VALUE AND ROLE OF PSA AS A TUMOUR MARKER OF RESPONSE/RELAPSE

Transcription

1 Session 3 Advanced prostate cancer VALUE AND ROLE OF PSA AS A TUMOUR MARKER OF RESPONSE/RELAPSE 1

2 PSA is a serine protease and the physiological role is believed to be liquefying the seminal fluid PSA are regulated by androgens (testosterone and dihydrotestosterone) 2

3 Prostate- specific antigen (PSA) is one of the few molecular markers routinely used for detection risk stratification monitoring 3

4 PSA is specific to the prostate but not to prostate cancer: benign prostate diseases cause increases in serum PSA and most men with increased PSA do not have prostate cancer. 4

5 PSA strongly discriminates different cancer stages: Higher in men with localized disease than in cancer- free controls, Is associated with stage and grade in localized disease and Is higher in patients with metastatic compared with localized disease. Men with a higher PSA at the time of initial therapy have increased risk of recurrence. 5

6 Relapse in 20 30% after primary treatment of localized prostate cancer Often detected by rise in serum PSA Routinely monitoring of PSA recommended by AUA, EAU, National Comprehensive Cancer Network 6

7 NCCN guideline PSA every 6 to 12 months for 5 years Thereafter anually EAU guideline 3,6 and 12 months, then every 6 months From third year anually 7

8 Definition: relapse Prostate Guideline from American Urological Association Biochemical relapse after radical prostatectomy, serum PSA level >0.2 ng/ml with a second confirmatory level above 0.2 ng/ml to define recurrence After radiotherapy: PSA level by 2 ng/ml above the nadir 8

9 Postoperative: detectable PSA after radical prostatectomy If low and stable, the reason could be benign prostate tissue left behind by surgery 9

10 Recurrence after prostatectomy o After 10 years 35% of all patients operated need salvage treatment o For Gleason 8-10 even 60% o 4% in Gleason 7 and PSA < 10ng/ml Immediate PSA recurrence Surgery Early PSA recurrence Late PSA recurrence 10

11 Key facts PSA recurrence is a sign of local failure, or distant metastases, or both Key facts Imaging plays no role in PSA <0,5 ng/ml., while curative local salvage therapy must take place at that time Key facts Overtreatment should be minimized 11

12 Immediate PSA recurrence An immediate postop PSA >0.03 ng/ml is the best predictor compared to Gleason and T- stage for recurrence defined by PSA >0.2 (accuracy 96%) (Kang J et al. J Urol 2015) Late PSA recurrence Slowly rising (PSADT>1 year): likely local recurrence If Gleason 6 : expectant (PSA takes >7 years to raise to 20 ng/ml) If Gleason 7 : likely benefit from local salvage RT If Gleason 8-10: rare Fast rising (PSADT < 1 year): likely disseminated, no local salvage, endocrine therapy? 12

13 After radiotherapy: PSA decreases slowly. The time to reach PSA nadir can be months to years Dependent on the after treatment size of the prostate and the pre- treatment PSA Predictive value: 13

14 PSA doubling time - PSADT Mostly used to monitor disease progression for patients after Surgery Radiotherapy surveillance No standardisation of calculation What is the lowest PSA The number of PSA values used Duration between PSA measures Several calculation tools available online 14

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16 The effect of ADT on PSA PSA in blood almost always decreases and then stabilizes for varying intervals Initial decrease in PSA due to Tumour regression ADT suppress transcription of the PSA gene, which is androgen dependent 16

17 The effect of ADT on PSA Failure of ADT to produce a reduction in 17

18 Treatment Starting androgen deprivation therapy PSA threshold For patients with systemic disease: Goal is delaying progression, reducing morbidity and mortality Start early before clinical development of metastases or after? 18

19 Treatment of PSA- only recurrences The timing and mode of treatment for PSA- only recurrences after RP or RT are still controversial. After RP, the therapeutic options are: Radiotherapy at least to the prostatic bed. (Complete) androgen deprivation (CAD, AD). Intermittent androgen deprivation (IAD). wait- and- see. 19

