Management of chronic pre-existing or treatment-emergent adverse events of the other systemic therapies. Michael J. Morris, MD

Transcription

1 Management of chronic pre-existing or treatment-emergent adverse events of the other systemic therapies Michael J. Morris, MD

2 Disclosures Research funding (institutional contracts): Sanofi Endocyte Progenics Genentech/Roche Unpaid consultant Endocyte Bayer Progenics

3 Side Effects: A consequence of what we use, when we use it, how much, how frequently, and on whom Docetaxel Enzalutamide Abiraterone Scher JCO 2016 Sip-T Cabazitaxel Radium

4 Probability of Overall Survival (%) Drug selection for first-line chemotherapy: mcrpc FIRSTANA Number at risk Time (months) DOC + PRED CBZ 20 + PRED CBZ 25 + PRED Median OS, months (95% CI) DOC + PRED 24.3 ( ) CBZ 20 + PRED 24.5 ( ) CBZ 25 + PRED 25.2 ( ) CBZ 20 vs DOC HR ( ) P = CBZ 25 vs DOC HR 0.97 ( ) P = Sartor, ASCO 2016, abst 5006

5 Sartor, ASCO 2016, abst 5006

6 Kellokumpu-Lehtinen, Lancet Oncol 2013

7 Chemotherapy: Dose and drug selection for mcrpc mcrpc: Who might benefit from CBZ as first line chemotherapy? Neuropathic patients DM, spinal stenosis, vascular disease, and other etiologies of neuropathy Edematous patients Edema from abiraterone, cardiovascular disease, venous insufficiency Pts at risk of neutropenia/marrow compromise Significant exposure to RT Diffuse marrow disease Consider doce 2 week schedule mcrpc first line doce? Still the SOC from a practice, regulatory, and financial (value) perspective Consideration for patients with hematuria Infiltrative bladder disease/pelvic RT

8 # patients evaluated Death Neutropenia Febrile neutropenia Fatigue Diarrhea Neuropathy Peripheral edema Dyspnoea Stomatitis Mucositis Chemotherapy non-castrate disease, high-grade tox Source Treatmen James N et al, 2016 ADT + STAMPEDE docetaxel ADT + zoledronic acid + docetaxel CHAARTED/E380 ADT + docetaxel Gravis G et al, 2013 GETUG-AFU ADT + docetaxel < <1 <1

9 Patrick-Miller, ASCO 2016, abstr 5004 QOL - CHAARTED Overall Fatigue Fact-Taxane Emotional Well Being

10 Chemotherapy for mcspc ( non-castrate ) Cognizance of who is chemotherapy appropriate. Febrile neutropenia and death are not beyond the realm of possible Chemotherapy induced fatigue and taxane tox is significant during treatment. Overall QOL, emotional well being, taxane-toxicities, and fatigue return to baseline or even better, after treatment.

11 Side Effects: A consequence of what we use, when we use it, how much, how frequently, and on whom Docetaxel Enzalutamide Abiraterone Sip-T Cabazitaxel Radium

12 Enza vs. abiraterone AE s (any grade) 302/Prevail Abi/pred (%) Pred (%) Enza (%) Placebo (%) Fatigue Edema Low K NR NR HTN Cardiac /Affirm Fatigue Edema NR NR Low K 17 8 NR NR Cardiac Adapted from Zhang et al, Expert Opin Pharm, 2014

13 Can we use less prednisone than 10 mg with abiraterone? IMAAGEN Trial, Abi/pred 5 mg, n=131 Tox Imaagen Grade 3-4 (%) 302 Grade 3-4 (%) 301 Grade 3-4 (%) HTN 23 4 NR Low K Hyperglycemia 6.9 NR NR Afib NR Edema 1.5 <1 3 Ryan, ASCO 2016, abstr 6081

14 Enza vs. abiraterone AE s 302/Prevail Abi/pred (%) Pred (%) Enza (%) Placebo (%) Fatigue Edema Low K NR NR HTN Cardiac /Affirm Fatigue Edema NR NR Low K 17 8 NR NR Cardiac Adapted from Zhang et al, Expert Opin Pharm, 2014

15 AA/pred vs. Enza: Preliminary data on a ph II crossover study, NCT , 57 pts per arm (British Columbia Cancer Agency) Parimi et al, ASCO 2016, Abstr 5059

16 AA/pred vs. Enza: Preliminary data on a ph II crossover study, NCT , 57 pts per arm Parimi et al, ASCO 2016, Abstr 5059

17 Abi vs. Enza CNS and Dose Reduction Events, 2196 AA/pred pts vs Enza pts, Medicare database CNS, HR = 1.32 Fatigue, HR = 1.30 Dose intensity <85% HR 1.29 Pilon et al., ASCO 2016, abstr 5078

18 Drug/Drug Interactions Benoist, Clin Pharmacokinet, 2016

19 Drug-Drug Interactions Substrate Drug Enza Abi CYP2C9 Warfarin, losartan AUC decrease NA CYP2C19 Omeprazole, esomeprazole, clopidogrel, citalopram, diazepam AUC decrease NA CYP2D6 Oxycodone, metoprolol, haloperidol, flecainide, paroxetine AUC decrease AUC increase CYP3A4 Oxycodone, methadone, simvastatin, nifedipine, fentanyl AUC decrease NA Benoist et al, Clin Pharmcokinetic, 2016

20 Abiraterone/Enzalutamide Abiraterone More cautious in cardiac patients Event rate, afib, K, fluid shifts Reduction in pred may induce new issues relating to HTN and low K Enzalutamide More cautious in the fatigued, frail, or depressive patient Dose reductions are feasible Care with polypharmacy

21 Conclusions We have choices for first-line chemotherapy Recognition of clinical state, pt comorbidities, likelihood of benefit, dose, and interval should be used to mitigate toxicities Decisions around toxicities should consider financial toxicity/value If up front CBZ, what to use for second line chemo? Abi and Enza Consider the whole patient Comorbid conditions Other meds Individualized approach, unlike many reimbursement mechanisms