New Innovative Drugs Evaluated with EVITA

Supplementary File 1 – EVITA Datasheets

Drug / Treatment Standard
Enzalutamide
Androgenreceptor antagonist / Docetaxel
Indication / Patients that benefit from treatment
Castration-resistant prostate cancer (with surgery and/or hormone-deprivation therapy) after docetaxel in order to improve survival / Patients with castration-resistant prostate cancer whohad previously received docetaxel

EValuation of pharmaceutical Innovations with regard to Therapeutic Advantage

Prostate cancer is the third leading cause of male cancer-related death in Europe(Ferlay et al., 2007).Although most men initially respond to androgendeprivation therapy, progression eventually occurs. Following chemotherapy, the median overall survival(OS) is less than twoyears (Crawford et al., 1989; Eisenberger et al., 1998).Tumour progression after androgendeprivation therapy remains hormonallydriven (Attar, Takimoto, & Gottardis, 2009; Mohler et al., 2004; Scher & Sawyers, 2005; Titus, Schell, Lih, Tomer, & Mohler, 2005). Intraprostatic levels of dihydrotestosterone and testosterone have been shown to remain elevated despite decreased serum levels (Titus et al., 2005), which is in part due to overexpressionof the androgen receptor itself(Holzbeierlein et al., 2004; Visakorpi et al., 1995). Preclinical models of prostate cancer have shown that androgenreceptoroverexpression shortens the period of tumour latency(Chen et al., 2004). Enzalutamide (formerly MDV3100) is an androgen receptorsignalling inhibitorthat has been tested in the phase III, double-blind, placebo-controlled trial of Scher et al.(2012).Patients were randomly assigned (2:1 ratio) to receive either oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients); inclusion criteria were a histologically or cytologically confirmeddiagnosis of prostate cancer, a, castration-induced levels oftestosterone <50 ng per deciliter (1.7 nmol perliter), previous treatment with docetaxel, andprogressive disease defined according to PCWG2criteria,including three increasing values for prostatespecific antigen (PSA) or radiologically-confirmedprogression with or without a previous rise in thePSA level. The primary end point was OS, which was defined as the time from randomisation to death from any cause. The study hada Jadad score of 5 approved by two independent examiners and therefore met the EVITA criteria and could be evaluated. Sinceenzalutamidewas compared to placebo as an addon therapy to docetaxel, the trial setting is A2, andthe treatment category is clearlyone as progressive prostate cancer islife-threatening. The modifier was taken to be the absolute risk reduction (ARR)inthe OS after 1 year (30%), which is 1.5. The trialresults showed a significantly better median OS for enzalutamide (18.4 months) versus placebo (13.6 months), earning a score of 6.5 in the efficiency profile. The grade 3-5 adverse effects were summarized together and were present at a frequency of 45% in all patients taking enzalutamide, versus 53% in the placebo group. Since the frequencies were considerably over 10%and similar between groups the risk profile was -4 for grades 4 and 5 adverse events and -2.5 for grade3 adverse events for both treatments. Notably,there was a higher incidence of fatigue, diarrhoea, hot flushes, musculoskeletal pain, and headache in the enzalutamidegroup than in the placebo group, but there were no differencesin hyperglycaemia, weight gain, hyperlipidaemia, or glucose intolerance. Thus, the development of a metabolic syndrome withenzalutamide was not likely. The risk score is therefore 0, leading to a final score of 6.5.

References

Attar, R. M., Takimoto, C. H., & Gottardis, M. M. (2009). Castration-resistant prostate cancer: locking up the molecular escape routes. Clin Cancer Res, 15(10), 3251-3255. doi: 10.1158/1078-0432.CCR-08-1171

Chen, C. D., Welsbie, D. S., Tran, C., Baek, S. H., Chen, R., Vessella, R., . . . Sawyers, C. L. (2004). Molecular determinants of resistance to antiandrogen therapy. Nat Med, 10(1), 33-39. doi: 10.1038/nm972

Crawford, E. D., Eisenberger, M. A., McLeod, D. G., Spaulding, J. T., Benson, R., Dorr, F. A., . . . Goodman, P. J. (1989). A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med, 321(7), 419-424. doi: 10.1056/NEJM198908173210702

Eisenberger, M. A., Blumenstein, B. A., Crawford, E. D., Miller, G., McLeod, D. G., Loehrer, P. J., . . . Lowe, B. A. (1998). Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med, 339(15), 1036-1042. doi: 10.1056/NEJM199810083391504

