Highlights in Prostate Cancer by xde24545

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									            Highlights in Prostate Cancer



                   Ian F Tannock MD, PhD
            Daniel E Bergsagel Professor of Medical Oncology
              Princess Margaret Hospital and University of
                                 Toronto




3/30/2010                   ESMO Lugano 2007
            Potential conflicts of interest

I have designed and chaired trials for
  Sanofi-Aventis and have received research
  funding.
I have advised multiple companies about
  design of trials for GU (especially prostate)
  cancer for which I have received
  contributions to my research fund.
I do not accept personal remuneration from
  companies

3/30/2010             ESMO Lugano 2007
       Androgen Deprivation Therapy (ADT) for
        Prostate Cancer: Important Questions

1. Is there a role for Maximum Androgen Blockade
   (MAB)?
2. Continuous versus Intermittent therapy?
3. Role of second and third-line hormonal therapies?
4. Toxicity of hormonal therapy?
5. Role of ADT as an adjuvant to surgery or
   radiotherapy?
6. Role of ADT in the patient with rising PSA after
   local therapy

3/30/2010           ESMO Lugano 2007
            The patient-based
            meta-analysis showed
            no significant benefit
            of MAB after 8000+
            pts and 27 trials

            MAB is expensive,
               has increased
            toxicity and should
                not be used

3/30/2010
             Intermittent versus Continuous
            Androgen Blockade for Advanced
                    Prostate Cancer




3/30/2010              ESMO Lugano 2007
3/30/2010   ESMO Lugano 2007
            There is one small published randomized trial
            of continuous versus intermittent treatment:
                De Leval et al: Clin Prostate Ca 2002;1:163-171


                          Intermittent Continuous
                          MAB (N=35) MAB (N=33)
       3-year rate           7+/-5%              39+/-11%
       of PSA-                                    P=0.005
       progression
       % time off               60%
       treatment

Three RCTs have been presented at ASCO or AUA


3/30/2010                     ESMO Lugano 2007
            At ASCO 2006: Phase 3 Study Of
            Intermittent Versus Continous MAB
                  (Calais da Silva et al for SEUG)

     N=626: T3/4 M0 or M1, responding to
     Cyproterone Acetate + LHRH agonist at 14
     weeks (PSA < 4 or by 80%)


       Intermittent                          Continuous
        treatment                            treatment

             Intermittent treatment restarted when
               PSA>20, or PSA>10 with symptoms

3/30/2010                 ESMO Lugano 2007
                                                                       Results of SEUG study
                                         Time to First Subjectiv e or Objectiv e Progression                                                                            Time to Any Death
                            1.0




                                                                                                                                    1.0
                            0.8




                                                                                                                                    0.8
Proportion No Progression

                            0.6




                                                                                                                 Proportion Alive
                                                                                                                                    0.6
                                                                                                   Cont
                                                                                                     Int
                            0.4




                                                                                                                                    0.4
                                                                                                                                                                                                             Cont
                            0.2




                                                                                                                                                                                                                Int




                                                                                                                                    0.2
                                  312   261        220   196   159    109     68        35   11    Cont
                            0.0




                                  314   269        216   179   146    115     59        24   10    Int                                    312   266        230    205    178    121     84        41   17    Cont




                                                                                                                                    0.0
                                                                                                                                          314   285        235    193    163    131     88        39   13    Int
                                  0           20          40         60            80        100           120
                                                                Months on Study
                                                                                                                                          0           20           40          60            80        100            120
                                                                                                                                                                           Months on Study


                                                         PFS: HR=0.88                                                                                            Overall survival
                                                           p = 0.32                                                                                                 HR=0.99

                                                         Median time off treatment in intermittent
                                                         arm = 1 year
                              3/30/2010                                                            ESMO Lugano 2007
                      Prostate cancer M+ and/or N+


                            Goserelin/Bicalutamide
German study:                    x 24 weeks
Miller et al:
ASCO 2007                     PSA < 4 mg/dl
                              Decrease > 90%