20 Treatment Starting androgen deprivation therapy PSA threshold A retrospective study including 1,352 patients with post- operative PSA recurrence showed no significant difference in the time to clinical metastases with early ADT (after PSA recurrence, but before clinical metastases) vs. delayed ADT (at the time of clinical metastases). After risk stratification, it was found that early ADT was able to delay the time to clinical metastases in high- risk patients with a Gleason score > 7 and/or a PSADT < 12 months. ADT had no overall impact on the PCa- specific mortality 20

21 PSA nadir post- ADT associated with otime to androgen- independent progression oclinical progression odeath opsa nadir less than 0.2 ng/ml have significantly longer interval to androgen- independent progression 21

22 Observation until development of metastatic disease an option in patients with: Gleason score < 7 PSA recurrence > 2 years after surgery PSADT > 10 months Median time to metastasis is 8 years Median time from metastasis to death 5 years 22

23 Treatment variable clinical course leaves uncertainty about how and when to treat life expectancy comorbidities 23

24 Treatment Hormones Systemic failure following radical prostatectomy is predicted with >80% accuracy if: PSA relapse < 1 year PSADT of 4-6 months Gleason score 8-10 Stage pt3b, ptxpn1 24

25 PSA progression or PSADT is not considered valid surrogate endpoint for drug approval Is often an enrolment criterion for clinical trials A trigger for clinical decision making 25

26 PSA response/progression in castration resistant prostate cancer Prostate Cancer Clinical Trials Working Group PCWG2 in Scher H et al. J Clin Oncol 2008,26,

27 Eligibility for trials based on PSA changes PSA progression PCWG2 (2007) sequence of rising values at a minimum of 1- week intervals Increase of 2.0 ng/ml Estimate pretherapy PSA- DT if 3 or more values available 4 or more weeks apart 27

28 Eligibility based on PSA changes 28

29 cycle but Suggested Outcome Measures for Phase II Clinical Trials in Prostate Cancer plan to PCWG2 continue through early rises For control/relieve/eliminate end Progression: points: for a Decline Record from baseline: the percent record change time from start of therapy baseline to minimum first (rise PSA or fall) increase at 12 that weeks, is > 25% and > 2 and ng/ml separately, above the the nadir, maximal and which is confirmed change by of a (rise second 12 or weeks fall) value at 3 any or more time weeks later (ie, a using confirmed a waterfall rising plot trend) The requirement of unless an increase of 5 ng/ml is decreased to 2 ng/ml, and the requirement 29 for a 50% increase is reduced to 25%.

30 Suggested Outcome Measures for Phase II Clinical Trials in Prostate Cancer Recognize that a favorable effect on PSA may be delayed for 12 weeks or more, even for a cytotoxic drug. Monitor PSA by cycle but plan to continue through early rises for a minimum of 12 weeks unless other evidence of progression. Ignore early rises (prior to 12 weeks) in determining PSA response 30

31 nadir, and Suggested Outcome Measures for Phase II Clinical Trials in Prostate Cancer which is confirmed by a second value 3 or 31

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34 PCWG3 defined a new outcome: No longer clinically benefitting (NLCB) - Treating through progression vs. The decision to change treatment: A drifter for 3.5 years At what level of detection of a molecular determinant associated with resistance, should a treatment be stopped 34

35 PSA- survival modeling The PSA- survival modeling framework was based on data from two phase III studies, COU- AA- 301 (chemotherapy- pretreated, n = 1,184) and COU- AA- 302 (chemotherapy- naïve, n = 1,081), 35

36 The effect of AA on PSA kinetics was significant (P < ) and comparable between the chemotherapy- naïve and - pretreated patients. PSA kinetics (e.g., PSA nadir, PSA response rate [ 30, 50, and 90%], time to PSA progression, PSA doubling time [PSADT]) were highly associated with OS in both populations. The model- based post- treatment PSADT had the strongest association with OS (hazard ratio ~0.9 in both populations). The models could accurately predict survival outcomes. 36

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38 Initiating imaging in asymptomatic patients on ADT and no known metastases, if treatment is planned in case of M1 disease St Gallen 2015 Iniqate imaging PSA- DT 38

39 Recommendations Use of PSA for clinical decision making PSA should not be used in isolation to make clinical decisions 39

40 Recommendations Use of PSA for clinical decision making At least two out of three criteria (PSA progression, radiographic progression, and clinical deterioration), should be fulfilled to stop treatment 82% If low levels of PSA is not obtained check serum testosterone Important to be aware of how different therapies affect PSA 40

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