First and second-line chemotherapy - OncologyPRO...FIRST AND SECOND-LINE CHEMOTHERAPY Session 5 Chemotherapy for castration refractory prostate cancer Oct-14 ESMO preceptorship 1 •high

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FIRST AND SECOND-LINE CHEMOTHERAPY

Session 5

Chemotherapy for castration refractory prostate cancer

Oct-14 1ESMO preceptorship



• high disease burden including those with visceral metastases, ≥4 bone metastases including ≥1 bone lesion beyond the vertebral column

• volume of bone metastases was measured by number of lesions and location (axial or appendicular skeleton) and not by stringent volume criteria, given the difficulties of measuring tumor volume in bone.

Oct-14 ESMO preceptorship 4



Therapies in Addition to Androgen-Deprivation Therapy:Therapies with demonstrated survival and quality-of-life benefits:● Docetaxel and prednisone should be offered• Benefit: moderate; • harm: moderate; • evidence strength: strong; • recommendation strength:

moderateTherapies with demonstrated survival benefit and unclear quality-of-life benefit:● Cabazitaxel and prednisone may be offered to men who experience progression with docetaxel• Benefit: moderate; • harm: moderate to high; • evidence strength: strong; • recommendation strength:

moderate

American Society of Clinical Oncology ClinicalPractice Guideline Committee approval:April 26, 2013;

2004


2010


Petrylak DP, Tangen CM, Hussain MH, et al:Docetaxel and estramustinecompared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520, 2004

SWOG 9916

OS 17.5 mo vs 15.6 mo



Berthold DR, Pond GR, Soban F, et al.: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 26:242-245, 2008

OS: median 19.2 mo vs. 17.8 mo vs 16.3 (MI arm)


18.6% alive after 3 years

TAX 327

Adverse Reaction

TAXOTERE 75 mg/m² every 3 weeks +

prednisone 5 mg twice daily n=332

Any %Grade

3/4 %

Anemia 67 5

Neutropenia 41 32

Thrombocytopenia 3 1

Febrile neutropenia 3 N/A

Infection 32 6

Epistaxis 6 0

Allergic Reactions 8 1

Fluid Retention* 24 1

Weight Gain* 8 0

Peripheral Edema* 18 0

Neuropathy Sensory 30 2

Neuropathy Motor 7 2

Rash/Desquamation 6 0

Alopecia 65 N/A

Nail Changes 30 0

First-line docetaxel-based chemotherapy – side effects


Adverse Reaction

TAXOTERE 75 mg/m² every 3 weeks +

prednisone 5 mg twice daily n=332

Any % Grade

3/4 %

Nausea 41 3

Diarrhea 32 2

Stomatitis/Pharyngit

is 20 1

Taste Disturbance 18 0

Vomiting 17 2

Anorexia 17 1

Cough 12 0

Dyspnea 15 3

Cardiac left

ventricular function 10 0

Fatigue 53 5

Myalgia 15 0

Tearing 10 1

Arthralgia 8 1

*Related to treatment

First-line docetaxel-based chemotherapy – side effects



Median survival 15.1 vs 12.7 monthsHR for death 0.70 (p<0.0001)


Median progression freesurvival 2.8 vs 1.4 months




Short response

to ADT

• limited evidence that patients with <16 months’ response to initial androgen-deprivation therapy (ADT) may respond better to chemotherapy than subsequent hormone therapies

Gleason and docetaxel

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TAX 327


Gleason and cabazitaxel

• Forty-seven patients • Patients received a median of nine cycles of

cabazitaxel. • Median progression-free survival was 7.0 months

(95% CI: 5.7-8.0). • At multivariate analysis, a higher Gleason score (≥

8) appeared to be associated with prolonged progression-free survival (hazard ratio: 0.36; 95% CI: 0.18-0.72);

• the higher Gleason score showed no statistical impact on overall survival.


Buonerba C et al. Future Oncol. 2013 Jun: 9:889-97


Short responseto ADT


aggressive disease

• Gleason score ≥8 and visceral metastases – are often considered candidates for chemotherapy, although definitive data supporting this approach do not exist


Survival according to metastatic side – TAX 327

lymph node-only metastases (median OS 26.7 months)

liver metastases with or without othermetastases median OS (10.0 months)

lung metastases with or without bone or lymph node metastases (median OS 14.4 months),

bone plus lymph node metastases (median OS 15.7 months),

bone-only metastases (median OS 19.0 months),


Short responseto ADT


aggressive disease

• Gleason score ≥8 and visceral metastases – are often considered candidates for chemotherapy, although definitive data supporting this approach do not exist

Visceralmetastases

• no comparative studies of chemotherapy and AR-targeting agents

• visceral metastases were an exclusion criterion for studies evaluating sipuleucel-T, abiraterone acetate plus prednisone in the chemotherapy-naïve setting and radium-223

