Vascular Targeted Photodynamic Therapy for Prostate Tumors

Transcription

1 Vascular Targeted Photodynamic Therapy for Prostate Tumors

2 Which of the following is true about focal therapy (FT)? 1. FT for prostate cancer is FDA approved in men with unilateral Gleason Grade Groups 1, 2, and 3 prostate cancer 2. The most common side effect of treahng an apical prostate cancer with FT is urinary inconhnence (between 3-5% require surgical management of inconhnence) 3. Compared to achve surveillance, FT reduces the likelihood of a posihve prostate biopsy at 24 months (aper starhng AS or receiving FT)

3 What is the biologic effect of vascular targeted photodynamic therapy? 1. LASER light energy causes heahng of Hssue resulhng in thermal necrosis 2. LASER light energy achvates a photosensihzer resulhng in vascular occlusion 3. LASER light energy achvates a monoclonal anhbody that targets tumor neovascularity 4. LASER light energy is delivered to the prostate via a catheter advanced into the inferior vesicle artery 5. Both 3 & 4 are correct LASER: light amplificahon by shmulated emission of radiahon

4 Vascular Targeted Photodynamic Therapy Immediately aper intravenous injechon the photosensihzer padeliporfin (4mg/kg over 10 minutes) is achvated by a 753 nm LASER light Drug achvahon triggers a biological cascade resulhng in vascular occlusion Padeliporfin selechvely ablates the organ through vascular occlusion with minimal damage to surrounding Hssues

5 Treatment Details Template Laser light Fibers

6 Ultrasound Treatment Guidance Control Prostate volume to be treated (dots indicate placement of light fibers) The treatment guidance system indicates the number of fibers and, for each fiber, the: Length of light emission PosiHon in the prostate Safe margin (5mm) from the neurovascular bundles, rectum and capsule

7 Energy Control: Customized Treatment Light Density Index (LDI) 1 determined by treatment guidance is a good predictor of necrosis volume and negahve biopsies 4 cm 4.5 cm 2.5 cm + 2 cm fibers (11.5 cm) 17.5 cc Length (sum of 10 fibers) = 24.5 cm Hemi- ablahon volume = 17.5 cc Hemi- ablahon treatment guidance LDI = 24.5 cm/17.5 cc = 1.40 Each prostate receives the energy needed to necrose the region thought to harbor the index cancer

8 MRI one week aper treatment Healthy prostate Hssue Area of necrosis

9 PCM301 Randomized Phase III Clinical Trial TOOKAD Soluble (Padeliporfin- dipotassium) Vascular- Targeted Photodynamic (VTP) therapy versus AcHve Surveillance in men with low- risk prostate cancer

10 Overview of PCM301 study design (European phase III; 47 centers in Europe) Inclusion criteria Low- risk prostate cancer pahents: Either 1 posihve core and 3-5mm CCL,* or 2-3 posihve cores and 5mm CCL per core Absence of Gleason pamern 4 or 5 PSA 10 ng/ml Clinical stage up to ct2a (rt2c, bilateral posihve biopsies permimed) Prostate volume 25 cc and 70 cc Exclusion criteria Any prior or current treatment for prostate cancer, including surgery, radiahon therapy (external or brachytherapy) or chemotherapy Any surgical intervenhon for benign prostahc hypertrophy Any condihon or history of illness or surgery that may pose an addihonal risk to men undergoing the VTP procedure ContraindicaHon to MRI or factors excluding accurate reading of pelvic MRI Life expectancy < 10 yrs * CCL = Cancer Core Length

11 Overview of PCM301 study design (European phase III) Study endpoints Primary endpoints Absence of any posihve core (i.e., no core with an amributable Gleason score) at month 24 Time to failure of treatment due to progression of cancer from low- to moderate- or high- risk* over the 24 month follow- up Secondary endpoints NegaHve biopsy at month 12** Volume of hypoperfusion area shown by MRI at Day 7 Serum PSA levels Safety: all Adverse Events and Serious Adverse Events Quality of life: Monthly follow- up of IPSS, IIEF- 15, EQ5D * Moderate or high risk defined as the observahon of: 4 cores or more posihve for cancer when considering all histological results during follow- up Or, at least one cancer core length greater than 5 mm Or, any Gleason primary or secondary pamern 4 or more Or, PSA>10ng/mL in 3 consecuhve measures Or, any T3 stage prostate cancer Or, any metastasis Or, prostate cancer- related death ** Retreatment allowed once if M12 biopsy posihve

