TM - CARE™ Education€¦ · TM. PERSPECTIVES. ESMO 2018. GENITOURINARY FACULTY . The content...

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E U R O P E A N S O C I E T Y F O R M E D I C A L O N C O L O G Y

M U N I C H , G E R M A N Y - O C T O B E R 1 9 - 2 3 , 2 0 1 8

A F O C U S O N G E N I T O U R I N A R Y C A N C E R S

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CA R E T M P E R S P E C T I V E S

E S M O 2 0 1 8

G E N I T O U R I N A R Y

F A C U L T Y

The content that follows is written in the language in which it was presented. The tables included have been drawn from the respective

ESMO 2018 abstracts. Background information and CARE™ Perspectives are provided following select ESMO 2018 abstracts.

I am pleased to provide background and perspectives on major clinical trials in prostate cancer (SPARTAN, LATITUDE, STAMPEDE and PROSPER); renal cell carcinoma (RCC) – emphasis on use of predictive biomarkers and emerging targeted therapies; and urothelial carcinoma (UC).

Dr. Sebastien HotteMcMaster University Hamilton, ON

C A R E ™ P E R S P E C T I V E S

TM

ESMO 2018 A Focus on Genitourinary Cancers

Background and commentary provided by the CARE™ Genitourinary Faculty

This CARE™ Perspectives Conference Report has been developed with Dr. Sebastien Hotte, CARE™ Genitourinary (GU) Faculty. This GU-focused report provides a summary of compelling stories and news presented at ESMO 2018 (Munich, Germany), framed in a Canadian perspective.

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PROSTATE CANCER MAJOR CLINICAL TRIALS IN PROSTATE CANCER

ENCOURAGING NOVEL AGENTS IN METASTATIC PROSTATE CANCER

RENAL CELL CARCINOMA THE USE OF PREDICTIVE BIOMARKERS IN RENAL CELL CARCINOMA MANAGEMENT

EMERGING TARGETED THERAPIES IN ADVANCED RENAL CELL CARCINOMA

UROTHELIAL CARCINOMA KEY ABSTRACTS ON UROTHELIAL CARCINOMA

1.

2.

3.

— 01

— 10

— 15

— 02

— 05

— 11

— 12

— 16

GENITOURINARY CANCERS

TABLE OF CONTENTS

01. PROSTATE CANCER

PERSPECTIVES ON ESMO 201801

Updates on SPARTAN, LATITUDE, STAMPEDE and PROSPER trials.

Data on emerging therapies in nmCRPC.

Major Clinical Trials in Prostate Cancer

Encouraging Novel Agents in Metastatic Prostate Cancer

MAJOR CLINICAL TRIALS IN PROSTATE CANCER

0201 - PROSTATE CANCER

ESMO 2018. 804P. Health-Related Quality of Life (HRQoL) After Progressive Disease (PD) in SPARTAN: a Phase 3 Trial of Apalutamide (APA) Versus Placebo (PBO) in Men with Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC) E. J. Small

Results Table. Group mean PRO scores after PD from 341 pts and 60 pts after Sx PD.

Conclusions: Relative to PBO, pts treated with APA had a longer MFS, with no decline in HRQoL through the time of Mets, and similar HRQoL after Mets. Sx PD was delayed with APA vs PBO and was associated with a decline in HRQoL in both groups. Thus, HRQoL decline for pts treated with APA was delayed because of a longer time to Sx PD.

a Includes pts with and without subsequent approved treatment for metastatic CRPC. SE, standard error.

SPARTAN

APA PBO

Baseline

Before Mets

After Metsa Baseline

Before Mets

After Metsa

All pts, n 797 772 157 396 384 184

Group mean (SE) FACT-P

117.2 (0.7)

117.4 (0.7)

112.5 (1.9)

116.6 (1.0)

116.6 (1.0)

114.5 (1.6)

Group mean (SE) FACT-G

84.1 (0.4)

83.9 (0.5)

80.7 (1.3)

83.4 (0.7)

83.2 (0.7)

81.8 (1.1)

APA PBO

Baseline

Before SX PD

After SX PDa

Baseline Before Sx PD

After Sx

PDa

Sx PD subgroup, n

64 64 30 63 63 30

Group mean (SE) FACT-P

115.2 (2.5)

117.0 (2.4)

108.6 (3.7)

117.8 (2.0)

114.5 (2.2)

105.6 (4.3)

Group mean (SE) FACT-G

84.4 (1.9)

84.2 (1.7)

78.6 (2.9)

85.2 (1.5)

82.6 (1.7)

75.3 (3.4)

Background: APA is a next-generation androgen receptor (AR) inhibitor recently approved by Health Canada and virtually identical to the results with ENZA, is associated with prolonged MFS and QoL maintenance (ASCO 2018). In addition to improved MFS and QoL, SPARTAN has shown APA to prolong PFS and reduce the risk of symptomatic progression (Sx PD) (Abstract 161, ASCO GUCS 2018). Moreover, Dr. Smith and colleagues have reported that APA decreased risk of metastasis independent of where metastasis first appeared and confirmed that MFS is significantly associated with OS and is a predictor of OS in high-risk nmCRPC (Abstract 5032 & 5033, ASCO 2018).

CARE™ PERSPECTIVE OF ABSTRACTS 804P AND 806P:

• 804P reported that APA could delay the tim2e to Sx PD, resulting in a delayed decline of HRQoL.

• 806P reported an APA dose of 240 mg/day proved to be efficacious for the majority of patients tested, and no significant differences in MFS were observed between those who received APA and those who received PBO.

• Of note, APA is also being explored in metastatic hormone sensitive prostate cancer (mHSPC) in the LACOG 0415 trial.

• Either APA or ENZA therapy in men with m0 CRPC and a rapid PSA doubling time (10 months or less) is likely to significantly improve disease control.

• Therapies being used earlier in disease course will affect later treatment sequencing.

• Abstracts 804P and 806P from ESMO 2018 reported new results from SPARTAN.