Ferlay, J., Autier, P., Boniol, M., Heanue, M., Colombet, M., & Boyle, P. (2007). Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol, 18(3), 581-592. doi: 10.1093/annonc/mdl498

Holzbeierlein, J., Lal, P., LaTulippe, E., Smith, A., Satagopan, J., Zhang, L., . . . Gerald, W. L. (2004). Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol, 164(1), 217-227. doi: 10.1016/S0002-9440(10)63112-4

Mohler, J. L., Gregory, C. W., Ford, O. H., 3rd, Kim, D., Weaver, C. M., Petrusz, P., . . . French, F. S. (2004). The androgen axis in recurrent prostate cancer. Clin Cancer Res, 10(2), 440-448.

Scher, H. I., Fizazi, K., Saad, F., Taplin, M. E., Sternberg, C. N., Miller, K., . . . de Bono, J. S. (2012). Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med, 367(13), 1187-1197. doi: 10.1056/NEJMoa1207506

Scher, H. I., & Sawyers, C. L. (2005). Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol, 23(32), 8253-8261. doi: 10.1200/JCO.2005.03.4777

Titus, M. A., Schell, M. J., Lih, F. B., Tomer, K. B., & Mohler, J. L. (2005). Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res, 11(13), 4653-4657. doi: 10.1158/1078-0432.CCR-05-0525

Visakorpi, T., Hyytinen, E., Koivisto, P., Tanner, M., Keinanen, R., Palmberg, C., . . . Kallioniemi, O. P. (1995). In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet, 9(4), 401-406. doi: 10.1038/ng0495-401

Drug / Treatment Standard
Abiraterone
Selective irreversible CYP17inhibitor / Docetaxel
Indication / Patients that benefit from treatment
Castration-resistant prostate cancer (with surgery and/or hormone-deprivation therapy) after docetaxel in order to improve survival / Patients with castration-resistant prostate cancer whohad previously received docetaxelchemotherapy

EValuation of pharmaceutical Innovations with regard to Therapeutic Advantage

Therapeutic Aim and Disease Category
Prevention / To reduce risk of disabling or impairing events
Treatment / To cure diseases, to substitute missing substances
indispensable to life, to modify or relieve symptoms
Severity grading of the diseases:
I. acute life-threatening or severe chronic disease
II. rehabilitation
III. less severe acute or chronic disease
IV. application outside a treatment context
Modifier
Prevention
NNT / ARR / Modifier
<20
20 - <50
50 - <100
100 - <175
175 - <300
300 - <500
500 - <1000
≥1000 / 5-100%
<5%
<2%
<1%
<0.57%
<0.33%
<0.2%
<0.1% / 2.0
1.75
1.5
1.25
1.0
0.75
0.5
0.25
Treatment
NNT / ARR / Modifier
<3
3 - <10
≥10 / >30%
10-30%
<10% / 2.0
1.5
1.0

Prostate cancer is the third leading cause of male cancer-related death in Europe (Ferlay et al., 2007). Although most men initially respond to the androgen-deprivation therapy, progression eventually occurs. Following chemotherapy treatment the median overall survival (OS) is less than two years (Crawford et al., 1989; Eisenberger et al., 1998). Tumour progression after androgen-deprivation therapy remains hormonally driven(Attar, Takimoto, & Gottardis, 2009; Massard & Fizazi, 2011; Mohler et al., 2004; Scher & Sawyers, 2005; Titus, Schell, Lih, Tomer, & Mohler, 2005).Intraprostatic levels of dihydrotestosterone and testosterone have been shown to remainelevated despite decreased serum levels (Titus et al., 2005). Furthermore, there is autonomous overexpression of key enzymesthat synthesiseandrogenic steroids (Stanbrough et al., 2006), andARsignalling pathways have been shown to be persistently activated (Titus et al., 2005). These data prompted the study of a systemic CYP17 inhibitor to thoroughly deplete intratumoural and other

