Timing of ADT and chemotherapy - Thomas Keane M.D. Medical University of South Carolina. Charleston S.C - Grand Rounds in Urology
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Timing of ADT and
chemotherapy
Thomas Keane M.D.
Medical University of South Carolina.
Charleston S.C.Conflicts • Tolmar, Ferring, Jannsen, Bayer.
2018 CRPC Treatment Options
• Agonists/Antagonists/Orchiectomy
• Androgen pathway targeting
– Apalutamide (anti-androgen)
− Abiraterone (androgen biosynthesis inhibitor)
− Enzalutamide (anti-androgen)
• Radiopharmaceuticals
− Radium 223
• Immunotherapy
− Sipuleucel-T
• Chemotherapy
− Docetaxel (1st line)
− Cabazitaxel (2nd line)
− IS EARLIER
.
BETTER?
− IF SO .
USA TodayNew concept • could these agents be applied to Hormone Sensitive Prostate Cancer a • Which agents and when ??
Discussion Topics • E3805 (CHAARTED) data review • Comparison with GETUG-AFU 15 • Who really should receive docetaxel? The high vs. low volume/risk disease debate • Safety and toxicity considerations
E3805 CHAARTED: ChemoHormonal Therapy vs.
Androgen Ablation for Metastatic Prostate Cancer
Evaluate every 3
STRATIFICATION ARM A: weeks while
ADT + Docetaxel receiving
Extent of Mets 75mg/m2 every 21 docetaxel and at
-High vs Low R days for maximum 6 week 24 then
cycles every 12 weeks Follow for time to
Age A progression and
≥70 vs < 70yo N overall survival
ECOG PS • Original design n=568 for high volume disease
D
- 0-1 vs 2 • Adjustments for allowance of low volume
O Chemotherapy at
CAB> 30 days disease and projected OS based on S9346 data
M investigator’s
-Yes vs No n=780
I discretion at
SRE Prevention progression
-Yes vs No Z ARM B:
E ADT (androgen Evaluate every
Prior Adjuvant ADT
deprivation therapy 12 weeks
≤12 vs > 12 months
alone)
• ADT allowed up to 120 days prior to randomization
• Intermittent ADT dosing was not allowed
• Standard dexamethasone premedication but NO DAILY PREDNISONE Sweeney C et al. ASCO 2014; Abstract LBA2.E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen Ablation for
Metastatic Prostate Cancer
1.0
• N=790 men accrued 07/28/06 - 0.9
Primary endpoint –
11/21/12 Overall survival
0.8
• Planned interim analysis at 53%
0.7
information met 10/13
• 01/16/14 median followup 29 0.6
months 0.5
Probability
• 136 (110 high volume) deaths 0.4 HR=0.61 (0.47-0.80)
p=0.0003
ADT alone vs. 101 (82 high 0.3 Median OS:
volume) deaths ADT+D ADT + D: 57.6 months
0.2
• 83.6% vs. 83.2% of deaths ADT alone: 44.0 months
from prostate cancer 0.1
0.0
0 12 24 36 48 60 72 84
OS (Months)
Sweeney C et al. ASCO 2014; Abstract LBA2. Arm TOTAL DEAD ALIVE MEDIAN
A 397 101 296 57.6
B 393 136 257 44.0E3805 CHAARTED: ChemoHormonal Therapy vs.
Androgen Ablation for Metastatic Prostate Cancer
OS by extent of metastatic disease at start of ADT
1.0 1.0
>4 bone lesions and
0.9 >1 lesion in any bony structure 0.9
beyond the spine/pelvis
0.8 OR 0.8
0.7
visceral disease 0.7
0.6 0.6
0.5 0.5
Probability
Probability
p=0.0006 p=0.1398
0.4 0.4 HR=0.63 (0.34-1.17)
HR=0.60 (0.45-0.81)
Median OS: 0.3
Median OS:
0.3
ADT + D: 49.2 months ADT + D: Not reached
0.2 ADT alone: 32.2 months 0.2 ADT alone: Not reached
0.1 0.1
0.0 0.0
0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84
High volume OS (Months) Low volume OS (Months)
Arm TOTAL DEAD ALIVE MEDIAN
Arm Sweeney C etTOTAL
al. ASCO 2014;ALIVE
DEAD Abstract LBA2.
MEDIAN
A 134 19 115 .
A 263 82 181 49.2 B 142 26 116 .
