1. End Points and Outcomes in Castration-Resistant Prostate Cancer: From Clinical Trials to Clinical Practice Howard I. Scher, Michael J. Morris, Ethan Basch, and Glenn Heller 1 J Clin Oncol 29:3695-3704 R4 채정민 /Prof 김시영

2. Introduction castration-resistant prostate cancer (CRPC) new therapies with diverse mechanisms of action biologic - sipuleucel-T (Provenge) cytotoxic - cabazitaxel (Jevtana) hormonal - abiraterone bone-seeking radioisotope - apharadine antibody that blocks the interaction between tumor and bone - denosumab (Xgeva) → proven benefit in phase III trials

3. Introduction clinician`s new issues how best to sequence these options what tests to perform how to interpret the test results heterogeneity of the disease difficulty in assessing disease in bone uncertainty of interpreting the clinical significance of post-therapy changes in PSA → need new and specific end points in clinical trials

4. Introduction Prostate Cancer Working Group 2 (PCWG2) in 2008 consensus guidelines for prostatic cancer post-treatment outcomes in two general categories to control, relieve, or eliminate disease manifestations to prevent or delay future disease manifestations prevent or delay future disease manifestations prolongation of life or a reduction in skeletal-related events (SREs) → regulatory requirements for FDA approval

5. Introduction control, relieve or eliminate disease manifestations careful interpretation of each disease manifestation ensure a drug is allowed sufficient time to work → prevent premature discontinuation consider indivisual end points control/relieve/eliminate & prevent/delay circulating tumor cells (CTCs) as an aid to monitoring CRPC

6. CLINICAL PRACTICE AND CLINICAL RESEARCH: SHARED GOALS OF TREATMENT 6 off-protocol (clinical practice) disease manifestations now and future predictable factors specific intervention assessment tool and time point decision making on-protocol (clinical research) study objectives eligibility criteria end points statistical design individuals for enrollment

7. 7

8. Patient Assessment 8 patient’s pretreatment evaluation complete history & physical examination symptoms and attribution of each one to disease prior therapy pre-existing comorbid conditions complete blood count & chemistry panel PSA & testosterone CT or MRI and a radionuclide bone scan bone turnover markers CTCs

9. Patient Assessment 9 prognosis functional status of the patient demographic characteristics presence or absence of pain disease manifestations (rising PSA, soft tissue disease, bone disease, symptom) individual parameters (performance status, site of disease, LDH, PSA level)

10. Patient Assessment 10 factors that predict sensitivity to treatment prior systemic therapy (focused on cytotoxic drug) amount of docetaxel priorly received time from last dose to progression prior response in a trial of mitoxantrone/prednisone and ixabepilone response rates were similar between refractory arm and responsive arm in a trial of cabazitaxel response rates was independent of the amount of prior docetaxel received → noncross-resistance

11. Patient Assessment 11 the PCWG2 defines castrate androgen < 50 ng/mL CYP17 inhibitors that produce androgen levels in the range of 1 to 2 ng/mL → androgen levels may need to be redefined molecular determinants are also under study receptor tyrosine kinase mutations gene expression profiles are also under study rebiopsy for profiling is not part of routine management

12. Drug 12 various new target agents → different outcome measures will be needed to assess different drugs essential to discuss for informed decision why a treatment is being offered risk/reward ratio of intervention planned

13. OUTCOMES BY DISEASE MANIFESTATION 13 treatment: success or failure ? mechanism of action of a drug & timing of benefit sipuleucel-T: several months, no effect on PSA or TTP but survival benefit serial monitoring changes in disease manifestations treat minimum of 12 weeks parameters are equivocal or discordant → continue treatment in the absence of clear-cut evidence of progression or worsening clinical status

14. PSA 14 post-therapy PSA measurements reflects tumor burden not all drugs worked immediately up to 20% of patients treated with docetaxel do not show declines until 12 weeks or more decline of 50% or more from baseline associated with survival → basis for regulatory approval misconstrued strength of association between PSA decline and survival every post-treatment PSA measurement only 17% of the variability in OS was explained by the time- dependent PSA

15. PSA 15  survival benefit for docetaxel 1. once every 3 weeks relative to mitoxantrone in TAX-327 patients with 50% or greater decline in PSA from baseline 60% reduction in mortality not confirmed with the weekly docetaxel schedule (no statistical power, but tendency) → 50% decline was not a surrogate for survival 2. in SWOG 99-16 [Southwest Oncology Group 99-16] post-treatment decline of 30% or more effect of treatment on outcome was not significant after adjusting for the 30% PSA decline not treatments are equivalent after adjusting for post-treatment PSA

16. PSA 16 a therapy that produces any degree of PSA decline, in the absence of other signs of deterioration or progression → continued in practice reporting PSA change data using waterfall plots maximal decline from baseline the degree of decline at a fixed time point (12 weeks) PSA progression: increase of 25% or more and absolute increase of 2 ng/mL or more from the nadir initial PSA decline during treatment: must be confirmed by a second value 3 or more weeks later

17. 17 stopping therapy in patients with apparent PSA progression alone is not appropriate MDV3100 abiraterone

18. Soft Tissue 18 follow RECIST criteria lack of standards for assessing disease at baseline and recording results outcome is not associated with survival → can bring misinformation

19. Bone 19 most frequent site of distant metastasis primary source of morbidity and mortality bone scans most common method of assessing bone lesions detect bone trauma, degenerative changes, infection, and other inflammatory processes → looks like disease progression