Efficiency Profile
RCTs showing evidence of / n. of RCT / p. rel. outcome / surr. outcome
Superiority / 0
1
≥2 / 0
+5
+7.5 / 0
+2.5
+3.75
Non-inferiority/equivalence
(in the presence of other RCT showing superiority) / 0
1
≥2 / 0
-1.67
-2.5 / 0
-0.83
-1.25
Non-inferiority/equivalence
(in the absence of other RCT) / any / 0 / 0
Non-inferiority/equivalence
(in the presence of other RCT showing inferiority) / 0
1
≥2 / 0
+1.67
+2.5 / 0
+0.83
+1.25
Inferiority / 0
1
≥2 / 0
-5
-7.5 / 0
-2.5
-3.75
Sum / 5
Modifier / 1.5
Efficiency score / 6.5

extragonadal sources of steroid ligands that might bind toandrogen and oestrogenreceptorsandlead to prostate cancer progression;this approach is rational because CYP17 is a key enzyme in the androgen and oestrogen biosynthetic pathway in the adrenal glands and tumour tissue (Miller, Auchus, & Geller, 1997). Abiraterone is a

RiskProfile
Severity grading / frequency / ther. inv. / ther. stand.
Adverse events (AE)
Grades 5 + 4
(death related to AE or life-threatening AE or disabling AE) / ≥10%
≥1%
≥0.1%
<0.1%
0 / -4
-3
-2
-1
0 / -4
-3
-2
-1
0
Grade 3
(severe and undesirable AE) / ≥10%
≥1%
≥0.1%
<0.1%
0 / -2.5
-2
-1
0
0 / -2.5
-2
-1
0
0
Grades 2 + 1
(moderate AE or mild AE) / ≥10%
≥1%
≥0.1%
<0.1%
0 / -1.5
-1
-0.5
0
0 / -1.5
-1
-0.5
0
0
Interactions
Frequent or serious clinical consequence
Occasional or may have clin. consequence
Dose change
Unlikely/probably or no clin. consequence
No information available / -2
-1.5
-1
0
-1 / -2
-1.5
-1
0
-1
Sum / -10 / -10
Risk score / 0
ther. inv. = therapy investigated, ther. stand. = therapeutic standard

selective irreversible CYP17 inhibitor (Barrie et al., 1994; O'Donnell et al., 2004)and has been tested in theCOU-AA-301randomised, double-blind, placebo-controlled phase 3 study (Fizazi et al., 2012). Patients were randomly assigned (in a 2:1 ratio) to receiveabiraterone (1000 mg,orally once daily) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone; patients were required to have had docetaxel chemotherapy previously. The primary endpoint was OS, defined as the time from randomisation to death from any cause. The study had a Jadad score of 5 approved by two independent examiners and therefore met the EVITA criteria and could be evaluated. Since abiraterone was compared to placebo as an add-on therapy to docetaxel, the trial setting is A2 and the treatment category is 1sinceprogressive prostate cancer is life-threatening. The modifier was the absolute risk reduction (ARR)inOS after one year (13%), which is 1.5. The trial results showed a significantly better median OS for abiraterone versus placebo, earning an efficiency profile score of 6.5. The adverse effects of every grade were over the 10% frequency threshold and comparable in both groups. One exception to this was the mineralocorticoid-related adverse events associated with abiraterone, which as expected were reported in a higher proportion of patients than in the placebo group. The risk score is therefore 0 and the final score 6.5.

References

Barrie, S. E., Potter, G. A., Goddard, P. M., Haynes, B. P., Dowsett, M., & Jarman, M. (1994). Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/C17-20 lyase). J Steroid Biochem Mol Biol, 50(5-6), 267-273.

Fizazi, K., Scher, H. I., Molina, A., Logothetis, C. J., Chi, K. N., Jones, R. J., . . . de Bono, J. S. (2012). Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol, 13(10), 983-992. doi: 10.1016/S1470-2045(12)70379-0

Massard, C., & Fizazi, K. (2011). Targeting continued androgen receptor signaling in prostate cancer. Clin Cancer Res, 17(12), 3876-3883. doi: 10.1158/1078-0432.CCR-10-2815

Miller, W. L., Auchus, R. J., & Geller, D. H. (1997). The regulation of 17,20 lyase activity. Steroids, 62(1), 133-142.

Mohler, J. L., Gregory, C. W., Ford, O. H., 3rd, Kim, D., Weaver, C. M., Petrusz, P., . . . French, F. S. (2004). The androgen axis in recurrent prostate cancer. Clin Cancer Res, 10(2), 440-448.