             Intermittent          N=335             Continous

             PSA > 10 mg/dl
             resume therapy                           PSA Progression
                                                      3 x rise

             PSA < 4 mg/dl                                Second line
             stop therapy                                 treatment

 3/30/2010                     ESMO Lugano 2007
                                                      Time to Progression
                                                                                Progression of disease (ITT)
                                        1.00




                                        0.75
       Survival Distribution Function




                                                                          Intermittent: median 16.6 months
                                        0.50

                                                                                                                 P = 0.17

                                        0.25


                                                   Continous: median 11.5 months

                                        0.00

                                               0      250        500          750        1000        1250         1500      1750   2000   2250
                                                                                    time to progression (days)
                                                       STRATA:         treatment=inter                  Censored treatment=inter
                                                                       treatment=konti                  Censored treatment=konti



3/30/2010                                                                    ESMO Lugano 2007
                                                              Overall survival
                                                                            Patient survival (ITT)
                                       1.00




                                       0.75
      Survival Distribution Function




                                                                                     Continous

                                       0.50
                                                  Intermittent



                                       0.25                          P = 0.7


                                       0.00

                                              0        500           1000                1500              2000              2500   3000
                                                                                 time to death (days)
                                                    STRATA:    treatment=inter                    Censored treatment=inter
                                                               treatment=konti                    Censored treatment=konti


3/30/2010                                                            ESMO Lugano 2007
                       Summary
   No difference in progression-free survival
 No difference in overall survival
 No difference in adverse events
 88% of patients off therapy on intermittent arm for
             more than 50% of time

There are now 4 RCT’s with a total of >1000
patients randomized that support non-inferiority of
intermittent ADT for PFS and overall survival


 3/30/2010                 ESMO Lugano 2007
            Should intermittent androgen blockade
            now be regarded as standard therapy?

In answer to the question:
“What would you do doctor if you were me?”
My response would be “Yes”


Advantages:
   Less time on a potentially toxic therapy
   Marked decrease in cost


3/30/2010               ESMO Lugano 2007
            Role of second and third-line
                  hormonal therapy




3/30/2010            ESMO Lugano 2007
            2nd and 3rd line hormonal therapy
• About 90% of men respond to initial therapy with
  orchidectomy or LHRH agonist
• At progression about one third respond to addition
  of a peripheral antiandrogen (e.g. flutamide,
  bicalutamide)
• Of those who respond and then progress about
  20% respond to withdrawal of the peripheral
  antiandrogen
• Men may respond to further hormonal treatments
  such as dexamethasone, estrogen, or ketoconazole
  and hydrocortisone

3/30/2010              ESMO Lugano 2007
            Antiandrogen withdrawal alone or with
                   ketoconazole for HRPC
                  (Small et al: JCO 2004;22: 1025-33)


   Randomized trial of 260 pts:
   PSA response:
     Antiandrogen withdrawal alone:           11%
              + ketconazole:                  27%

       There was delay in time to progression of
       disease, but no difference in survival




3/30/2010                ESMO Lugano 2007
              Side effects of hormonal therapy

            • Impotence
            • Gynecomastia (increased breast
              tissue, sometimes with tenderness)
            • Hot flashes (“male menopause”)
            • Loss of muscle and bone
            • Anemia
            • Increased risk of cardiovascular
              events

3/30/2010                 ESMO Lugano 2007
        Role of Bisphosphonates in Preventing
                      Bone Loss

   Several randomized trials have shown that
   pamidronate or zoledronate can prevent
   bone loss due to hormone treatment


   A trial presented at ASCO 2006
   suggested that Zoledronate given annually
   is effective in preventing bone loss



3/30/2010            ESMO Lugano 2007
     Smith et al: J Urol 2003;169:2008-12
                                                 Bone
     Michaelson et al: ASCO 2006               density at
                                                1-year

                       Zoledronate 4mg      5.6% increase
                         every 3 mos
  106 men
starting ADT
                         Placebo            2.2% decrease
                                            3.1% decrease
    40 men
 starting ADT
                       Zoledronate 4mg      4.0% increase
                         every 12 mos