The following abstracts cover updates on major clinical trials in metastatic and non-metastatic prostate cancer (mPC/nmPC), including the SPARTAN, LATITUDE, STAMPEDE and PROSPER studies, supported by background and CARE™ Faculty Perspectives.

Additional SPARTAN abstract of interest:

Conclusions: 240 mg/d APA provided efficacious drug exposure for the majority of pts, including those who required dose reductions/interruptions due to AEs. The MFS benefit was similar across the range of APA exposure. Dose reductions/interruptions due to AEs did not reduce the efficacy of APA.

ESMO 2018. 806P. Relationship Between Apalutamide (APA) Exposure and Metastasis-Free Survival (MFS) in Patients (pts) With Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC) From SPARTAN

M. R. Smith

Background: LATITUDE demonstrated similar survival benefits to STAMPEDE and CHAARTED with the addition of abiraterone acetate and prednisone (AAP) to docetaxel. LATITUDE also showed that AAP delayed the need for subsequent therapy, emphasizing the importance of early referral after progression to maximize the use of available treatments.

ESMO 2018. LBA5_PR. Radiotherapy (RT) to the primary tumour for men with newly-diagnosed metastatic prostate cancer (PCa): Survival results from STAMPEDE (NCT00268476)

C. C. Parker

Results: 2061 men with newly-diagnosed M1 PCa were randomised Jan 2013 - Sep 2016. Randomised groups were well balanced: median age 68 yr; median PSA 97ng/ml; 18% early docetaxel; metastatic burden: 40% lower, 54% higher, 6% unknown. Prostate RT improved FFS (HR=0.76, 95%CI 0.68, 0.84) but not overall survival (HR = 0.92, 95%CI 0.80, 1.06). Subgroup analysis showed improved overall survival for prostate RT in 819 men with lower metastatic burden (HR=0.68, 95%CI 0.52, 0.90) but not in 1120 men with higher metastatic burden (HR = 1.07, 95%CI 0.90, 1.28). RT was well-tolerated during (5% Grd3-4 SOC+ RT) & after treatment (Grd3-4 <1% SOC, 4% SOC+RT). Conclusions: Radiotherapy to the prostate did not improve survival for unselected patients with newly-diagnosed metastatic prostate cancer, but, in a pre-planned analysis, did improve survival in men with a lower metastatic burden. Therefore, prostate radiotherapy should be a standard treatment option for men with oligometastatic disease. Background: There is interest in oligometastatic disease. (Limited systemic metastatic tumours for which local ablative therapy could be curative). (H. Kaneda. Oligometastases: Defined by prognosis and evaluated by cure. Elservier. Vol 3, 2015, p1-6. https://doi.org/10.1016/j.ctrc.2015.01.001.)

LATITUDE / STAMPEDE LATITUDE / STAMPEDE CONTINUED

Results: 901 of 990 eligible M1 pts were evaluable. Median age 67yr, median PSA 96ng/ml, median follow up 42mth. 473 pts were high risk & 428 low risk according to LATITUDE criteria. AAP treated pts had clinically & statistically significant OS improvements in both high (HR: 0.54, 95% CI [0.41-0.70]; p<0.001) & low (HR: 0.66, 95% CI [0.44-0.98]; p=0.041) risk groups. Pts receiving AAP also benefited from prolonged FFS within both high (HR: 0.31, 95% CI [0.25-0.39]; p<0.001) & low risk groups (HR: 0.238, 95% CI [0.17-0.33]; p<0.001). No evidence of heterogeneity between risk groups was found in OS or FFS (interaction p-value, p=0.385 & p=0.294 respectively). Further analyses incorporating the alternative CHAARTED volume definition was done with similar outcomes.

Conclusions: Men with primary mHSPC treated with AAP plus ADT had a significant increase in OS & FFS compared to those receiving ADT alone, irrespective of risk/volume sub-classification. These results show AAP treatment benefit across all mHSPC pts, irrespective of M1 risk/volume sub-stratification using conventional imaging.

CARE™ PERSPECTIVE OF LBA4:

• Late-Breaking Abstract 4 (LBA4) evaluated the heterogeneity of AAP’s effect on OS and failure-free-survival (FFS) in those with metastatic vs. nonmetastatic disease treated with AAP + ADT or ADT.

• In those newly diagnosed with mHSPC, LATITUDE results support the use of AAP in the high-risk population.

• STAMPEDE showed improved outcomes in both metastatic and nonmetastatic HSCP patients.

• Results presented in LBA4 showed improved OS and FFS in men treated with AAP + ADT compared to ADT independent of risk/volume (although the absolute magnitude of OS improvement was less in men with low volume/risk disease).

• These results support the use of AAP in all mHSCP patients.

ESMO 2018. LBA4. Effects of Abiraterone Acetate plus Prednisone/Prednisolone in High and Low Risk Metastatic Hormone Sensitive Prostate Cancer

A. P. Hoyle

CARE™ PERSPECTIVE OF ABSTRACT LBA5_PR:

• This large randomized trial suggests that men with low metastatic burden may benefit from RT to the primary disease.


THIS PHASE II DATA SUGGESTS CAB FIRST

COULD BE BET TER THAN ABI/ENZA FIRST FOR THIS

CHALLENGING PATIENT GROUP


ESMO 2018. 805P. A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic (M0) castration-resistant prostate cancer (CRPC): results of PROSPER by age and region

K. Fizazi

Results: 1401 men were enrolled with a median age of 74 y (standard deviation, 7.8 y). Baseline characteristics were generally similar across regions and age groups. Baseline use of bone-targeting agents was higher in North America compared with the other 2 regions. A greater proportion of pts aged ≥ 75 y had and ECOG PS of 1 than pts aged < 75 y. In all men, ENZA reduced the risk of metastasis or death by 71% (HR, 0.29; 95% CI, 0.24-0.35; P < 0.0001). The risk reduction with ENZA use was similar across all subgroups. Safety results were generally similar among all subgroups, except that more pts in the group aged ≥ 75 y reported adverse event as the primary reason for discontinuation (13% with ENZA vs 10% with PBO) than in the overall pt population (9% with ENZA vs 6% with PBO), and more pts in North America reported falls (15%) than in Europe (7%) or rest of world (10%). Conclusions: In men with M0 CRPC and rapidly rising PSA, ENZA treatment resulted in a clinically meaningful and statistically significant reduction of developing metastases or death. Results were consistent across subgroups of pts by age and geographic region.