O'Donnell, A., Judson, I., Dowsett, M., Raynaud, F., Dearnaley, D., Mason, M., . . . Jarman, M. (2004). Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer, 90(12), 2317-2325. doi: 10.1038/sj.bjc.6601879

Stanbrough, M., Bubley, G. J., Ross, K., Golub, T. R., Rubin, M. A., Penning, T. M., . . . Balk, S. P. (2006). Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res, 66(5), 2815-2825. doi: 10.1158/0008-5472.CAN-05-4000

Drug / Treatment Standard
Radium 223 (Xofigo/Alpharadin)
Bone-seeking alpha-emitting radioisotope / No accepted standard of care, possible alternatives:
-bisphosphonates (e.g. zoledronate)
-bone-seeking radioisotopes (e.g. 89Sr and EDTMP-153Sm)
Indication / Patients that benefit from treatment
Hormone-refractory prostate cancer with symptomatic skeletal metastases:pain, spinal-cord compression, pathological fractures, and pancytopenia / Patients with castration-resistant prostate cancer who have tumour progression withsymptomatic bone metastases

EValuation of pharmaceutical Innovations with regard to Therapeutic Advantage

Prostate cancer is the third leading cause ofmale cancer-related death in Europe (Ferlay et al., 2007).Advanced prostate cancer preferentially metastasises to bone, possiblydue to osteomimicry or altered expression of adhesion molecules(Armstrong et al., 2011; Josson, Matsuoka, Chung, Zhau, & Wang, 2010).Almost 90% of patients with castration-resistant prostate cancer treated with first-line chemotherapy have radiographic evidence of bone metastases(Petrylak et al., 2004; Tannock et al., 2004). The subjective quality of life is greatly affected by the morbidity caused bycomplications of osseous metastases, such as pathologic fractures, spinal cord compression, and pain. Additionally, pain is a strong independent prognostic factor forsurvival(Armstrong, Garrett-Mayer, de Wit, Tannock, & Eisenberger, 2010; Armstrong et al., 2007a; Armstrong et al., 2007b; Halabi et al., 2008). Therefore, agents which reduce the pain and suffering caused by metastatic prostate cancer may improve not only quality of life, but

also life-span(Harrison, Wong, Armstrong, & George, 2013).Until recently, bonemetastases have beentreated with bisphosphonates(e.g., zoledronate) and bone-seeking beta-emitting radioisotopes (e.g., 89Sr and EDTMP-153Sm). Zoledronate reduces the risk of skeletal-related events, but does not extend survival (Saad et al., 2004). Beta-emitting radioisotopes are limited by the fact that their low-energy radiation has a track length of up to several millimetres in tissues, which limits the dose since adverse events (such as myelosuppression)canarise at higher doses(Finlay, Mason, & Shelley, 2005; Lewington, 2005). Incontrast, alpha-emitters produce high-energy radiation with a range of less than 100 μm and might therefore be able to not only reduce the symptoms, but also have increased anti-tumour activity. Radium 223 is a bone-seeking alpha-emitting radioisotope and has beentested in a randomised, multicentre, placebo-controlled phase II study (Nilsson et al., 2007) and in a phase III randomised trial (Kuczyk et al., 2012). In the phase II study, patients were randomly assigned to receive either four intravenous injections of 223Ra (50 kBq/kg, 33 patients) or placebo (31 patients). The primary endpoints were change in bonealkaline phosphatase (ALP) concentration and time to skeletal-related events. Secondary endpoints included, amongst others, overall survival (OS). In the phase II study, patients were randomly assigned (in a 2:1 ratio) to either receive sixinjections of Ra-223 (50 kBq/kg) or placebo. The primary endpoint was OS. Sinceboth studies had Jadad scores of 5 approved by two independent examiners they met the EVITA criteria and could be evaluated. The trial setting is A2 sincethere is no approved standard treatment for bonemetastases in castration-resistant prostate cancer and radium 223 was compared to placebo. The treatment category is clearlyonesince progressive prostate cancer is life-threatening. The modifier was the absolute risk reduction (ARR)in OS after 50 weeks (ca. 16%), a score of 1.5. The results of both studies showed significantly better median OS for radium 223 versus placebo (phase II: 15/10.7 month; phase III 14/11.2 month) earning a total efficiency score ofnine. The adverse effects of every grade were over 10% frequency and generally lower in the radium 233 groups(e.g. serious adverse effects: 43%/55% in the phase III study; 24%/45% in the phase II study). The exception was constipation, which was related to radium 223 and was seen in 12 (out of 33) versus 2 (out of 31) patients in the placebo group(phase II study). This generally high butcomparable frequency of adverseevents resulted in a risk score of0 and a final score of 9.

