How should we sequence therapy? Dipartimento Scienze Radiologiche, Oncologiche e Anatomo Patologiche; Oncologia B. “Sapienza” Università di Roma Enrico

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?”


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


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.



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!!


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!!!


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% /



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.






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


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


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.


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)


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















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.


A possible algorithm:

CRPC treated with TXT

Only Bone mts

Alpharadin + Zometa or

Denosumab

Yes






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


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


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).


Only Bone mts

Alpharadin + Denosumab or

Zometa

Yes

At least 3 months of TXT

No

No






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


… 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



Only Bone mts


Zometa

Yes


No

No


PS=2

YesHormonal therapies

Yes






“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 …


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!



- 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.


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


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…



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!!



Only Bone mts


Zometa

Yes


No

No


Cabazitaxel Abiraterone MDV3100Chose what you want but use

it well… docetaxel included!

PS=2

Yes

No

Hormonal therapies

Yes

Documents

How should we sequence therapy? Dipartimento Scienze Radiologiche, Oncologiche e Anatomo Patologiche; Oncologia B. “Sapienza” Università di Roma Enrico