Background: The PROSPER trial previously reported ENZA’s strong ability to prolong time to metastasis in patients with CRPC. PROSPER trial results have demonstrated a three year improvement metastasis-free survival (MFS) and maintained or improved quality of life (QoL) in men with nmCRPC treated with ENZA. This nmCRPC population is at a high-risk of developing mCRPC. PROSPER data is supported by results from the PREVAIL and STRIVE trials (ASCO GUCS 2018).

PROSPER

CARE™ PERSPECTIVE OF ABSTRACT 805P:

• Abstract 805P from ESMO 2018 analyzed the results from PROSPER in terms of age and region, showing positive and similar results for treatment with ENZA across subgroups.

• ENZA has been approved by the FDA and Canadian regulatory bodies are currently reviewing.

• This therapy will likely soon be available in Canada as a treatment option for nmCRPC.

“

”PAG E : 05

ENCOURAGING NOVEL AGENTS IN METASTATIC PROSTATE CANCER

ESMO 2018. 792O. A randomized phase II study of cabazitaxel (CAB) vs (ABI) abiraterone or (ENZ) enzalutamide in poor prognosis metastatic castration-resistant prostate cancer (mCRPC) K. N. Chi

Results Table. Summarized outcomes of 95 patients randomized to CAB or ABI/ENZ. Clinical benefit rate (CBR), OR, SD, PSA progression (TTPP), time to progression (TTP), and OS results are presented below.

Conclusions: Treatment with CAB vs ABI/ENZA resulted in similar outcomes. There was a trend in favour of CAB for survival. Genomic correlations will be presented.

Background: Men with poor prognostic features have been thought to be more refractory to current therapies, especially ARATs. CAB is a taxane chemotherapy commonly prescribed for mCRPC in Canada that may be efficacious in earlier settings (ASCO GUCS 2018; informed by the TROPIC trial and others).

CARE™ PERSPECTIVE OF ABSTRACT 792O:

• Results on the phase II study of patients with a poor prognosis:

• CAB and ABI/ENZA had similar outcomes but CAB trended towards stronger OS. Of note, men on OZM-054 could cross over to the other therapy upon progression with first agent.

• This phase II data suggests CAB first could be better than ABI/ENZA first for this challenging patient group (with poor prognostic features).

• More studies on patient biomarkers could inform physicians on which groups could benefit most from CAB versus anti-AR therapy, and eventually lead to a more efficacious use of CAB and other therapies (predictive biomarker guided therapy).

Arm A (CAB) Arm B (ABI/ENZ) HR (95% CI) P

CBR (%) 82 86 0.16

PSA50 (%) 56 60 0.68

OR (%) 11 12 >0.90

SD>12 weeks (%) 62 46 0.15

Median TTPP (m) 7.4 4.8 0.73 (0.42 - 1.29) 0.28

Median TTP (m) 5.3 4.1 0.86 (.53 - 1.40) 0.56

Median OS (m) NR 15.5 0.56 (0.25 - 1.22) 0.14

This section focuses on data presented on emerging therapies treating metastatic castration-resistant prostate cancer (mCRPC), augmented with CARE™ Faculty Perspectives.


ESMO 2018. 812P. Post hoc responder analysis of health-related quality of life (HRQL) in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel in the phase III PROSELICA and FIRSTANA trials

A. T. Vuillemin

Results: In PROSELICA, 57.2% and 59.4% of pts receiving C20 and C25 had FACT-P TS improvements; in FIRSTANA, 63.5%, 62.3% and 57.7% of pts receiving C20, C25 and D75 had FACT-P TS improvements. In FACT-P responders, FACT-P TS improvements occurred as early as Cycle (C) 1 (mean change from baseline: PROSELICA C20 10.4, n = 264; C25 10.6, n = 266; FIRSTANA C20 11.7, n = 206; C25 11.7, n = 202; D75 9.0, n = 195); these were largely maintained. For pts with a pain response in PROSELICA, FACT-P TS improvements occurred as early as C1 (C20 6.8, n = 71; C25 11.1, n = 81) and were maintained until C8 (C20 10.6, n = 43; C25 9.6, n = 44). In FIRSTANA, FACT-P TS improvements in pts with a pain response were seen as early as C1 or C2 (C1: C20 15.5, n = 41; C25 12.5, n = 41; D75, 7.9, n = 32) and maintained until C9 (C20 9.0, n = 27; C25 10.5, n = 26; D75 16.4, n = 20). In pts with a tumor or PSA response, HRQL was maintained for all treatment arms in both studies. Additional results for clinical responder subgroups and FACT-P subscales will be presented.

CARE™ PERSPECTIVE ON ABSTRACT 812P:

• Current findings (results from FIRSTANA) support the use of docetaxel/prednisone before CAB (ASCO 2018).

• For men who go on to receive CAB, this post hoc study suggests improved and maintained HRQL after receiving CAB.

Background: Previously, the PROSELICA trial looked at the non-inferiority of 20 mg/m2 CAB (C20) versus 25 mg/m2 CAB (C25) in patients with mCRPC post-docetaxel and the FIRSTANA trial looked at the superiority of C20 and C25 over 75 mg/m2 docetaxel in chemo-naïve patients with mCRPC. Quality of life was poorly reported in these original trials.

CARE™ TREATMENT CONSIDERATIONS FOR LOCALIZED AND ADVANCED PROSTATE CANCER

Members of the CARE™ Genitourinary Faculty initially developed an algorithm for the management of

mCRPC in 2014. Since its initial creation, the CARE™ Prostate Cancer Treatment Algorithm has gone through

multiple updates by leading KOLs and has been further augmented by CARE™ Working Group discussions.

