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How should we sequence therapy?
• Dipartimento Scienze Radiologiche, Oncologiche e Anatomo Patologiche;
Oncologia B.“Sapienza” Università di Roma
Enrico CortesiRoberto Iacovelli
New Perspectives in Metastatic Prostate Cancer
The Mediterranean School ofOncology
Denosumab and Continous Care in PCa. Enrico Cortesi
• Typical patient presentation as they move through different stages
Under the care of ONCOLOGIST
Under UROLOGIST care
Nonmetastatic Metastatic
Local therapy
Androgen deprivation
Therapies after LHRH agonists
andantiandrogens
First-line therapy
Salvagetherapy
Death
Under ONCOLOGIST care
Higano C, et al. In: Figg WD, et al. Drug management of prostate cancer; 2010.
Burden of disease
Asymptomatic Symptomatic
Castrate sensitive Castrate resistant
Natural History of Prostate Cancer
Sequential therapies in metastatic PCa Enrico CortesiFrom Oliver Sartor ASCO 2012 Educational Session
Sequential therapies in metastatic PCa Enrico Cortesi
How many patients have 2nd line?
Docetaxel
2nd line
ADT
mPCa
100% of pts (…I hope!)
25% of pts2
50-60% of pts1
1- Ryan et al. ASCO 2012; 2-Berthold et al. Ann Oncol. 2008 Oct;19(10):1749-53.
…It’s reductive ,I know, but now the hot question is: “what is the best second line?”
Sequential therapies in metastatic PCa Enrico Cortesi
Why a sequential therapy?
Mitoxantrone* 12.7
In few years 4 studies reported a significant improvement of OS in CRPC patients after docetaxel failure.
Placebo* 10.9
Placebo 13.6
Alpharadin 14.0
Overall Survival
Cabazitaxel* 15.1
Abiraterone* 14.8
MDV3100 18.4
Placebo 11.2
Mitoxantrone* 3.1
Placebo* 6.6
Placebo 2.9
Cabazitaxel* 6.4
Abiraterone* 10.2
MDV3100 8.3
PSA-PFS
* Plus Prednisone
Sequential therapies in metastatic PCa Enrico Cortesi
How to choose a sequential therapy?
Several considerations:
• Patient progressed to docetaxel have a median survival from 11 to 13.5 mos
• The median improvement in OS with new agents is 3-5 mos
• CHT is confirmed to be effective in CRPC
• Hormonal Therapy is confirmed to be effective in CRPC
• Patients with good PS ask for more treatment
• Tumor related symptoms must be palliate, when possible, with active drugs.
Sequential therapies in metastatic PCa Enrico Cortesi
How to choose a sequential therapy?
MDV3100 OS=18.4 +
Alpharadin OS=14.0
Cabazitaxel PFS=6.4 Abiraterone PFS=10.2+Increase of OS of 16 mos!!
Patients with visceral mets:
Patients with bone mets only:
+ MDV3100 PFS=8.3 + Abiraterone
PFS=10.2 + Cabazitaxel PFS=6.4
This would be great but is not
EBM!!!!
Increase of OS of 24 mos!!
Sequential therapies in metastatic PCa Enrico Cortesi
Mitoxantrone 3.1
Placebo 6.6
Placebo 2.9
Cabazitaxel 6.4
Abiraterone 10.2
MDV3100 8.3
PSA-PFS
How to choose a sequential therapy?Why trials are not comparable!
Mitoxantrone and placebo are longer considered equally and placebo PSA-PFS showed greater variability!
patients selection might make a difference!!!
Sequential therapies in metastatic PCa Enrico Cortesi
Difference in patient populations in APC phase III trials
The reason why thesestudies are not comparable!
Caba Abi MDV3100 Alph
Age 68 69 69 70
ECOG ≤1 93% 90% 91.2% 86%
mPSA (ng/ml) 143.9 198.8 107.7 159
Bone disease 80% 89% 91.3% 100%
Soft Tiss dis 25% / 70.9% 0%
Liver dis / 11% 11.6% 0%
Only 1 prev therapy
69% 70% 72.4% /
PD TXT < 3m last dose
48% /
Sequential therapies in metastatic PCa Enrico Cortesi
How to choose a sequential therapy?