12 Baseline demographics TOOKAD VTP arm Ac.ve surveillance arm Age (years) (n=206) (n=207) Mean ± SD 64.2 ± ±67 Ethnic origin (n=206) (n=207) Caucasian 202 (98%) 206 (100%) Other 4 (2%) 1 (<1%) BMI (kg/m²) (n=201) (n=202) Mean ± SD 26.5± ±4.0

13 TOOKAD VTP arm Ac.ve surveillance arm Time since diagnosis (months) (n=206) (n=207) Mean ± SD 6.3± ±7.9 Stage at diagnosis (TNM) (n=206) (n=207) T1a 1 (0.5%) 0 T1c 177 (85.9%) 180 (87.0%) T2a 28 (13.6%) 27 (13%) Es.mated prostate volume (cc) (n=206) (n=207) Mean ± SD 42.5± ±11.76 PSA (ng/ml) (n=206) (n=207) Mean ± SD 6.2± ±2.0 Total number of cores in biopsy (n=206) (n=207) Mean ± SD 13.6± ±3.6 Total number of posi.ve cores (n=206) (n=207) Mean ± SD 2.1± ±0.7 Total cancer core length (mm) (n=206) (n=207) Mean ± SD 4.3± ±2.4 Gleason score (n=206) (n=207) (1.5%) 1 (0.5%) (1.5%) 2 (1.0%) (97.1 %) 204 (98.6 %) Prostate cancer lobe distribu.on (n=206) (n=207) Unilateral 157 (76%) 163 (79%) Bilateral 49 (24%) 44 (21%) Baseline cancer characterishcs

14 Co- primary Efficacy Endpoints TOOKAD VTP [N=206] n (%) Surveillance [N=207] n (%) p- value Nega.ve biopsy at 24 months 101 (49%) 28 (14%) < Number of subjects who progressed 58 (28%) 120 (58%) < Reasons for progression: Gleason >=4 49 (24%) 91 (44%) < More than 3 cores posihve 23 (11%) 58 (28.%) < Cancer core length >5mm 25 (12%) 51 (25%) PSA >10ng/mL (in 3 consecuhve measures) 3 (1%) 14 (6%) 0.01 Any T3 prostate cancer 0 4 (2%) - Metastasis Prostate cancer- related death Emergence of Gleason pa[ern 4 was the primary cause of progression

15 Results: end- of- study biopsy results and progression Absence of posi.ve biopsy at 24 month* Co- primary endpoint analysis in ITT populahon Median.me to progression (in months) TOOKAD VTP (N=206) 101 (49%) 95%- CI=[42%- 56%] %- CI=[ ] Overall p- value for the co- primary analysis: p<0.001 *In either the treated or contralateral lobe Ac.ve Surveillance (N=207) 28 (14%) 95%- CI=[9%- 19%] %- CI=[ ] Comparison TOOKAD VTP vs. Ac.ve Surveillance RR= %- CI=[ ] HR= %- CI=[ ] Progression: moderate or high risk defined as the observahon of: 4 cores or more posihve for cancer Or, at least one cancer core length greater than 5 mm Or, any Gleason primary or secondary pamern 4 or more Or, PSA>10ng/mL in 3 consecuhve measures Or, any T3 stage prostate cancer Or, any metastasis Or, prostate cancer- related death

16 Time to progression ITT populahon HR= %- CI=[ ] p<0.001 Note: Shape of Kaplan Meier curves is greatly affected by effect of censorship ager 24 months

17 Progression by primary Gleason pamern Post- hoc analysis in ITT populahon TOOKAD VTP (N=206) AcHve Surveillance (N=207) Comparison TOOKAD VTP vs. AcHve Surveillance Progression to GS % 95%- CI=[18%- 29%] 43.5% 95%- CI=[37%- 50%] HR= %- CI=[ ] (p < ) Progression to GS 7 with pg4 2.4% 95%- CI=[0.3%- 4.5%] 7.2% 95%- CI=[4%- 11%] HR= %- CI=[ ] (p = 0.009) Progression to GS 7 with pg3 20.9% 95%- CI=[15%- 26%] 36.2% 95%- CI=[30%- 43%] HR= %- CI=[ ] (p < )