Armstrong AJ et al. Clin Cancer Res 2010,16,203-211Oct-14 24ESMO preceptorship

Number of treatment cycles

Optimal duration

No survival benefit of

more than 10 cycles

Number of cycles

Pond et al. Eur Urol 2012,61,363-369Oct-14 25ESMO preceptorship

0.5 0.7 0.9 1.0 1.1 1.3 1.5

All patients

Age ≤ 68 yearsAge ≥ 69 years

PSA <115 ng/mLPSA ≥115 ng/mL

No painPain

KPS ≤80%KPS ≥90%

FACT-P <109FACT-P ≥109

Favors

Docetaxel q3w

Favors

Mitoxantrone

Berthold D et al. J. Clin. Oncol. 2008; 26:242-45

No visceral diseaseVisceral disease

Berthold D et al. J. Clin. Oncol. 2008; 26:242-45

Treatment related to age


• 175 patients aged >75 yr with CRPC treated with first-line docetaxel

• nine French tertiary care cancer centres from 2000 to 2007.

• Median age was 78 yr.

• Ninety-five patients (54%) received a standard 3-wk regimen (SR), and 80 patients (46%) received an adapted regimen (AR)delivered on a weekly schedule with various times for rest periods

First-line docetaxel-based chemotherapy inCRPC patients aged >75 yr.

Italiano A et al. European urology 55 ( 2 0 0 9 ) 1368–1376Oct-14 27ESMO preceptorship

First-line docetaxel-based chemotherapy inCRPC patients aged >75 yr.

Italiano A et al. European urology 55 ( 2 0 0 9 ) 1368–1376

Age by itself should not be used as a criterion to deny patientswith CRPC a potentially effective chemotherapy.


Armstrong AJ et al. Clin Cancer Res 2010,16,203-211

PSARadiologic progress.Pain progress.

Progression factors:



Cross-resistance

It is unknown whether treating patients with hormone therapies and immunotherapies affects their subsequent response to chemotherapy

cross resistance can occur between different taxanes

between taxanes and androgen-targeting agents

between androgen-targeting agents

In vitro data have shown that docetaxel, cabazitaxel, abiraterone acetate, and enzalutamide all inhibit AR nuclear translocation

these data may have clinical implications when combining and sequencing these drugs

Mezynsky J et al. Ann Oncol 2012,23,2943-2947

PSA decline of > 50% in 9/35 ptt.

31

Can androgen deprivation potentially decrease the efficacy of taxanes? Docetaxel after abiraterone

Oct-14 ESMO preceptorship

Mezynsky J et al. Ann Oncol 2012,23,2943-2947

Docetaxel after abiraterone

PSA decline of > 50% in 9/35 ptt.

Median time to PSA progression 4.5 mo.Median overall survival 12.5 mo.

Median overall survival in the TAX 327 trial was 18.9 mo.

32

Can androgen deprivation potentially decrease the efficacy of taxanes? Docetaxel after abiraterone

Oct-14 ESMO preceptorship


Post hoc analysis abiraterone-cabazitaxel cab-abi

tumor response of both agents, particularly cabazitaxel, was lower when

administered as higher-line therapy

Abi→Cab treated patients: 6.5

months

Cab→Abi treated patients: 8.1

months

No significant diff. in OS, but in PFS

Retrospective analysis of cabazitaxel and abiraterone

63 patients received Cab→Abi(cabazitaxel prior to abiraterone) and

69 patients received Abi→Cab

Int J Cancer. 2014 Sep 20

http://www.ncbi.nlm.nih.gov.ep.fjernadgang.kb.dk/pubmed

Combination treatment



When to start chemotherapy?

Docetaxel: adjuvant, hormone sensitive, hormone resitant

decision will be highly individualized,

based on the presence of symptoms,

comorbidities,

previous therapies,

available treatment options,

and risk of clinical progression,

patient preference based on an informed risk/benefit discussion.


When to start chemotherapy?

Docetaxel: adjuvant, hormone sensitive, hormone resitant

Cabazitaxel: visceral metastases, only bone metastases, previous experience with chemotherapy

• FIRSTANA (NCT01308567) is a head-to-head phase III study comparing docetaxel plus prednisone with cabazitaxel plus prednisoneas first-line chemotherapy in mCRPC;

• PROSELICA (NCT01308580) is comparing twocabazitaxel doses (20 mg/m2 and 25 mg/m2) as second-line chemotherapy for mCRPC; and

• TAXYNERGY (NCT10718353) is evaluating the role of an early switch in taxane therapy based on suboptimal decline in PSA levels (<30%) within 3 months



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First and second-line chemotherapy - OncologyPRO...FIRST AND SECOND-LINE CHEMOTHERAPY Session 5 Chemotherapy for castration refractory prostate cancer Oct-14 ESMO preceptorship 1 •high