The Prostate Cancer Algorithm was updated at ESMO 2017 and ASCO GUCS 2018 before being expanded to

include localized (pre-metastatic) treatment considerations at ASCO 2018. What follows is the current version

of the CARE™ Treatment Considerations for Localized and Advanced Prostate Cancer.

Conclusions: More than half of the pts experienced HRQL improvements, which were maintained. Pts with a pain response experienced HRQL improvements.


See supplementary pages that follow.

CARETM LOCALIZED PROSTATE CANCER ALGORITHM

LOW RISK

INTERMEDIATE RISK

HIGH RISK

PSA

GLEASON SCORE

CLINICAL STAGE (DRE)

LOWDEFINED AS:

TREATMENT OPTIONS:

INTERMEDIATE HIGH

<10 >2010-20

< 6 7 8, 9, 10

T1a - T2b T2c T3, T4

PSA, Gleason score, and digital rectal exam should be taken into context with other patient factors to guide treatment decision (ie: age, performance status, comorbidities, symptoms, and patient preference)

A consideration - patients with localized prostate cancer (PC) should be assessed both by a radiation oncologist and a urologist.

• Brachy

• Possibility in younger patients • External beam RT (EBRT) or branchytherepy (branchy)

• Possibility in older patients

• Brachyboost +/- short course ADT (4-6 months)

• Possibility for Gleason score of 3-4

nmCSPC

nmCRPC

mHSPC

Rarely - ex lost during treatment

Suggested therapy options and approach to follow

These generalized approaches benefit from reference to provincial cancer guidelines

* For treatment option, refer to Advanced Prostate Cancer

Algorithm on next page

National Comprehensive Cancer Network (NCCN) guidelines for PC stratify localized disease into 5 categories: Very low, low risk, intermediate risk, high risk and very high risk.

Active surveillance

Active surveillance

ADT alone Radiation alone

Cryotherapy (Cryo)

Cryotherapy (Cryo)

Radical prostatectomy (RP)



Radiotherapy (RT)

Radiotherapy (RT)

Radiotherapy (RT) +/- ADT • Palliative Intent • Palliative Intent • +/- adjuvent EBRT (for high risk

pathologic features) or salvage EBRT (for biochemical failure)

• EBRT (+/- brachyboost) + long course ADT (minimum 18 months)

WITH PSA FAILURE /PROGRESSION:

*

• Prefered option for Gleason score of 6

CARE™ Prostate Cancer Treatment Algorithms

CARETM Faculty have produced Prostate Cancer Treatment Algorithms for both localized and advanced disease. First produced in 2016, they have been updated at ASCO GU 2018 and are included as a supplement to the CARETM at ESMO 2018 Report.

• Dr. Alan So (VGH)

• Dr. Ricardo Rendon (QEII)

Participating CARETM GU Faculty include:

• Dr. Sebastien Hotte (Juravinski)

• Dr. Sandeep Sehdev (TOH)

Observation Intermittent ADT Continuous ADT

1

• Dr. Denis Soulières (CHUM)

• Dr. Anil Kapoor (McMaster University)

• Dr. Brita Danielson (U of A)


SUPPLEMENTARY CARETM CONTENT TO ESMO 2018 REPORT

High Intensity Focused Ultrasound (HIFU)

High Intensity Focused Ultrasound (HIFU)

‡

‡

‡ Limited evidence for use of this modality

CARETM ADVANCED PROSTATE CANCER ALGORITHM

mHSPC

Androgen Deprivation Therapy (ADT) + Docetaxel (DT)

ADT + Abiraterone acetate + prednisone (AA+P)

ADT Alone

ADT + AA+P or Enzalutamide (ENZ) or Cabazitaxel (CT)

• Decision rationale for choosing the various therapy options (include clinical support) • Best supportive care (palliative care)

• Enrollment in new clinical trials

DT Consider switching to

CT if intolerant

AA+P or ENZ ADT Alone

• Monitoring required every 2-3 months for disease progression• Change treatment regimen if there is any sign of progression

• Refer to Medical Oncologist at any sign of progression• Disease progression has occurred if 2 of 3 of the following are true:

PSA increase, clinical progression or radiographic progression

• Monitoring required every 1-2 months • Change treatment regimen if there is any sign of progression

• Consider best supportive care (palliative care)• Consider use of Denosumab (or other osteoprotective therapy) for prevention/treatment of bone metastases

LOW-VOLUME DISEASEADT continued at all times

mCNPC and mCSPC

mCRPC

AA+P or ENZ or CT or Radium 223

CT or Radium 223 DT or Radium 223

AA+P or ENZ

Patients with mHSPC - strongly consider referral to med-onc.

These generalized approaches benefit from reference to provincial cancer guidelines

HIGH-VOLUME OR HIGH-RISK DISEASE

• >3 Bone Metastases • Gleason Score ≥ 8• Visceral Metastases

Referral to Medical Oncologist strongly recommended

CHAARTED definition: Visceral disease or ≥ 4 bone lesions with ≥ 1 bone lesions beyond the vertebral bodies or pelvis.LATITUDE definition: 2 or more of the following:

0801 - PROSTATE CANCER - SUPPLEMENTARY CARETM CONTENT

DT Consider switching to

CT if intolerant

• Abiraterone and enzalutamide have shown benefit in docetaxel-naïve and post-docetaxel patients. 3

• Among patients who initially have a response to enzalutamide or abiraterone, virtually all eventually acquire secondary resistance, reducing the activity of subsequent AR targeted agents. Efficacy of taxanes appears to be independent of this resistance and should be considered.

• When chemotherapeutic agents are being considered, docetaxel/prednisone should currently be offered before cabazitaxel. The FIRSTANA Trial supports the use of this sequence. 4

• For patients with bone metastases, radium-223 offers a survival benefit.

• Palliative care should be offered early to all patients.

