Updates on Use of Radiopharmaceu3cals in Clinical Trials August 22, 2017 Evan Y. Yu, M.D. Professor of Medicine (Oncology) University of Washington Fred Hutchinson Cancer Research Center
Discussion Topics Radium-223 background Ongoing clinical trials with Radium-223 Combina@on therapy Earlier disease states Biomarkers and pa@ent selec@on Lute@um Ac@nium 8/21/17
Radium-223 Mechanism of Ac3on Radium-223 acts as a calcium mimic Naturally targets new bone growth in and around bone metastases Radium-223 is excreted by the small intes@ne Ca Sr Ba Ra
Radium-223 Mechanism of Ac3on Range of alpha-particle Radium-223 Bone surface Alpha-par@cles induce double-strand DNA breaks in adjacent tumour cells1 Short penetra@on of alpha eminers (2-10 cell diameters) = highly localized tumour cell killing and minimal damage to surrounding normal @ssue Perez et al. Principles and Prac.ce of Radia.on Oncology. 5th ed. LippincoN Williams & Wilkins; 2007:103.
ALSYMPCA Trial Overall Survival Results 100 90 80 HR 0.695; 95% CI, 0.552-0.875 p=0.00185 % 70 60 50 40 30 20 10 Placebo, n = 268 Median OS: 11.2 months Radium-223, n=541 Median OS: 14.0 months 0 Month 0 3 6 9 12 15 18 21 24 27 Radium- 223 541 450 330 213 120 72 30 15 3 0 Placebo 268 218 147 89 49 28 15 7 3 0 Parker C et al. N Engl J Med 2013;369:213-23.
ALSYMPCA Overall Survival Stra3fied by Prior Docetaxel Use 100 90 80 Prior docetaxel use HR = 0.710 95% CI, 0.565, 0.891 P = 0.00307 100 90 80 NO prior docetaxel use HR = 0.745 95% CI, 0.562, 0.987 P = 0.03932 70 70 60 60 % 50 40 Radium-223, n = 352 Median: 14.4 months % 50 40 Radium-223, n = 262 Median: 16.1 months 30 30 20 10 Placebo, n = 174 Median: 11.3 months 20 10 Placebo, n = 133 Median: 11.5 months 0 Month 0 4 8 12 16 20 24 28 32 36 40 Radium-223 352 327 238 155 88 45 27 5 1 0 0 Placebo 174 152 104 61 35 15 5 4 1 1 0 0 Month 0 4 8 12 16 20 24 28 32 36 Radium-223 262 236 168 119 70 31 14 7 1 0 Placebo 133 113 74 42 24 14 9 3 1 0 Parker GU ASCO 2013
ALSYMPCA: Adverse Events of Interest Haematologic Radium-223 (n=509) n (%) All Grades Grades 3 or 4 Placebo (n=253) n (%) Radium-223 (n=509) n (%) Placebo (n=253) n (%) Anemia 136 (27) 69 (27) 54 (11) 29 (12) Neutropenia 20 (4) 2 (1) 9 (2) 2 (1) Thrombocytopenia 42 (8) 14 (6) 22 (4) 4 (2) Non-Haematologic Bone pain 217 (43) 147 (58) 89 (18) 59 (23) Diarrhea 112 (22) 34 (13) 6 (1) 3 (1) Nausea 174 (34) 80 (32) 8 (2) 4 (2) Vomiting 88 (17) 32 (13) 10 (2) 6 (2) Constipation 89 (18) 46 (18) 6 (1) 2 (1) Parker C et al. N Engl J Med 2013;369:213-23.
ALSYMPCA: Predisposing Factors for Hematologic Toxicity Parameter es3mates for maximum percentage decrease from baseline during on-treatment period in Hb, neutrophils and platelets Baseline variable Parameter es@mates Hb (n=870) Neutrophils (n=867) Platelets (n=870) P value Parameter es@mates P value Parameter es@mates P value Study tx (Ra-223/Pbo) -1.57 0.027-18.56 < 0.0001-10.18 < 0.0001 Current use of bisphosphonates (Y/N) -1.21 NS -0.08 NS -1.22 NS Prior use of Doce (Y/N) -1.32 NS -3.04 0.023-6.04 < 0.0001 EOD 6 mets including superscan (Y/N) Prior EBRT to bone for pain (Y/N) Total ALP ( 220 U//L / < 220 U/L/) -2.54 0.008-3.45 NS -6.59 0.001 2.21 0.001 3.91 0.003 2.30 NS -3.07 < 0.0001-2.11 NS -4.91 0.001 Parker et al., J Clin Oncol 31, 2013 (suppl; abstr 5038)
Should Radium-223 be Used Before or Ager Chemotherapy? Only FDA approved for pa@ents lacking visceral metastasis Stringent eligibility requirements for treatment Ini@al ANC 1,500/L with subsequent 1,000/L Hb 10 g/dl PLT 100,000/L with subsequent 50,000/L Requires pre-authoriza@on, while chemotherapy with docetaxel does not More likely to be able to administer all 6 doses in the pre- vs. post-chemotherapy segng
Overall Survival of Radium +/- Abiraterone or Enzalutamide from Early Access Program Post hoc exploratory analysis of the Interna@onal Early Access Program. Abi, abiraterone; Enza, enzalutamide; OS, overall survival Saad F, et al. Lancet Oncol. 2016;17(9):1306-16. Slide adapted from Neal Shore.