3/30/2010              ESMO Lugano 2007
 >73,000 men age>65 treated for localized Ca
 prostate 1992-1999, observed through 2001
            >1 in 3 received ADT

Events per 1000   Diabetes      CHF       MI     Sudden
 person-years                                     death
 No treatment      20.9         61.3      10.9    9.0

 LHRH agonist      29.0         72.3      13.6    12.9

  Orchiectomy      24.5         63.3      13.2    12.5



3/30/2010              ESMO Lugano 2007
            Role of hormonal therapy as
            adjuvant to prostatectomy or
                  radiation therapy




3/30/2010            ESMO Lugano 2007
                          Background

1.      RT with concomitant and 3yr adjuvant ADT improves PFS and
        survival for men with locally-advanced prostate cancer
        compared to RT alone
 (EORTC Bolla et al NEJM 1997;337:295 & Lancet 2002;360:103)
2.      Long-term adjuvant ADT after RT improved PFS and overall
        survival compared to RT alone
 (RTOG 85-31: Pilepich et al, IJROBP 2005;61:1285-90)
3.      Neoadjuvant and concurrent short course ADT improves PFS
        with a trend to improved overall survival
 (RTOG 86-10: Pilepich et al, IJROBP 2001;50:1243-52)
4.      No benefit of neoadjuvant ADT pre-surgery, small RCT
        suggests benefit of adjuvant ADT for high-risk patients
 (Messing et al, NEJM 1999;341:1781-8 & Lancet Oncol 2006;7:472-9)

     3/30/2010                ESMO Lugano 2007
            ASCO 2007: Phase 3 Study Of RT+ Concurrent
             and 6 mos vs 3 yrs adjuvant ADT for locally-
                      advanced prostate cancer
                     (Bolla et al: EORTC 22961)

                 Locally Advanced Prostate Cancer
                         N = 1117  970


   RT/ADT + ADT                              RT/ADT + ADT
     for 6 mos                                 for 3 years


                 Hypothesis: 6mos of ADT will not
                  be inferior to 3 years of ADT
3/30/2010                 ESMO Lugano 2007
            Clinical Progression Free Survival

     100
      90
                                                     LADT
      80
      70
      60
      50                                   SADT
      40
      30                HR= 1.93, p<0.0001
      20
      10
       0
            0   1   2    3      4      5        6      7    8   9
                                                    years
3/30/2010                    ESMO Lugano 2007
                          Overall survival
       100
                                                  HR: 1.43
        90
                                                                  Long ADT
        80
        70
        60
                                                                  Short ADT
        50
                    P-Value: 0.6543
        40                                                 P-value: 0.019
                    (H0: SADT non-
        30                                                 (H0: LADT superior)
                    inferior)
        20
        10
            0
                0   1    2     3        4     5       6      7    8     9
                                                          years
3/30/2010                          ESMO Lugano 2007
            ADT during and after radiotherapy

• Non-inferiority of short-term ADT can NOT be
  confirmed.
• Shorter PFS with short-term ADT is not surprising
  (many patients will have remission with
  reintroduction of ADT).
However:
• Strong trends to improved survival with concurrent
  and long-term ADT with radiotherapy indicate that
  this should remain the standard of care



3/30/2010              ESMO Lugano 2007
       Rising PSA after local treatment: is
              there a role for ADT?




3/30/2010          ESMO Lugano 2007
        What is the probability that rising PSA after
            local treatment will lead to death?