1. PROGRESSIONAdvanced PC prognosis is associated with a number of factors: performance status, presence of visceral metastases, presence of bone pain, extent of disease on bone scan, serum lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) levels. The CUA recommends that “PSA should not be used as the sole criteria for progression, and assessment of response should incorporate clinical and radiographic progression”. 2

Following first-line treatment, patients with metastatic disease need to be more vigorously monitored.

Members of the CARETM Genitourinary Faculty recommend the following for patients with mHSPC, mCNPC and mCSPC:

• Patients be assessed every 2-3 months:• with clinical assessment, PSA, CBC and metabolic panel (including LFTs and alkaline phosphatase). • note: assesment for treatment toxicty needs to occur more frequently (every 3-6 months).

• Imaging is recommended to be completed every 6 months based on this statement, including:• a bone scan and chest, abdomen and pelvis CT (in some Canadian regions imaging is encouraged every 3 months).

When any of the following 2 out of 3 have occurred, current line of treatment can no longer be considered effective. Next line of treatment should be initiated with patient referral considered.

1. Rising PSA 2. Radiologic progression 3. Clinical deterioration

2. SEQUENCINGSequencing decisions are critical to optimizing overall survival in advanced prostate cancer. There is little guidance on treatment sequencing. Current research findings suggest:

EVERY 1-2 MONTHS:CLINICAL ASSESSMENT PSA

EVERY 3-6 MONTHS:IMAGING:

BONE & CHEST SCAN, ABDOMEN AND PELVIS CT

CARETM RECOMMENDATIONS FOR MONITORING mCRPC PROGRESSION WITH PATIENT ASSESSMENTS:

REFERENCES

1. B. Shayegan et al. Development of a Management Algorithm for Prostate Cancer Patients with a Biochemical Recurrence after Radical Therapy. CUA Online 2018, Abstract #MP-1.4.

2. Fred Saad, Kim Chi, Antonio Finelli, Sebastien Hotte, Jonathan Izawa, Anil Kapoor, Wassim Kassouf, Andrew Loblaw, Scott North, Ricardo Rendon, Alan So, Nawaid Usmani, Eric Vigneault, Neil Fleshner. The 2015 CUA-CUOG Guidelines for the management of castration-resistant prostate cancer. 3-4, s.l. : Can Urol Assoc J, April 2015, Vol. 9. https://www. cua.org/themes/web/assets/files/guidelines/en/cua-cuog-guidelines.pdf.

3. Beer TM, Armstrong AJ, Sternberg, CN, et al. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study. Genitourinary Cancers Symposium. Presented January 30, 2014. Abstract LBA1.

4. Oudard, S et al. Cabazitaxel Versus Docetaxel As First-Line Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer: A Randomized Phase III Trial- FIRSTANADailyMed. ZYTIGA(abiraterone acetate) tablet [Janssen Biotech, Inc.]. J Clin Oncol. 2017 Jul 28:JCO2016721068. doi: 10.1200/JCO.2016.72.1068.DailyMed. [Online] Janssen Biotech, Inc.

5. D. Khalaf et al. Phase 2 randomized cross-over trial of abiraterone + prednisone (ABI+P) vs enzalutamide (ENZ) for patients (pts) with metastatic castration resistant prostate cancer (mCPRC): Results for 2nd-line therapy. Journal of Clinical Oncology, 36, 2018 (Supplement Abstract #5015).

6. K. Chi et al. Subsequent treatment after abiraterone acetate + prednisone (AA + P) in patients (pts) with newly diagnosed high-risk metastatic castration-naïve prostate cancer (NDx-HR mCNPC): Detailed analyses from the phase 3 LATITUDE trial. Journal of Clinical Oncology, 36, 2018 (Supplement Abstract #5028).

CARETM MANAGEMENT CONSIDERATIONS – ADVANCED PROSTATE CANCER

CBC METABOLIC PANEL

To View the Full CARETM Prostate Cancer Algorithm on Localized and Advanced Disease, visit:

www.CAREeducation.com/page-gu/


02. RENAL CELL CARCINOMA

Two LBAs on using predictive biomarkers in mRCC.

Updates on ATLAS, JAVELIN, KEYNOTE-427 and CheckMate 214 trials.

The Use of Predictive Biomarkers in Renal Cell Carcinoma Management

Emerging Targeted Therapies in Advanced Renal Cell Carcinoma

1002 - RENAL CELL CARCINOMA

Conclusions: Our data support use of Cabo in a PD-L1 unselected population and possibly in combination with checkpoint blockers irrespective of PD-L1 status.

Background: PD-L1 status is becoming an increasingly used biomarker in mRCC, and PD-L1 expression on tumour cells has previously been shown to predict for improved outcomes in patients receiving nivolumab + ipilimumab treatment.


• Data from METEOR and CABOSUN trials suggest cabozantinib is a treatment option for both first- and second-line. This analysis shows greater PFS, OS and ORR than everolimus (METEOR)and sunitinib (CABOSUN), irrespective of PD-L1 status.

• METEOR and CABOSUN results suggest cabozantinib be used in the PD-L1 unselected population.

• Further studies are being conducted to investigate cabozantinib in combination with checkpoint inhibitors.

THE USE OF PREDICTIVE BIOMARKERS IN RENAL CELL CARCINOMA MANAGEMENT

ESMO 2018. LBA31. Molecular correlates dif ferentiate response to atezolizumab (atezo) + bevacizumab (bev) vs sunitinib (sun): results from a Phase III study (IMmotion151) in untreated metastatic renal cell carcinoma (mRCC)

B. I. Rini

Results: IMmotion151 met its co-primary endpoint, demonstrating improved PFS with atezo + bev vs sun in PD-L1+ pts (HR, 0.74 [95% CI: 0.57-0.96]; P = 0.02) across MSKCC groups. PFS was also improved in pts with sarcomatoid histology (HR, 0.56 [95% CI: 0.38-0.83]). High Teff GE was associated with PD-L1 expression by IHC and longer PFS in atezo + bev vs sun pts (HR, 0.76 [95% CI: 0.59-0.99]). High Angio GE was associated with improved PFS in the sun arm (HR, 0.59 [95% CI: 0.47-0.75]) but did not differentiate clinical activity between atezo + bev vs sun (HR, 0.95 [95% CI: 0.75-1.19]). Atezo + bev improved PFS vs sun in the low Angio subset (HR, 0.68 [95% CI: 0.52-0.89]). Angio GE was higher (P=4.28e-06) in favourable vs intermediate/poor MSKCC risk groups. PD-L1+ prevalence was higher (63% vs 39%) and Angio GE was lower (P=4.73e-16) in sarcomatoid vs non-sarcomatoid tumours.

