity responsible for the study

The authors.

Funding

a creative research program grant from Samsung Medical Center.

Disclosure

All authors have declared no conflicts of interest.

Background

Since smoking has a causal relationship not just with oncological outcomes but also with aggravating the general health conditions of upper tract urothelial carcinoma (UTUC) survivors, our specific aim is to introduce an individualized risk-based surveillance regimen which interacts with smoking status.

Methods

We identified 714 non-metastatic UTUC patients who underwent radical nephroureterectomy (RNU). The patients were stratified by pathologic stage, chronological age, and smoking status. The risks of UTUC death and non-UTUC death were estimated by using parametric models for time-to failure with Weibull distributions.

Results

The hazard rate (HR) of non-UTUC death overtime gradually increased in all age groups regardless of the smoking status, whereas that of UTUC-related death markedly decreased according to the pT stage and was affected by the smoking status. Among current smokers, the baseline HR of UTUC-related death in pT3/4 was higher than that of pT ≤ 2, and remained high even ten years after RNU. Among heavy smokers, the HR of UTUC-related death in all pT stages increased at baseline, and maintained the risks even the survival period increased after RNU. We simulated specific time points when the risk of non-UTUC death was greater than that of UTUC-related death. We further simulated age-specific, stage-specific, and smoking status specific time points when the risk of non-UTUC death exceeds the risk of UTUC-related death. Specifically, among heavy smoker patients aged >80, non-UTUC related death risk exceeded the risk of UTUC related death at 1 year after RNU for ≤pT1, at 2 years for pT2, at 7 years for pT3, and at 9 years for pT4.

Conclusions

The Weibull model revealed that accumulative smoking exposure would strongly affect over time the risk elevation and prolongation of UTUC related death more than elevating over time the risk of non-UTUC death. Therefore, for UTUC heavy smokers with advanced pT stages, more than 5 years of surveillance duration is recommended, even for patients who are over 80 years old.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Post-transplant malignancy (PTM) has been well established complication of kidney transplantation, but the reported data was mainly from Caucasian population. This study was conducted to determine the incidence and mortality rate of PTM in Praram 9 Hospital.

Methods

We retrospectively retrieved medical data of 858 patients who underwent kidney transplantation at our center over the past 27 years.

Results

There were 57 of 858 (6.6%) patients developed malignancy. The most common site of PTM was genitourinary tract cancer (26 of 57, 45.6%), of which transitional cell carcinoma (TCC) was represented in the highest range (20/26, 79.2%), followed by renal cell carcinoma (RCC, 4/26) and prostate cancer (2/26). The second and third most common PTM were hepatocellular carcinoma (HCC, 9 of 57, 15.5%) and colon cancer (5 of 57, 8.6%), respectively. Lung cancer, post transplantation lymphoproliferative disease were also found (n = 4, each). Other malignancies were as followed: skin cancer (3), breast cancer (3), pancreatic cancer (1), thyroid cancer (1), parotid gland cancer (1) and gastrointestinal stromal tumor (1). The overall mortality rate of PTM was 64.91%. Among 20 patients with TCC, up to 8 patients died from this cancer (mortality rate 40%). Albeit, the mortality rate was zero in skin cancer and RCC of both native and transplanted kidney.

Conclusions

Transitional cell carcinoma was not only the most common PTM in contrast to the Caucasian data, but it also caused the high mortality rate among Thai kidney transplant patients. Our study suggests that a more aggressive surveillance for TCC is required in both pre and post kidney transplant recipients for the early detection and treatment of this cancer. This surveillance should be expanded to the other Asian population in other countries.

Legal entity responsible for the study

Suthanit Laowalert.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.