ERA 223: Abiraterone +/- Radium-223 for No/ Minimally Symptoma3c bone mcrpc ClinicalTrials.gov Iden@fier: NCT02043678. Accessed 3/28/2017. Slide adapted from Neal Shore.
PEACE-3: Enzalutamide +/- Radium-223 for No/ Minimally Symptoma3c bone mcrpc PI: Silke Gillessen Primary Endpoint: rpfs by PCWG2 ClinicalTrials.gov Iden@fier: NCT02194842. Accessed 3/28/2017. Slide adapted from Neal Shore.
Randomized Phase 2 Trial of Radium-223 for mhspc N = 204 Primary Endpoint: rpfs at landmark Slide adapted from PI: Ajjai Alva NCT02582749
Phase 2 study of Sip-T +/- Rad-223 N = 34 Primary Endpoint: PA2024 T cell proliferation Slided adapted from PI: E. Antonarakis NCT02463799 Presented by Charles G Drake MD / PhD
Study Design & Primary Objec3ves * * * N=45 No limits on number of prior therapies *All are con@nued on GnRH agonist/antagonist **Pembrolizumab 200mg IV q3 wks Stra@fied by high/low volume of bone metastases; alk phos levels Primary Immune objec@ves: cell infiltra@on Characterize into the changes metasta@c in immune bone biopsies cell response from baseline bone and to week blood 8 Secondary objec@ves: safety and tolerability, preliminary efficacy of the combina@on NCT03093428; Slided adapted from PI: Lauren Harshman
DNA Repair Gene Altera3ons are Common in Metasta3c Prostate Cancer 23% of metasta@c castra@on-resistant prostate cancers harbor DNA repair altera@ons The frequency of DNA repair altera@ons increases with disease progression Robinson D et al. Cell 2015; 161:1215-28. 11.8% of men with metasta@c prostate cancer have a germline altera@on in 16 DNA damage repair genes Age and family history did not affect muta@on frequency Pritchard CC et al. N Engl J Med. July 6,2016.
RAPARP Phase 1 Trial Slide adapted from PI: Kelly\Knudsen; Co-PI: Rettig (UCLA), Spondave (UAB); Graff (OHSU), Sartor (Tulane) N=30 NCT03076203
PET/CT and Metasta3c Biopsies to Study Mechanisms of Resistance to Radium-223 Eligibility assessment and informed consent Pretreatment metasta@c biopsy, if appropriate PET1 PIs: Ramos, Yu Begin treatment Metasta@c biopsy, if appropriate PET2 a PET3 Survival monitoring b Metasta@c biopsy, if appropriate and not done arer PET2 a In some cases, PET2 may show progression of disease and in those instances, would represent PET3 in this schema. This scan will occur at 12 weeks ± 2 weeks from ini@a@on of therapy. b Survival monitoring will occur in 3-month intervals. PET: positron-emission tomography
DNA Repair Genes and Response to Radium-223 Retrospec@ve analysis of 49 pa@ents received radium-223 since May 2013 26 of 49 (53.1%) pa@ents had a response to radium-223 defined as 30% decline in PSA, 30% decline in alkaline phosphatase or normaliza@on of CTCs 10 of 26 pa@ents previously underwent DNA sequencing 4 of 10 had an altera@on in a DNA repair gene BRCA2, CHEK2, MRE11A, SPOP Prospec@ve trial planned to perform pre-radium-223 metasta@c biopsy and next genera@on sequencing at baseline (UW, Tulane, JH, UCSF, UBC) Determine response in pa@ents with and without DNA repair gene altera@ons
177 Lu-DOTAGA PSMA (aka PSMA-I&T) 68 Ga-PSMA 177 Lu-PSMA cycles 68 Ga-PSMA Baum RP et al. J Nucl Med. 2016; 57:1006-13.
177 Lu-PSMA-617 Rahbar K et al. J Nucl Med. 2017; 58:85-90.
177Lu-PSMA 225Ac-PSMA Abstract 1431 at SNMMI 2016 annual mee@ng
Take Home Points Radium-223 offers significant survival benefit for pa@ents with bone mcrpc and symptoms Many combina@on trials are ongoing with radium-223 and 2 nd genera@on androgen pathway inhibitors, immuno-oncology agents and now PARP inhibitors Promising trials are underway u@lizing radium-223 in pa@ents in earlier disease states who lack symptoms Both predic@ve and response biomarkers are necessary and are being explored in a limited number of trials There are many promising other radiopharmaceu@cals in development with both beta- (e.g. Lute@um) and alphaeminers (e.g. Ac@nium) tagged to PSMA an@bodies or small molecules
Acknowledgements Neal Shore Emmanuel Antonarakis Lauren Harshman Ajjai Alva W. Kevin Kelley Jorge D. Ramos ScoN Tagawa
Thank You! evanyu@uw.edu 206-288-6292 25