Conclusions: These prospectively tested biomarker results validate molecular signatures that differentiate clinical outcomes with VEGF inhibition and immunotherapy in 1L mRCC. Moreover, these data identify tumour genomic profiles associated with prognostic risk groups and sarcomatoid histology. Findings from this study further our understanding of the biology of kidney cancer and inform future strategies to enable personalized therapy in mRCC pts.

Background: In previous phase II and III studies, atezo and bev showed better PFS than sun (IMmotion150).


• Late-Breaking Abstract 31 demonstrated that the presence or absence of certain biomarkers can affect outcomes.

• By identifying genomic profiles and better understanding renal cell biology, therapies can continue to become more personalized and therefore more efficacious in this patient population.

ESMO 2018. LBA34. PD-L1 status and clinical outcomes to cabozantinib, sunitinib and everolimus in patients with metastatic clear-cell RCC treated on CABOSUN and METEOR clinical trials

T. K. Choueiri

Results: Table. Treatment comparison on PFS by PD-L1 expression from METEOR and CABOSUN clinical trials.

METEOR CABOSUN

TC PD-L1 Expression

Median, mos (95% CI)

HR (95%CI)

Median, mos (95% CI)

HR (95%CI)

<1%

Cabo (n=112): 8.5 (7.2 - 13.5) 0.46

(0.32 - 0.66)

Cabo (n=52): 11.0 (6.8 - 15.6) 0.47

(0.26 - 0.86)

Everolimus (n=106):

4.1 (3.7 - 6)

Sunitinib (n=33) 5.0

(3-12.9)

>=1%

Cabo (n=38): 5.6 (4.5 - 7.4) 0.66

(0.40 - 1.11)

Cabo (n=9): 8.4 (1.1 - 16.6) 0.46

(0.18 - 1.21)

Everolimus (n=50):

3.7 (2 - 5.3)

Sunitinib (n=16) 3.1 (1.6 - 10.1)

This section presents two Late-Breaking Abstracts that emphasize the importance of predictive biomarkers in managing metastatic renal cell carcinoma (mRCC).


Pts with PD-L1+ tumors A + Ax (N=270) S (N=290)

PFS per BICR (primary endpoint) Median (95% CI), mo

Statified hazard ratio (95% CI); 1-sided p value

13.8 (11.1, not estimable) 7.2 (5.7, 9.7)

0.61 (0.475, 0.790); p < .0001

Confirmed objective response rate per BICR Objective response rate (95% CI), %

Stratified odds ratio (95% CI); 1-sided p value

55.2 (49.0, 61.2) 25.5 (20.6, 30.9)

3.732 (2.532, 5.371); p < .0001

Pts irrespective of PD-L1 expression A + Ax (N=442) S (N=444)

Pts per BICRMedian (95% CI), mo

Stratified hazard ratio (95% CI); 1-sided p value

13.8 (11.1, not estimable) 8.4 (6.9, 11.1)

0.69 (0.563, 0.840); p < .0001

Confirmed objective response rate per BICRObjective repsonse rate (95% CI); %

Stratified odds ratio (95% CI); 1-sided p value

51.4 (46.6, 56.1) 25.7 (21.7, 30.0)

3.098 (2.300, 4.148); p <.0001

ESMO 2018. LBA6_PR. JAVELIN Renal 101: a randomized, phase 3 study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC)

R. J. Motzer

Results Table. PFS per BICR, stratified hazard ratio and stratified odds ratio of 886 patients who were randomized to receive A + Ax or S. Results of patients with PD-L1+ tumours and irrespective of PD-L1 expression.

Conclusion: This randomized phase 3 trial met its primary objective of significantly improving PFS in pts with PD-L1+ aRCC treated with A + Ax vs S. PFS and OR benefit was also observed in pts irrespective of PD-L1 expression and across all prognostic risk groups. The safety profiles were consistent with those of prior studies of each drug. These results support A + Ax as a potential new 1L standard-of-care for pts with aRCC.

EMERGING TARGETED THERAPIES IN ADVANCED RENAL CELL CARCINOMA

METEOR AND CABOSUN RESULTS SUGGEST CABOZANTINIB BE USED IN THE PD - L1 UNSELEC TED

POPUL ATION .

“”

The following Abstracts cover upcoming therapies in advanced RCC, specifically on the ATLAS, JAVELIN, KEYNOTE-427 and CheckMate 214 trials, supported by background information and CARE™ Faculty Perspectives.

1201 - RENAL CELL CARCINOMA

PAG E : 1 1

EMERGING TARGETED THERAPIES IN ADVANCED RENAL CELL CARCINOMA CONTINUED

ESMO 2018. 875P. Characterization of Response to Nivolumab Plus Ipilimumab (N+I) or Sunitinib (S) in Patients (Pts) With Previously Untreated Advanced Renal Cell Carcinoma (aRCC): CheckMate 214

B. I. Rini

Results

Table. Results of intermediate/poor-risk aRCC patients receiving nivolumab + ipilimumab vs. sunitinib.