• Zhou et al (J Clin Oncol 2005;23:6992-8)
  498 and 661 men had PSA failure after RP and
  RT repectively (Total = 1159)


                             PSA DT           PSA DT
                           <3mos (18%)      >3mos (82%)
    5yr prostate-             31%               1%
    specific mortality

 Gleason score >7 was also predictive of mortality


3/30/2010                ESMO Lugano 2007
                          Median survival has
                          not been reached
                          at 16 yrs
3/30/2010   ESMO Lugano 2007
        Role of ADT in men with rising PSA after
         radical prostatectomy or radiotherapy

• Several studies indicate that the interval between
  first detected rise in PSA and development of
  symptomatic metastases may be several years
• Only for men with rapid PSA doubling time should
  hormonal therapy be considered


   “In metastatic or progressive PCa, immediate versus symptom-onset
   institution of ADT results in a moderate decrease (17%) in relative risk
   (RR) for PCa-specific mortality, a moderate increase (15%) in RR for
   non-PCa-specific mortality, and no overall survival advantage.
   Therefore, the Panel cannot make a strong recommendation for early
   ADT initiation.” Loblaw et al: ASCO guideline, JCO 2007;25:1596-605


3/30/2010                       ESMO Lugano 2007
    All we are doing by measuring PSA and then not
      acting on the information is causing anxiety.
    We are converting healthy men into PSA cripples

            The solution is to stop measuring PSA!


3/30/2010                ESMO Lugano 2007
      Chemotherapy for Prostate Cancer




3/30/2010         ESMO Lugano 2007
              Important Questions

• Docetaxel and prednisone was established as preferred
  first-line chemotherapy for hormone refractory
  disease: can additional agents improve outcome?
• Should chemotherapy be used in minimally symptomatic
  patients?
• Which agents for men well enough to receive second-
  line chemotherapy?
• Should bisphosphonates be used in men with bone
  metastases?


 3/30/2010            ESMO Lugano 2007
            Principles of Management for symptomatic
               hormone-refractory prostate cancer
                              (HRPC)

• Optimize pain control with regular dosing of narcotic
  medication, such as morphine
• Give regular laxatives to control the constipation
  that will be caused by morphine
• Give local radiotherapy to dominant sites of pain
• Consider chemotherapy or bone-seeking
  radioisotopes for those with general symptoms or
  rapidly progressive disease


3/30/2010                ESMO Lugano 2007
                       TAX 327 Study
                  (Tannock et al, NEJM, 2004;351:1502-12)



                                      Docetaxel 75 mg/m2
                                      q3wks x 10 cycles

             1006
                                      Docetaxel 30 mg/m2 weekly
            patients                  for 5 of 6 weeks x 5 cycles
              with
             HRPC
                                      Mitoxantrone 12 mg/m2 q3
                                      wks x 10 cycles

              All patients received prednisone 10mg/day

3/30/2010                   ESMO Lugano 2007
             TAX 327: Endpoints
  • Primary endpoint:
     Overall survival (OS)
  • Secondary endpoints:
     Pain response (if Pain Intensity ≥ 2 or
      Analgesic Score ≥ 10)
     PSA response (if PSA ≥ 20)
     Measurable tumour response
     QOL (10% improvement in FACT-P)
     Safety
3/30/2010          ESMO Lugano 2007
                                         Overall Survival
                           1.0
                                                                Docetaxel 3wkly

                                                                Docetaxel wkly
                                                                Mitox 3 wkly
Probability of Surviving




                           0.5




                           0.0
                                 0   6       12            18    24        30
     3/30/2010                                    Months
            TAX 327: Updated survival

                Docetaxel Docetaxel Mitoxantrone
                 q 3wks    weekly
% dead            85.1%         85.3%     88.1%
Median           19.2 mos     17.8 mos   16.3 mos
survival
Hazard Ratio       0.79         0.87
                 P=0.004       P=0.09
3-year            18.6%         16.8%     13.5%
survivors


3/30/2010            ESMO Lugano 2007
            TAX 327: Secondary Endpoints

                 DOC q          DOC q wk MTZ q
                 3wk                     3wk

    Pain Response 34.6%         31.2%      21.7%
    Rate          p=0.01        p=0.08
    PSA Response 45.4%          47.9%      31.7%
    Rate         p=0.0005       p<0.0001
    QOL Response 21.9%          22.6%      13.1%
    rate         p=0.009        p=0.005


