Current Concepts in Extending Systemic and Local Therapies to Maximize Prostate Cancer Control. Tanya Dorff, MD

Transcription

1 Current Concepts in Extending Systemic and Local Therapies to Maximize Prostate Cancer Control Tanya Dorff, MD

2 DISCLOSURE Grant/Research Support from Bayer Consultant for Bayer, EMD Serono and Janssen On the Speakers Bureau for Exelixis and Prometheus

3 Overview Localized disease: multidisciplinary management Includes genetic counseling Metastatic hormone sensitive (mhspc): intensified upfront therapy extends survival Abiraterone, docetaxel maybe more to follow Novel therapies for metastatic castration-resistant prostate cancer (mcrpc) Optimizing use of existing therapies Genomic targeted therapies (PARP, pi3k ) Immunotherapy

4 Staging: NCCN 3/2018

5 The Case for Adjuvant ADT for high risk localized ECOG (Messing) trial in LN+ showed significant benefit to immediate ADT SWOG 9921 trial showed benefit in LN+ as well as other high risk groups with 2 years adjuvant ADT Messing EM et al. NEJM 1999; 341:1781 Dorff TB et al JCO 2011; 29:2040

6 The case for Adjuvant radiation therapy for high risk localized prostate cancer For T3 patients, adjuvant radiation reduced risk of metastasis at 10 years Decreased use of ADT at 5 years: 21% on observation vs 10% on XRT arm HR 0.45 ( ) Thompson et al JAMA 2006; 296:2329

7 In LN+ should we use both ADT + XRT? Retrospective analysis, suggests patients with 4+ nodes may not benefit from adjuvant Radiation Abdollah F et al J Clin Oncol 2014; 32:doi/ /JCO

8 Decipher: Select patients for Radiation Post RP? Genomic Classifier Identifies Men With Adverse Pathology After Radical Prostatectomy Who Benefit From Adjuvant Radiation Therapy Low risk (GC<0.4) High risk (GC 0.4) Salvage Adjuvant Prostatectomy 22 gene panel RNA selected from patients with recurrence PRIMARY USE: select adjuvant therapy after prostatectomy Den., et al.,j Clin Oncol, 2015, 33: Ross AE et al. PCAN 2014; 17:64-9

9 Future: clinical trials in localized prostate cancer ENZART NCT DFCI NCT ENZARAD NCT EORTC NCT Setting Agent(s) Accrual goal Intermed Risk Intermed Risk High Risk No LNs x pelvis Intermed, limited hi risk Enzalutamide HypoFx XRT Enzalutamide EBXRT ADT + XRT Enza vs Bical ADT + XRT +/- Apalutamide Status 70 Recruiting 64 Completed 802 Ongoing 990 Opening soon

10 Genetic Testing BRCA 1 & 2 mutations are more common in prostate cancer than previously thought - Pritchard et al NEJM 2016 Only 20% of a panel of experts felt genetic testing should be done in a majority of advanced prostate cancer patients - 93% supported testing in men with + family history - 74% supported testing in men dx prostate CA < 60 years Gilessen S et al Eur Urol 2018; 73:178

11 ADT: managing side effects Hot flashes (gabapentin 1, venlafaxine 2 ) Metabolic syndrome: Diet/Exercise, metformin 3, statins Cognitive changes (focus/attention): methylphenidate Emotional changes: SSRI Bone mineral density: Bisphosphonates or denosumab 60 mg SQ q6 months 4 Resistance and Aerobic Exercise can improve muscle mass, physical function Toremifene also helpful 5,6 1. Loprinzi C et al. Ann Oncol 2009; 20: Irani J et al. Lancet Oncol 2010; 11: Nobes JP et al BJU Int 2012; 109: Smith MR et al. NEJM 2009; 361: Smith MR et al. JCO 2008; 26: Smith MR et al. J Urol 2008; 179:15

12 Early chemotherapy improved survival in metastatic hormone sensitive prostate cancer (HSPC): CHAARTED Sweeney CJ et al. NEJM 2015; 373: ESMO update: med f/u 57 mo, no OS benefit for low volume (aka oligomets) Sweeney CJ et al, ESMO 2016; abstr 720pd

13 STAMPEDE: (Docetaxel) in mhspc James N et al., Lancet 2016; 387:1163 For Overall Survival: BUT HR 0.79, 95% CI , p=0.019 all patients Toxicity must be considered HR 0.82, 95% CI , p=0.475 pts with mets

14 Early abiraterone improves survival in metastatic HSPC: LATITUDE 2 of 3 high risk features: - Gleason bone metastases - Visceral metastases Fizazi K et al. NEJM 2017; DOI: /NEJMoa

15 STAMPEDE: up-front abiraterone James N et al, NEJM 2017 DOI /NEJMoa Hi risk local or Node+ Relapsing p definitive tx 2 of: Stage T3/4 >1 of: PSA >4 & PSADT <6 mo PSA 40ng/ml PSA >20 Gleason 8-10 Mets or Node +

16 Sydes MR et al. Ann Oncol 2018; 29: nonc/mdy072 No difference between abiraterone and docetaxel for mhspc

17 Trials will answer the combination and other agents utility for mhspc intensification questions Study Agent(s) Accrual Goal Status ARASENS (Bayer) NCT SWOG S1216 TITAN NCT ARCHES NCT Docetaxel ADT +/- ODM-201 ADT +/- orteronel (TAK700) STAMPEDE ADT + abiraterone +/- enzalutamide Next generation questions: - Which drug for which patient? - Shorter duration? 1300 Completed Accrual 1313 Completed Accrual ADT +/- apalutamide 1052 Completed Accrual ADT +/- enzalutamide 1150 Ongoing? Ongoing