Outcome N+I int/poor-risk pts S int/poor-risk pts

Total n = 425 CR n = 40 PR n = 137 Total n = 422 CR n = 5 PR n = 107

BOR (95% CI), % 42 (37–47) 9 32 27 (22–31) 0.68 25

Median (range) time to response, months 2.8 (0.9–11.3) 2.8 (0.9–11.0) 2.8 (1.4–11.3) 3.0 (0.6–15.0) >0.90 3.1 (0.6–15.0)

Median (95% CI) duration of response, months NR (21.8–NE) NR NR (18.8–NE) 18.2 (14.8–NE) 0.15 18.2 (13.9–NE)

Pts with ongoing response in responders, n/N (%) 128/177 (72) 34/40 (85) 34/40 (85) 71/112 (63) 0.28 66/107 (62)

12-month PFS rate (95% CI), % 50 (44–55) 97 (83–100) 97 (83–100) 43 (37–48) 0.56 79 (69–86)

18-month OS rate (95% CI), % 78 (74–81) 100 (100–100) 100 (100–100) 68 (63–72) 9 92 (85–96)

BOR, best overall response; NE, not estimable; NR, not reached; PR, partial response

Conclusions: Pembro monotherapy showed encouraging efficacy and acceptable tolerability in pts with advanced ccRCC. Updated analyses will be presented using additional follow-up data and outcomes by PDL-1 status and other relevant subgroups.

CARE™ PERSPECTIVE OF LBA6_PR AND ABSTRACT 875P:

• Late-Breaking Abstract 6_PR and Abstract 875P both featured results that suggest combination therapy (avelumab + axitinib and nivolumab + ipilimumab) are superior to sunitinib monotherapy for first-line therapy of aRCC.

• In LBA6_PR, patients with aRCC with no prior therapy were randomized to receive avelumab + axitinib (442 pts) or sunitinib (444 pts). As suggested in earlier single arm studies, patients who received avelumab + axitinib showed improved PFS and OR benefits. Data were still immature with regards to survival. The complete response (CR) rate appears lower than for previous trials (CM214, IMMOTION151) but may improve with longer follow-up.

• In Abstract 875P, nivolumab + ipilimumab also demonstrated stronger ORR and OS than sunitinib in patients with intermediate/poor risk disease, and specifically, had more complete and durable responses and better quality of life than sunitnib.

• JAVELIN Renal 101 and CheckMate 214 support the use of avelumab + axitinib and nivolumab + ipilimumab (intermediate and poor risk patients) over sunitinib, suggesting potentially new standards of care for the aRCC patient population.


ESMO 2018. 871P. KEYNOTE-427 Cohort A: Pembrolizumab Monotherapy as First-Line Therapy in Advanced Clear Cell Renal Cell Carcinoma (ccRCC)

F. Donskov

Results: At data cutoff (Oct 6, 2017), median (range) follow-up was 7.2 (0.9-11.7) mo. 110 pts enrolled; 107 were included in efficacy analysis (opportunity for ≥1 postbaseline assessment). Treatment was ongoing for 64 (58.2%) pts. Median age (range) was 64 (29-87) years; 78% were male. 37.3%, 47.3%, and 15.5% had IMDC risk categories of favorable, intermediate, and poor, respectively. Confirmed ORR by ICR was 33.6% (n = 36; 95% CI 24.8-43.4) with 1 complete response (0.9%) and 35 (32.7%) partial responses. 39 (36.4%) had stable disease. ORR for pts with favorable or intermediate/poor risk IMDC was 27.5% and 37.3%, respectively. Median DOR was not reached (range 1.4+ to 8.2+ mo); 86.1% of responders had response ≥3 months. Median PFS was 6.9 (95% CI 5.1-NR) mo; PFS rate at 6 mo was 53.6%. OS rates at 3 and 6 mo were 97.2% and 92.4%, respectively. 73.6% of pts had a treatment-related adverse event (AE); most common (≥10%) were fatigue (23.6%), pruritus (21.8%), diarrhea (16.4%), rash (12.7%), and arthralgia (11.8%). 18.2% experienced a grade 3-5 treatment-related AE; 1 pt had grade 5 pneumonitis.

Conclusions: Pembro monotherapy showed encouraging efficacy and acceptable tolerability in pts with advanced ccRCC. Updated analyses will be presented using additional follow-up data and outcomes by PDL-1 status and other relevant subgroups.

Background: Beginning in 2016, the KEYNOTE-427 phase II trial looked at pembrolizumab (pembro) as a first-line therapy in advanced clear cell RCC (ccRCC) and non-ccRCC.

CARE™ PERSPECTIVE OF ABSTRACT 871P:

• After receiving 200 mg of pembro IV for 2 years or until progressive disease/toxicity, the ccRCC cohort showed strong efficacy and tolerability, suggesting that some patients may achieve benefit from PD1/PDL1 CPI monotherapy. However, it is not yet clear which patients could receive monotherapy or which patients need combination treatment with CTLA4 inhibitor or anti-VEGF therapy.

• Results from the non-ccRCC cohort are expected in the future.

JAVELIN RENAL 101 AND CHECKMATE 214 SUPPORT THE USE OF AVELUMAB +

A XITINIB AND NIVOLUMAB + IPILIMUMAB (INTERMEDIATE AND POOR RISK PATIENTS)

OVER SUNITINIB , SUGGESTING POTENTIALLY NEW STANDARDS OF CARE

FOR THE ARCC PATIENT POPUL ATION .

“

”1402 - RENAL CELL CARCINOMA

PAG E : 13

03. UROTHELIAL CARCINOMA

Trials on novel monoclonal antibodies in UC.

Key Abstracts on Urothelial Carcinoma


KEY ABSTRACTS ON UROTHELIAL CARCINOMA

ESMO 2018. LBA32. Nivolumab (N) Alone or in Combination With Ipil imumab (I) in Patients (pts) With Platinum-Pretreated Metastatic Urothelial Carcinoma (mUC), Including the Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Expansion From CheckMate 032

J. E. Rosenberg

Results

Table. Results of the expanded N1I3 cohort and extended follow-up data from the CheckMate 032 trial.