3/30/2010           ESMO Lugano 2007
                                                                                     Effect of docetaxel on minimally
                                                                                          symptomatic patients
                                        • Many patients with minimal pain still had
                                          substantial impairment of quality of life

                                                                                QL Response of pts with minimal symptoms
                                   30




                                                                                       Deterioration in QL
                                                                                50
                                   25




                                                                                 p=0.009 p=0.005
 % of Patients with QOL Response




                                                                                                                                  p=0.073
                                                                                40
                                         % of Patients with QOL Deterioration
                                   20




                                                                                                      p=0.005        p=0.052       p=0.073

                                                                                                                      p=0.052
                                                                                30




                                                                                         p=0.009
                                   15



                                                                                20
                                   10



                                                                                10
                                   5



                                                                                0
                                   0




                                                                                            D3+P      D1+P    M+P       D3+P    D1+P   M+P
                                                                                     D3+P   D1+P       M+P             D3+P     D1+P     M+P
                                                                                               All Patients          Minimally Symptomatic Patients
3/30/2010
                                                                                       All Patients                 Minimally Symptomatic Patients
                   SWOG 99-16 Study
                (Petrylak et al: NEJM 2004;351:1513-20)


                                      Docetaxel +
              770 pts                 estramustine
               with
               HRPC                   Mitoxantrone +
                                      prednisone

            Study shows:
            1. Small difference in survival in favour
                 of docetaxel arm
            2. Greater toxicity with estramustine

3/30/2010                 ESMO Lugano 2007
             TAX-327 and SWOG 9916


  • The studies confirm the palliative benefit of
    Mitoxantrone + Prednisone, and this remains
    appropriate treatment for patients who are
    averse to side effects of Docetaxel
  • Estramustine adds only toxicity and should not
    be used
  • On the basis of its survival advantage,
    Docetaxel + Prednisone is appropriate treatment
    for many patients with HRPC


3/30/2010             ESMO Lugano 2007
            Several trials are comparing
            docetaxel + prednisone +/-
            a biological agent, including:
   • Antiangiogenic agents (bevacizumab, VEGF-
     TRAP)
   • DN-101 (high dose calcitriol)
   • OGX-011 (anti-clusterin – to stimulate
        apoptosis)
   • Atrasentan (endothelin receptor antagonist)
   • Vaccines (GVAX: GM-CSF transduced
        irradiated prostate cancer cells )


3/30/2010             ESMO Lugano 2007
            Second-Line Chemotherapy




3/30/2010           ESMO Lugano 2007
            Mitoxantrone after docetaxel and vice versa

  Investigator         M → D            D → M       Comments
Michels et al       N=33             N=35       Results favor
                    RR=44%           RR=15%     initial docetaxel.

Saad et al          N=20 eval
                    RR=85%
Oh et al            N=33         N=35        Docetaxel active
                    RR=60%       RR=6%       independent of
                    PFS 16.3 wks PFS 6.1 wks sequence.
Joshua et al        N=20                        Weekly docetaxel.
                    RR=45%
Rosenberg et al                      N=41       Part of rand.
                                     RR=20%     Phase 2 study
Berthold et al      N=25             N=71       D weekly and 3-
(TAX 327)           RR=28%           RR=10%     weekly combined
3/30/2010                    ESMO Lugano 2007
              Satraplatin and Prednisone Against
             Refractory Cancer (Sternberg et al,
                    ASCO 2007; N=950)


                   R
                              Satraplatin 80mg/m2 po daily 1-5
                   A
                              q35d + Prednisone 5mg po BID
  Metastatic
                   N
                   D
HRPC after 1       O
 prior chemo       M
                              Placebo po daily 1-5 q35d +
 (~50% prior       I
                              Prednisone 5mg po BID
  docetaxel)       Z
                   E