Factors to be considered for a second line therapy after docetaxel failure:
- Type of disease: bone only vs. visceral;- Time to PD after docetaxel discontinuation;- Total dose of docetaxel received;- Patient clinical status and PS- Risk to resistance to therapy.
Sequential therapies in metastatic PCa Enrico Cortesi
How to choose a sequential therapy?
Factors to be considered for a second line therapy after docetaxel failure:
- Type of disease: bone only vs. visceral;- Time to PD after docetaxel discontinuation;- Total dose of docetaxel received;- Patient clinical status and PS- Risk to resistance to therapy.
Denosumab and Continous Care in PCa. Enrico Cortesi
Time of M0 to M1 and Death in Progressive, Nonmetastatic CRPC
Time to Bone Metastasis Time to Death
25 mos 46.8 mos
Smith MR, et al. Cancer. 2011;117:2077-2085.
Mos Since Randomization6 30 48 66
0
0.2
0.4
0.6
0.8
Prob
abili
ty o
f Bo
ne M
etas
tase
s
0
0.1
0.3
0.5
0.7
0.91.0
12 18 24 36 42 6054
Cumulative incidence function95% CI
Mos Since Randomization6 30 48 66
0
0.2
0.4
0.6
0.8
Prob
abili
ty o
f Dea
th
0
0.1
0.3
0.5
0.7
0.91.0
12 18 24 36 42 6054
Kaplan-Meier estimate95% CI
Denosumab and Continous Care in PCa. Enrico Cortesi
Timing of Disease Progression in Prostate Cancer
Castration-Resistant Prostate Cancer
M0 M1 Asymptomatic M1 Symptomatic
M0 M1 M1+
A continuum, but not equal in time
25-30 10-12 10-15
Mos
Sequential therapies in metastatic PCa Enrico Cortesi
Bone Health in Prostate cancer:
Skeletal Complications
Negative impact on survival[5]
Men with prostate cancer without skeletal fracture survived 39 mos longer than
those with a fracture
Increased medical costs[1]
Treatment of bone complications more than doubles the total treatment costs for patients with
bone metastases
Impaired mobility[6]
Hip fracture associated with a 50% long-
term disability rate; 25% require nursing home care
Diminished quality of life[2-4]
History of a skeletal complication
is associated with lower QoL in breast and
prostate cancer
1. Groot MT, et al. Eur Urol. 2003;43:226-232. 2. Weinfurt KP, et al. Ann Oncol. 2005;16:579-584.3. Weinfurt KP, et al. Med Care. 2004;42:164-175. 4. Saad F, et al. Eur Urol. 2004;46:731-740. 5. Oefelein MG, et al. J Urol. 2002;168:1005-1007. 6. Riggs BL, et al. Bone. 1995;17:505S-511S.
Sequential therapies in metastatic PCa Enrico Cortesi
Changes in Functional Assessment of Cancer Therapy-General (FACT-G) scores indicate that skeletal complications reduce health-related quality of life in patients with prostate cancer.
Weinfurt et al. Ann Oncol 2005
SRE and Quality of Life (QoL)
Sequential therapies in metastatic PCa Enrico Cortesi
Reduction of SRE is an assets in activity of new molecules for PCa
Abiraterone Acetate vs. Placebo• Reduce the time to SRE of 25% of the patients having a skeletal event (9.9 vs. 4.9 months) • Reduce the rate of pain palliation among patients with a baseline pain score of 4 or more and at least one post-baseline pain score (44% vs. 27%, P = 0.002).
Cabazitaxel vs. MitoxantronePain response rates were similar in the two groups; there was no significant difference between the treatment groups in time to pain progression.
Enzalutamide (MDV3100) vs. PlaceboReduce the risk of first skeletal event of 38%;Increase the time to first skeletal event from 13.3 to 16.7 months
Sequential therapies in metastatic PCa Enrico Cortesi
Bone Health in Prostate cancer:
Alpharadin reported increase of OS and TTSF in patients treated or unfit for docetaxel with exclusive bone disease.