1603 - UROTHELIAL CARCINOMA

ESMO 2018. LBA33. A Phase Ib/2 study of neoadjuvant pembrolizumab (pembro) and chemotherapy for locally advanced Urothelial Cancer (UC)

C. J. Hoimes

Results: Cohort I completed accrual on phase 1b/2 and safety & efficacy analysis for 40 evaluable pts are presented. Median age 65 yrs, 75% male, 10% had mixed UC histology, and PD-L1 combined positive score ≥10 was 52%. No DLTs in 6 pts on phase 1b. There was 1 death on post radical cystectomy (RC) day 9 due to mesenteric ischemia (ileal conduit). One pt did not have RC due to AE (gr4 thrombocytopenic purpura); UC in remission at 14mo. One pt with presumed gr3 MI during cycle 4 had a negative inpatient cardiac workup and completed therapy and RC without further gr3/4 AE. One gr4 hyponatremia and ten gr3 events did not preclude RC (2-each thromboembolism, elevated creatinine, hyponatremia;1-each: dehydration, emesis, neutropenic fever, infection). Gr 3/4 cytopenias occurred in 57% of pts. Median number of doses given for pembro=5, C=4, G=8. Of 35 pts who had RC (4 refused, 1AE) the median time to surgery was 18.5wks from registration, and 5.3wks from last dose. Baseline stage was cT2 51%, cT3 44%, cT4a 5%. The proportion of patients with pCR or absence of muscle invasive disease (PaIR) was 60% (95% CI: 42, 74) and did not correlate with baseline PD-L1 score. At 14 months (1.6 – 33.3) median follow up, the estimated 12mo relapse free-, overall-, and disease specific survival, is 80%, 94%, and 97%, respectively.

Conclusions: Neoadjuvant GC with pembro in locally advanced UC has manageable toxicity, a comparable time to surgery as NAC, and is associated with robust disease downstage and control rate that warrants further study.

Background: Previous successes of pembro in the metastatic setting have suggested that it could be efficacious in the locally advanced UC setting.

N3 n=78

N3I1 n=104

N1I3 n=92

Minimum follow-up, mo

797 772 157

ORR (95% CI), % 117.2 (0.7) 117.4 (0.7) 112.5 (1.9)

PD-L1 ≥1% 84.1 (0.4) 83.9 (0.5) 80.7 (1.3)

PD-L1 ≥1% 26 (14–41) 25 (14–38) 24 (12–40)

Median DOR (95% CI), mo

30.5 (8.3–NE)

22.3 (12.8–NE)

22.9 (9.8–NE)

Median PFS (95% CI), mo

2.8 (1.5–5.3)

2.6 (1.4–3.9)

4.9 (2.7–6.6)

Median OS (95% CI), mo

9.9 (7.3–21.1)

7.4 (5.6–11.0)

15.3 (10.1–27.6)

NE, not estimable

CARE™ PERSPECTIVE OF ABSTRACT LBA32:

• Expanded follow-up data presented on the patient group receiving 1 mg/kg nivolumab and 3 mg/kg ipilimumab, who had locally advanced or mUC and had been heavily pretreated.

• This cohort showed the highest ORR of 38%, with a 58% ORR in PD-L1 ≥1% patients, as presented in the table above.

• These results support further investigation of the nivolumab + higher dose ipilimumab treatment regimen in the first-line setting.

Conclusions: The combination of N1I3 demonstrated higher ORR and longer PFS and OS than previous reports of PD-1/PD-L1 monotherapies in this PD-L1 unselected pt population with a manageable safety profile. These results support the ongoing phase 3 trial of N1I3 vs chemotherapy in previously untreated mUC (CheckMate 901; NCT03036098).

CARE™ PERSPECTIVE OF ABSTRACT LBA33:

• This early-stage trial investigated pembro in combination with gemcitabine + cisplatin chemotherapy.

• For now all that can be said is pembro is well tolerated and appears to yield impressive pathological responses when combined to NAC.

What follows are results from two phase III trials augmented with one early-phase study presented at ESMO 2018, on novel monoclonal antibodies in urothelial carcinoma (UC). CARE™ Faculty Perspectives and background information follow each Abstract.

KEY ABSTRACTS ON UROTHELIAL CARCINOMA CONTINUED

ESMO 2018. 865PD. RANGE, a phase 3, randomized, placebo-controlled, double-blind trial of ramucirumab (RAM) and docetaxel (DOC) in platinum-refractory urothelial carcinoma (UC): overall survival results

D. P. Petrylak

Results: 530 pts were randomized to RAM+DOC (n = 263) or PL+DOC (n = 267). Median follow-up time was 7.4 months. There was a trend toward improved OS for pts treated with RAM+DOC vs PL+DOC, which did not meet statistical significance (median, 9.4 vs 7.9 months; HR, 0.89; 95% CI, 0.72-1.09; p = 0.2461). Prespecified analyses showed OS improvement with RAM+DOC in pts in the Europe/ROW geographical strata (median, 8.8 vs 7.1 months; HR, 0.78; p = 0.0421) and in pts with primary bladder tumors (median, 9.7 vs 7.0 months; HR, 0.78; p = 0.0521). Previously reported PFS and ORR results were confirmed (PFS, median 4.1 vs 2.8 mo; HR 0.70; p = 0.0002; ORR, 25.9% [95% CI, 20.6-31.1] vs 13.9% [95% CI, 9.7-18.0]). Grade ≥3 adverse events were reported at a similar frequency in both arms with no unexpected toxicities. Biomarker results will be presented.

CARE™ PERSPECTIVE OF ABSTRACT 865PD:

• OS results of the RANGE study, expanding upon previously reported PFS and ORR results.

• Although there was a trend for OS in pts receiving RAM + DOC, it did not meet prespecified criteria for success.

• It is unlikely that this combination will become a standard treatment in Canada for pts with platinum-refractory UC.

Conclusions: In pts with platinum-refractory advanced UC, RAM+DOC showed statistically superior PFS, improved ORR, and a trend toward improved OS compared to PL+DOC.

THESE RESULTS SUPPORT FURTHER INVESTIGATION OF

THE NIVOLUMAB + HIGHER DOSE IPILIMUMAB TRE ATMENT REGIMEN IN THE

FIRST- LINE SET TING .

“

”PERSPECTIVES ON ESMO 201817

PAG E : 1 6

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