18 IniHaHon of radical therapy reduced from ~30% to ~6% at 24 months TOOKAD ITT populahon AS

19 Urinary funchon (IPSS) is transiently worse at 3 months but bemer than control at months aper treatment Safety populahon Worse Bemer IPSS = InternaKonal Prostate Symptom Score

20 Sexual funchon (IIEF) is marginally worse for the first year but essenhally the same as controls at 24 months Safety populahon Bemer Worse IIEF= InternaKonal Index of ErecKle FuncKon

21 PCM301 Safety (reviewed by independant DSMB) Number of Subjects with AE in Category Significant Adverse Events TOOKAD Soluble VTP N = 197 (n%) AS N = 207 n (%) p- value a Renal and urinary disorders Dysuria 54 (27.4) 5 (2.4) <0.001 Haematuria 56 (28.4) 6 (2.9) <0.001 MicturiHon urgency 21 (10.7) 2 (1.0) <0.001 Frequency 20 (10.2) 6 (2.9) Urinary inconhnence 19 (9.6) 10 (4.8) Urinary retenhon 32 (16.2) 2 (1.0) <0.001 ReproducHve system disorders EjaculaHon failure 16 (8.1) 1 (0.5) <0.001 ErecHle dysfunchon 74 (37.6) 24 (11.6) <0.001 Perineal pain 30 (15.2) 1 (0.5) <0.001 Hematospermia 12 (6.1) 5 (2.4) ProstaHc pain 6 (3.0) ProstaHHs 10 (5.1) 10 (4.8) a From Pearson s chi- square test if at least 5 subjects in each group reported the specific AE and from Fisher exact test otherwise

22 TOOKAD Soluble VTP Safety Profile by grade of AE Number of pa.ents (%) TOOKAD Soluble VTP all events [N=197] TOOKAD Soluble VTP drug, device, or procedure related events [N=197] Ac.ve Surveillance [N=207] Grade 1 (Mild) 49 (24.9%) 54 (27.4%) 42 (20.3%) Grade 2 (Moderate) 94 (47.7%) 81 (41.1%) 52 (25.1%) Grade 3 (Severe) 40 (20.3%) 19 (9.6%) 19 (9.2%) Grade 4 (Life- threatening) 3 (1.5%) 1 (0.5%) 1 (0.5%) Grade 5 (Death) 1 (0.5%) 0 (0%) 0 (0%) Missing 0 (0%) 0 (0%) 0 (0%) No case of photosensihvity or recto- urethral fistula Most adverse events related to the renal and urinary system (67.5% of pahents) and to the reproduchve system (61.7% of pahents) Note: Safety data has been reviewed by an independent Data Monitoring Board

23 PCM301 Conclusions o First randomized prospechve mulh- center trial of focal therapy versus AS o SubstanHally reduced rates of progression, especially to higher- grade cancer o SubstanHally more treated pahents converted biopsy to negahve o SubstanHally lower inihahon of radical therapy o Excellent safety profile o Very good preservahon of genitourinary funchon

24 Acute Enrichment of Androgen Responsive Genes in LNCaP- AR Tumors at 6hr Post VTP Treatment FDR q value= NES=2.10

25 ADT and VTP Displays PotenHal AddiHve Effects : Hormone SensiHve Localized Tumor Model (SQ LNCaP- AR) n=14 n=14 P< n=17 n=16 P< A77&79 ADT in LNCaPAR, 2million, 1min delay, 150mW

26 Summary: Prostate Cancer Treated with VTP Compensatory acute up- regulahon of pro- survival androgen receptor (AR) signaling may occur InhibiHon of the AR pathway might provide for effechve combinahon therapy in conjunchon with VTP

27 Conclusions Focal therapy effechvely ablates prostate Hssue Vascular targeted photodynamic therapy is a non- thermal approach to focal therapy Focal therapy has bemer post- treatment QOL than whole- gland therapies The pahent populahon best served by focal therapy has yet to be determined