References

Armstrong, A. J., Garrett-Mayer, E., de Wit, R., Tannock, I., & Eisenberger, M. (2010). Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer. Clin Cancer Res, 16(1), 203-211. doi: 10.1158/1078-0432.CCR-09-2514

Armstrong, A. J., Garrett-Mayer, E., Ou Yang, Y. C., Carducci, M. A., Tannock, I., de Wit, R., & Eisenberger, M. (2007a). Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer. J Clin Oncol, 25(25), 3965-3970. doi: 10.1200/JCO.2007.11.4769

Armstrong, A. J., Garrett-Mayer, E. S., Yang, Y. C., de Wit, R., Tannock, I. F., & Eisenberger, M. (2007b). A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis. Clin Cancer Res, 13(21), 6396-6403. doi: 10.1158/1078-0432.CCR-07-1036

Armstrong, A. J., Marengo, M. S., Oltean, S., Kemeny, G., Bitting, R. L., Turnbull, J. D., . . . Garcia-Blanco, M. A. (2011). Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol Cancer Res, 9(8), 997-1007. doi: 10.1158/1541-7786.MCR-10-0490

Finlay, I. G., Mason, M. D., & Shelley, M. (2005). Radioisotopes for the palliation of metastatic bone cancer: a systematic review. Lancet Oncol, 6(6), 392-400. doi: 10.1016/S1470-2045(05)70206-0

Halabi, S., Vogelzang, N. J., Kornblith, A. B., Ou, S. S., Kantoff, P. W., Dawson, N. A., & Small, E. J. (2008). Pain predicts overall survival in men with metastatic castration-refractory prostate cancer. J Clin Oncol, 26(15), 2544-2549. doi: 10.1200/JCO.2007.15.0367

Harrison, M. R., Wong, T. Z., Armstrong, A. J., & George, D. J. (2013). Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease. Cancer Manag Res, 5, 1-14. doi: 10.2147/CMAR.S25537

Josson, S., Matsuoka, Y., Chung, L. W., Zhau, H. E., & Wang, R. (2010). Tumor-stroma co-evolution in prostate cancer progression and metastasis. Semin Cell Dev Biol, 21(1), 26-32. doi: 10.1016/j.semcdb.2009.11.016

Kuczyk, M. A., Parker, C., Heinrich, D., O'Sullivan, J. M., Fossa, S. D., Chodacki, A., . . . Sartor, A. O. (2012). Overall survival benefit and safety profile of radium-223 chloride, a first-in-class alpha-pharmaceutical: Results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases. Onkologie, 35, 182-182.

Lewington, V. J. (2005). Bone-seeking radionuclides for therapy. J Nucl Med, 46 Suppl 1, 38S-47S.

Nilsson, S., Franzen, L., Parker, C., Tyrrell, C., Blom, R., Tennvall, J., . . . Bruland, O. S. (2007). Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol, 8(7), 587-594. doi: 10.1016/S1470-2045(07)70147-X

Petrylak, D. P., Tangen, C. M., Hussain, M. H., Lara, P. N., Jr., Jones, J. A., Taplin, M. E., . . . Crawford, E. D. (2004). Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med, 351(15), 1513-1520. doi: 10.1056/NEJMoa041318

Saad, F., Gleason, D. M., Murray, R., Tchekmedyian, S., Venner, P., Lacombe, L., . . . Zheng, M. (2004). Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst, 96(11), 879-882.

Tannock, I. F., de Wit, R., Berry, W. R., Horti, J., Pluzanska, A., Chi, K. N., . . . Eisenberger, M. A. (2004). Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med, 351(15), 1502-1512. doi: 10.1056/NEJMoa040720

Drug / Treatment Standard
Prostvac-VF
Vaccine containing two recombinant viralvectors (vaccinia and fowlpox) and three immune co-stimulatory molecules (B7.1, ICAM-1, and LFA3) / Docetaxel
Indication / Patients that benefit from treatment
Castration-resistant prostate cancer (with surgery and/or hormone deprivation therapy) without prior docetaxel chemotherapy to improve survival / Patients with castration-resistant prostate cancer without previous docetaxelchemotherapy

EValuation of pharmaceutical Innovations with regard to Therapeutic Advantage