                  2:1
 3/30/2010              ESMO Lugano 2007
                  Endpoints

 Primary
   Progression Free Survival (PFS)
   Overall Survival (OS)
      700 events needed to detect HR of 0.77
      with 90% power
 Secondary
   Time to Pain Progression (TPP)
 Other Pre-specified Endpoints
   Pain response
   Tumor response
   PSA response
3/30/2010        ESMO Lugano 2007
                                       Progression Free Survival
                              100
   Survival Probability (%)


                              90
                              80                                                            S      P
                              70                                          Median (wks)     11.1    9.7
                              60                                          HR: 0.67 (95% CI: 0.57 - 0.77)
                              50             Satraplatin                  Log-Rank P = 0.0000003
                              40                   + Prednisone
                              30
                              20       Placebo
                              10       + Prednisone
                               0
                                   0    10     20     30     40      50       60     70     80      90
                                                               Weeks


3/30/2010                                             ESMO Lugano 2007
        Secondary and other endpoints

All were significantly better for the
 satraplatin arm:
• Time to pain progression (P<0.001)
• PSA response rate (P<0.001)
• Pain response rate (P<0.005)
• Measurable disease response rate (P=0.001)



3/30/2010         ESMO Lugano 2007
            Major concerns with the trial

The basic tenet of a phase 3 trial is that it
   should compare experimental therapy with
   the current standard of care
Should the control arm be:
A. Therapy that has been approved by
   regulatory bodies such as the FDA? (or
   minimal treatment if there are no
   approved therapies)?      or
B. Therapy that is most commonly applied in
   the oncologic community?

3/30/2010             ESMO Lugano 2007
             Important questions

Is satraplatin + prednisone better palliation than
  prednisone alone?
                               Yes
Is prednisone alone the standard treatment for men who
  are fit enough to receive second-line chemotherapy?
                               No
Is satraplatin superior to chemotherapy with other
  drugs (e.g. docetaxel if not used first line;
  mitoxantrone after docetaxel)
      I don’t know and this trial doesn’t tell us

3/30/2010            ESMO Lugano 2007
                     Zoledronate Study
             (Saad et al, JNCI 2002;94:1458-68 and 2004;96:879-82)




                                       Zoledronate 8mg q3wks

            643 pts with
               HRPC                    Zoledronate 4mg q3wks

                                        Placebo q3wks
  1. 8mg dose caused renal insufficiency and
     dropped. 8mg/4mg not better than placebo
  2. Less bone events with 4mg dose (44%)
     compared to placebo (33%, p=0.02) but no
     difference in QL
  3. More low-grade toxicity with zoledronate
3/30/2010                     ESMO Lugano 2007
            Use of Zoledronate with Chemotherapy

• Zoledronate is a useful drug to decrease bone
  events in selected patients.
• Some cases of osteonecrosis of the jaw
• Annual zoledronate is sufficient to prevent
  osteopenia in patients on long-term anti-androgen
  therapy
• I know of no evidence to support use of this
  expensive drug at 3-weekly intervals with
  chemotherapy


3/30/2010               ESMO Lugano 2007
            Translational Research in Prostate
                   Cancer (ASCO 2007)
• Circulating Tumour Cells (CTC) are a strong predictor
  of survival in men receiving chemotherapy (240
  evaluable pts: Moreno et al, Abst 5016)
• A gene expression pattern of 24 genes was
  associated with systemic progression after PSA
  relapse (416 pts: Jenkins et al, Abst 5017)
• High Androgen Receptor levels in the prostatectomy
  specimen predict short duration of response to ADT
  (63 pts: Cordon-Cardo et al, Abst 5065)
• Elevated C-reactive protein predicts short survival
  and SREs in patients receiving docetaxel (160 pts:
  Graff et al, Abst 5074)
3/30/2010               ESMO Lugano 2007
             Acknowledgements

• The many investigators who collaborated
  in the trials that I have described –

• The patients who participated in the trials
  and thereby contributed to knowledge
  about how to best treat this disease




3/30/2010         ESMO Lugano 2007
                   The End

            Thank you for inviting me to
                      Lugano


            And now....

3/30/2010           ESMO Lugano 2007

								
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