20. 20 Flare phenomenon

21. Bone 21 remain on study or treatment until two new bone lesions are observed two new lesions on the first scan → subsequent follow-up scan 6 weeks or longer after the first scan

22. Metastasis prevention 22 in Trial 147, nonmetastatic CRPC patients RANK ligand inhibitor denosumab versus placebo denosumab significantly improved both median bone metastasis–free survival by 4.2 months and time to first occurrence of bone metastasis OS times were similar previous trials with atrasentan and zibotentan were unsuccessful

23. Skeletal-related events (SREs) 23 defined as pain requiring a change in oncolytic therapy spinal cord compression need for radiation therapy or surgical intervention development of hypercalcemia trial objective: reducing the morbidity of bone metastases full approval despite the drug failing to show a survival benefit or effect on PSA in a phase III registration trial of the RANK ligand inhibitor denosumab superior to zoledronic acid in a head-to head comparison

24. Patient-Reported Outcomes (PROs) 24 control, relief, and elimination of symptoms such as pain important therapeutic objectives assessed using validated self-reporting Questionnaires presence of pain is an adverse prognostic factor for survival PRO instruments most appropriate for measuring treatment impact in clinical trials important for FDA labeling

25. Patient-Reported Outcomes (PROs) 25 transient increases in pain may occur before improvement → those occurring in the first 12 weeks should be ignored if no definite progression mitoxantrone, docetaxel, and abiraterone modest reductions in pain intensity samarium (radionuclide) substantial pain improvements

26. Patient-Reported Outcomes (PROs) 26 pain palliation rates in the TROPIC trial cabazitaxel showed no significant difference compared with mitoxantrone low with either treatment, at fewer than 10% anorexia, anxiety, constipation, diarrhea, sleep disturbance, mucositis, nausea, pain, peripheral sensory neuropathy, rash, vomiting, urinary symptoms, global health-related quality of life, and interference of symptoms with usual activities potential toxicity

27. CLINICAL PRACTICE VERSUS FDA REGULATORY APPROVAL: LEVEL OF EVIDENCE 27 prolonging life the delay or prevention of death from disease gold standard for drug approval delay and prevention of SREs is also standalone end point of clinical benefit led to the approval of several bone-targeted agents other composite time-to-event progression measures have not faired as well

28. Time to Progression 28 progression-free survival (PFS) time from study entry or random assignment to disease progression in bone or soft tissue, symptoms, or death not confounded by the effect of subsequent treatments occur months to years → higher number of events → trials with smaller sample sizes comparable end point in the phase II and phase III trials definitions of progression based on PSA and radiographic progression have been unsatisfactory → biomarker-derived progression end points have shown only modest associations with survival

29. CTCs 29 cells with stem cell–like properties which originate from primary tumor or metastatic sites one cell in 1 billion of the circulating cells in the blood enrichment → detection and characterization no standardized definition of a CTC and detection assays in various studies CellSearch (Veridex) only CTC assay cleared by the FDA for use in the clinic

30. CTCs 30 characteristics morphologically intact nucleus surrounded by cytoplasm when stained with 4,6- diamidino-2-phenylindole expresses cytokeratin 8, 18, or 19 not express the mononuclear cell determinant CD-45 CTC counts trend toward higher values in relation to PSA level and extent of disease in bone the association is modest → each parameter provides independent information

31. CTCs 31 clearance for use was obtained first for breast, colorectal, prostate cancers baseline CTC number was prognostic for survival in univariate and multivariate analyses for prostate cancer ≤ 4 in 7.5mL blood → favorable ≥ 5 in 7.5mL blood → unfavorable post-therapy CTC number was more predictive than a decline of 50% or more in PSA in multivariate analysis only CTC count and LDH were prognostic PSA was no longer predictive

32. CTCs 32 the FDA clearance states “presence of CTC in the peripheral blood, as detected by the CellSearch Circulating Tumor Cell Kit, is associated with decreased progression free survival and decreased overall survival in patients treated for metastatic breast, colorectal or prostate cancer…Serial testing for CTC should be used in conjunction with other clinical methods for monitoring” investigators are not yet using CTC enumeration testing need more data and more standardized methods

33. CTCs 33 unfavorable counts (Danila et al, unpublished data) 25% in the pre-chemotherapy population 50% in patients receiving first-line chemotherapy, 70% in patients receiving second-line chemotherapy unfavorable at baseline → serial monitoring after each cycle of therapy conversions from unfavorable to favorable tend → maximal at 8 weeks trials are ongoing in breast cancer about relationship between no a CTC conversion and outcome

34. CTCs 34 use of the CTC assay will require further qualification CTC enumeration in the phase I/II trial of abiraterone favorable conversion rates significant survival benefit analyses are ongoing to define a biomarker panel including CTCs that is prognostic for survival after treatment the panel will be prospectively studied in a phase III trial → MDV3100 (AFFIRM; NCT00974311), TAK-700 (NCT01193257), ipilimumab (NCT01057810)

35. Conclusions in CRPC, difficult to determine effectiveness of a new treatment what metrics to use choose the right treatment at the right time due to CRPC characteristics complexity of the disease overall assessing disease in bone interpreting PSA results after therapy biomarkers continue to be refined in this disease, which should provide more specific end points and clinical guidance in the future 35