18 Screen#3 Screen#2 Screen#1 BL PSA, ng/ml Optimizing use of existing therapies: Ensure Drug Is No Longer Working Before Stopping Treatment Start 7 Symptomatic Progression (bone) A Drifter for 3.5 YEARS Palliative Radiation Time, months Imaging Time Points Scher HI, et al. J Clin Oncol. 2011;29:

19 Sequencing: less effect of abi after enza, and enza after abi Abiraterone response after prior treatment with enzalutamide 1 Enzalutamide versus docetaxel in men with CRPC progressing after abi 2 1. Loriot Y, et al. Ann Oncol 2013;24: Suzman DL, et al. Prostate. 2014; 74:

20 Antonarakis et al, NEJM ARV7 explains some of the cross-resistance ARV7 Predicts Less Response to Enzalutamide and Abiraterone But response to Docetaxel is not impacted by ARv7 Antonarakis et al, 2015.

21 PLATO: Should we continue AR targeted therapy through subsequent lines of tx, similar to LHRH? Presented by: G. Attard, ASCO NCT

22 Using and sequencing cabazitaxel FIRSTANA: cabazi vs doce 1 st mcrpc: No difference 1 Cabazi 20 mg/m 2 vs 25mg/m 2 : No difference in OS 2 Retrospective series: Doce-Cabazi-Abi better than Doce-Abi-Cabazi 3 1.Oudard et al. JCO 2017; 35:3189 (FIRSTANA) 2. Eisenberger et al. JCO 2017; 35:3198 (PROSELICA) 3. Sonpavde et al. CGUC 2015; 13:309

23 Novel agents: Pi3K/AKT targeted tx (for PTEN loss) PTEN loss present in up to 60% of prostate cancer Cross-talk with AR Ipatasertib is AKT inhibitor

24 Novel agents: PARP Inhibitors (for DDR) Pritchard et al, 2016 (right) Mateo et al, NEJM 2015 (below)

25 Theranostics: individualize treatment plans based on phenotype rather than genomics Not all mcrpc tumors are PSMA + Treatment with Lu177-PSMA 617 Emmett L et al. J Med Rad Sci 2017; 64:52 Pre-treatment Post-treatment

26 Novel agents: Epigenetic modification BET bromodomain inhibitors, EZH2 inhibitors in early phase clinical trials

27 Immunotherapy has established value in mcrpc (but there have been multiple negative phase 3 trials) Schellhammer PF et al Urology 2013; 81:1297

28 No benefit for PROSTVAC in phase III J. Gulley (NCI) ASCO 2018

29 Objective responses are uncommon with Sip-T, but can occur Drake C et al. Urology 2013; 81:381 A. Dorff May TB 2010 et al. Clinical before GU SipT B. Cancer Oct ; 12:e55 post SipT, with T recovery

30 Pembrolizumab in mcrpc: KEYNOTE-199 Top right: objective response Bottom right: PSA changes DeBono JS. ASCO 2018; oral present

31 Ongoing immunotherapy trials Agents Trial # Accrual goal Locations Sip T +/- Radium223 Radium223 +/- pembrolizumab SipT + immed vs delayed ipi Enza +/- atezolizumab SipT + atezolizumab NCT Cedars Sinai Hopkins NCT Dana Farber NCT UCSF MDACC NCT US sites closed to accrual NCT City of Hope U Hawaii

32 Chimeric Antigen Receptor (CAR) T Cell-Based Therapy Conventional TCR:MHC Chimeric antigen receptor Escape mechanisms in most cancers MHC down-regulation / defective antigen presentation of TAAs Immunosuppressive tumor-infiltrating immune cells Advantages over other immunotherapy strategies: 1. Direct attacking of tumor-associated antigens 2. MHC-independent 3. Less opportunity for immune escape Adapted from Roberts et al, Leuk & Lymphoma 2017.

33 PSCA as a prostate cancer CAR target Normal tissue expression PSCA Tumor tissue expression PSA (KLK3) PSMA PSCA PSMA Gtex TCGA

34 A Phase I clinical trial to evaluate PSCA-CAR T cells for the treatment of patients with mcrpc Toxicity and disease response evaluations will be evaluated as described above. CT =! Inpatient approx days 0-14 Bx = biopsy given within a window of 3-10 days after last dose of lymphodepleting regimen Cy* = lymphodepletion chemotherapy, cytoxan +/- fludarabine PB = peripheral blood for correlative studies Study Population: Patients eligible for the proposed study should have 1) pathologic diagnosis of prostate cancer, LTFU = (2) long metastatic term follow castration up resistant prostate cancer (mcrpc) (Note: castration will be defined by a testosterone <50 ng/dl achieved by orchiectomy or LHRH agonist/antagonist therapy), 3) disease progression on the last line Enrollment: of therapy based min 6, on: max rising 27; goal PSA 12 with at 2 MTD/RP2D consecutive values 7 days apart or measurable disease with an increase in 20% or more of longest diameters of measurable lesions or non-measurable disease with 1 or more new lesions in soft tissue, or 2 or more new lesions in bone, and (4) prior abiraterone or enzalutamide, but not both. Patients may also have had 1) chemotherapy for castration-sensitive prostate cancer, but not for castration-resistant disease, 2) prior radiotherapy, provided it was rendered > 28 days prior to treatment, or 3)

35 Conclusions Genetic counseling Consider ADT adjuvant for high risk in addition to XRT Supportive care key for long-term ADT patients Continue enza, abi beyond PSA progression but not when ready for new therapy PARP inhibitors completing phase 3 testing genomic profiling relevant Immunotherapy still a work in progress