Treatment with other agents which prevent SREs is feasible.
This treatment should be considered the first option in patients without visceral disease.
Simultaneous treatment with other antineoplastic agents (specially hormonal agents) may be feasible due to the low toxicity.
Sequential therapies in metastatic PCa Enrico Cortesi
A possible algorithm:
CRPC treated with TXT
Only Bone mts
Alpharadin + Zometa or
Denosumab
Yes
Sequential therapies in metastatic PCa Enrico Cortesi
How to choose a sequential therapy?
Factors to be considered for a second line therapy after docetaxel failure:
- Type of disease: bone only vs. visceral;- Time to PD after docetaxel discontinuation;- Total dose of docetaxel received;- Patient clinical status and PS- Risk to resistance to therapy.
Sequential therapies in metastatic PCa Enrico Cortesi
Time to PD to previous TXT: Cabazitaxel
CABA seems to be more active in:- patients who progress rapidly after TXT discontinuation and - received at least 3 cycles of TXT.
Bono et al. Lancet 2010; 376: 1147–54
Sequential therapies in metastatic PCa Enrico Cortesi
Time to PD to previous TXT: Abiraterone
Abiraterone seems to act better in patients exposed to docetaxel for at least 3 months
Abiraterone is equally effective in patients progressed before or after 3 months from last dose of TXT
Sequential therapies in metastatic PCa Enrico Cortesi
Time to PD to previous TXT:
Retrospective analyses of abiraterone and cabazitaxel phase III trials showed as:-The time from last dose of docetaxel to PD is not a selection criteria- Cabazitaxel and abiraterone are more effective in patients who receive correct treatment with docetaxel (at least 3 month).
CRPC treated with TXT
Only Bone mts
Alpharadin + Denosumab or
Zometa
Yes
At least 3 months of TXT
No
No
Sequential therapies in metastatic PCa Enrico Cortesi
How to choose a sequential therapy?
Factors to be considered for a second line therapy after docetaxel failure:
- Type of disease: bone only vs. visceral;- Time to PD after docetaxel discontinuation;- Total dose of docetaxel received;- Patient clinical status and PS- Risk to resistance to therapy.
Sequential therapies in metastatic PCa Enrico Cortesi
Patient PS:
Most of patients enrolled in phase III trials are ECOG-PS = 0-1, no benefit was reported in patients with PS = 2.
MDV 3100
Caba
Abi
Sequential therapies in metastatic PCa Enrico Cortesi
… then we have not evidence to treat patients with ECOG-PS=2, but…
How many are these patients?
pts ECOG-PS=2
Caba vs Mtx 8%
Abi vs Pbo 10%
MDV3100 vs Pbo 8%
Alph vs Pbo 13%
Recently we presented a meta-analysis at SIURO 2012 that reports that also these patients achieved a benefit from treatment.
Probably, in real world the number of these patient is greater!
In the overall cohort treatment reduce the risk of death of 25% (HR 0.758; 95% CI 0.574-0.999, p=0.049).The benefit was greater for patients treated with hormonal therapies compared to CHT (HR 0.74 vs 0.81) even if not significant.
Altavilla, Iacovelli , Cortesi, et al. Oral presentation at SIURO2012
Sequential therapies in metastatic PCa Enrico Cortesi
CRPC treated with TXT
Only Bone mts
Alpharadin + Denosumab or
Zometa
Yes
At least 3 months of TXT
No
No
A possible algorithm:
PS=2
YesHormonal therapies
Yes
Sequential therapies in metastatic PCa Enrico Cortesi
How to choose a sequential therapy?
Factors to be considered for a second line therapy after docetaxel failure:
- Type of disease: bone only vs. visceral;- Time to PD after docetaxel discontinuation;- Total dose of docetaxel received;- Patient clinical status and PS- Risk to resistance to therapy.
Sequential therapies in metastatic PCa Enrico Cortesi
“The risk to be refractory to treatment”:
62% of patients had PD as best response a 3 mos with Cabazitaxel.
35% of patients had PD as best response a 3 mos with Abiraterone.
Abiraterone indirectly reduce the risk of PD as best response but …
Sequential therapies in metastatic PCa Enrico Cortesi
100
80
60
40
20
00
Prog
ress
ion-
Free
(%)
3 6 9 15 1812
546542
489400
340204
16490
123
00
AAPL
4630
Time to Progression or Death (Months)
AA + PPL + P
“The risk to be refractory to treatment”:
The risk to be refractory to abiraterone in CRPC CHT naïve is less than 10%!
<10% CRPC CHT naive
35% CRPC CHT treated
Factor which increase
resistance…probably resistance to therapy is not influenced by the type of therapy but by several molecular pathways that need to be investigated!
Sequential therapies in metastatic PCa Enrico Cortesi
How to choose a sequential therapy?
- PSIs not an exclusion criteria: PS2 had the probability of 25% the risk of death if treated but no evidence are available as far as the best second line.
- Type of disease bone vs. visceralPatients with bone mets should be first treated with Alpharadin. NO head to head trials are available with other agents but this may consent to have a possibility for further bone or visceral progression.
- Time to PD after docetaxel discontinuationAvailable evidences do not showed a benefit for abiraterone or cabazitaxel based on time from last dose of docetaxel to PD.
- Total dose of docetaxel received;The availability of “second lines” is not a criteria to avoid treatment with docetaxel.
Sequential therapies in metastatic PCa Enrico Cortesi
How to choose a sequential therapy?New evidences may help the clinicians!
Interim Analysis Results of COU-AA-302, a Randomized, Phase 3 Study of Abiraterone Acetate (AA) in Chemotherapy-Naïve Patients With Metastatic Castration-Resistant
Prostate Cancer (mCRPC)
100
80
60
40
20
00
Prog
ress
ion-
Free
(%)
3 6 9 15 1812
546542
489400
340204
16490
123
00
AAPL
4630
Time to Progression or Death (Months)
AA + PPL + P
546542
538534
482465
452437
2725
00
524509
503493
02
120106
258237
412387
100
80
60
40
20
00
Surv
ival
(%)
3 12 15 27Time to Death (Months)
33
AA + PPL + P
6 9 30242118
AAPL
AA + P (median, mos): NRPL + P (median, mos): 27.2
HR (95% CI): 0.75 (0.61-0.93)
P value: 0.0097
AA + P (median, mos): NRPL + P (median, mos): 8.3
HR (95% CI): 0.43 (0.35-0.52)
P value: < 0.0001
PFS 0S
Sequential therapies in metastatic PCa Enrico Cortesi
How to choose a sequential therapy?New evidences may help the clinicians …or not!
The correct position for abiraterone will be in chemotherapy naïve CRPC, in next future ….
MDV3100 and Cabazitaxel will not be the only second lines available, new agents are in advanced phase of study: TAK700, cabozatinib, ipilimumab, etc…
We will now need more comparative studies better thantrials for new agents.
Meanwhile…
Sequential therapies in metastatic PCa Enrico Cortesi
How to choose a sequential therapy?
MDV3100 OS=18.4 +
Alpharadin OS=14.0
Cabazitaxel PFS=6.4 Abiraterone PFS=10.2+Increase of OS of 16 mos!!
Patients with visceral mets:
Patients with bone mets only:
+ MDV3100 PFS=8.3 + Abiraterone
PFS=10.2 + Cabazitaxel PFS=6.4
This would be great and might
make sense ….
Increase of OS of 24 mos!!
Sequential therapies in metastatic PCa Enrico Cortesi
CRPC treated with TXT
Only Bone mts
Alpharadin + Denosumab or
Zometa
Yes
At least 3 months of TXT
No
No
A possible algorithm:
Cabazitaxel Abiraterone MDV3100Chose what you want but use
it well… docetaxel included!
PS=2
Yes
No
Hormonal therapies
Yes