B 251 110 141 32.2CHAARTED -4 YEAR MEDIAN FOLLOW UP • Median OS- 57.6 chemohormonal VS 47.2 mts ADT alone. HR 0.72. p=0.0018, • High- Vol DZ (513) 51.2 VS 34.4 mts , • Mortality Risk Reduction- 36% p=0.001, • Median Overall survival benefit from chemotherapy was 16.8 mts, • Low volume disease - no evidence of improved survival when docetaxel was added, • Prior local therapy: Docetaxel –no survival benefit in low volume pts but a non significant survival benefit was reported in the high volume subgroup (median survival)-66.9 vs 51.7 mts. • Results - benefit was more evident in high vs low volume subgroups and burden of metastases determined by conventional imaging may help select pts for this strategy. J Clin Oncol 75.3657.2018
STAMPEDE: Docetaxel and/or Zoledronic Acid in Hormone-Naive
Metastatic PCa
First overall survival analysis of patients enrolled in the following 4 study arms:
• Standard of care (SOC; n = 1,184) • Zoledronic acid (ZDA) + SOC (n = 593)
• Docetaxel (Doc) + SOC (n = 592) • Doc + ZDA + SOC (n = 593)
SoC Doc + SoC ZDA + SoC Doc + ZDA + SoC
Median overall survival 67 mo 77 mo 80 mo 72 mo
Hazard ratio (p-value) Ref* 0.76 (0.003) 0.93 (0.44) 0.81 (0.02)
Median failure-free 21 mo 37 mo 21 mo 37 mo
survival
Hazard ratio (p-value) Ref* 0.62 (HR=0.72 (0.57-0.91) HR=1.01 (0.75-1.36)
p=0.005 p=0.955
Median OS: Median OS:
ADT + D: 22.9 months ADT + D: 58.9 months
ADT alone: 12.9 months ADT alone: 54.2 months
Biochemical PFS Overall Survival
Gravis et al. Lancet Oncol. 2013; 14:149-58.Key Differences between GETUG-AFU 15 and
CHAARTED
GETUG-15 CHAARTED
N 385 790
Docetaxel cycles Up to 9 (median 8) 6
Gleason 8-10 56.1% 68.6%
PSA median (ng/mL) ADT 25.8; ADT+D 26.7 ADT 50.5; ADT+D 56.0
High volume/risk 21.6%1 65.1%2,3
Discontinuations early for toxicity 20.3% 12.5%
Treatment related deaths 4 (2.1%) 1 (0.3%) but 8 (2%) unknown
Median followup 50 months (data cutoff July 31, 2011) 29 months
Subsequent docetaxel with CRPC (%) ADT (62); ADT+D (28) ADT 129/174 (74.1) ; ADT+D 49/145 (33.8)
Subsequent potent AR therapy with CRPC (%) ADT (Summary of Factors that may have Contributed to Different Results between GETUG-AFU 15 and CHAARTED • Study size/statistical power • Prognosis and staging definitions and disease risk/volume were different • ? Toxicity e.g. deaths and early discontinuations and the use of other subsequent therapies were different
Grade 3-5 Hematologic Toxicity from TAX327 in mCRPC vs.
GETUG-AFU 15 vs. CHAARTED
Toxicity TAX327 (%) GETUG-AFU 15 (%) CHAARTED (%)
Neutropenia 32 32* 12
Febrile neutropenia 3 7* 6
Death 0.3 2.1 0.3^
*After 56% accrual and 4 treatment-related deaths, DSMC recommended GCSF days 5-10 with Grade ¾ neutropenia rate decline from 41%
to 15%, febrile neutropenia decline from 8% to 6% and no more deaths.
^2% of deaths were unknown
Key Conclusion: Tough to interpret toxicity data with incomplete information on growth factors and
prophylactic antibiotics, but, is there some a sense that docetaxel may surprisingly be more toxic in mHSPC?
Tannock IF et al. N Engl J Med 2004; 351:1502-12.Pharmacokinetics • Franke, RM et al. examined the relative clearance of docetaxel in 10 non-castrated and 20 castrated men with prostate cancer. • Docetaxel pharmacokinetics were significantly altered in the castrated men with an approximately 100% increase in docetaxel clearance and accordingly two-fold reduction in AUC as compared to the men who were not castrated. • Human and rat-model data were presented to suggest a mechanism for this difference in clearance as increased hepatic uptake of docetaxel via increased anion transporter expression in the setting of castration. (8) • There has been suggestion in CHAARTED/STAMPEDE of greater toxicity with Docetaxel in the castration sensitive state but perhaps greater drug exposure also suggests potential for greater efficacy.
Docetaxel PK varies with Castration State
• 10 non-castrate and 20 castrate
men with similar demographics
• Clearance of docetaxel in castrate
men was 100% increased with 2
fold reduction in AUC
• Erythromycin breath test indicated
hepatic CYP3A4 activity, for
docetaxel metabolism, was not
different
• Castrate rats have higher AUC of
docetaxel in liver compared to
intact animals
50% decrease in docetaxel clearance associated with >430% increase in odds of
grade ¾ neutropenia*
Franke RM et al. J Clin Oncol 2010; 28:4562-67; *Bruno R et al. J Clin Oncol 1998; 16:187-96.What are the Implications of these PK Differences?
Between Different Trials
• May explain some of the greater hematologic
toxicity but also survival benefit observed in
castration-sensitive compared to castration-
resistant trials
• Why was there greater hematologic toxicity in
GETUG-AFU 15 compared to CHAARTED?
• How many patients were non-castrate vs. castrate
in each trial?
• GETUG-AFU 15: 47% initiated ADT within 15 days of
enrollment
• CHAARTED: initiated ADT median 1.1 months to
enrollment
• How much GCSF was used in each trial?Question ? • If toxicity is greater with the use of Docetaxol in the pre- castrate state might not efficacy also be ? • We need a trial.
But What About Docetaxel Before Medical
Castration?
The Rationale????
Does one existProstate Cancer Cell Lines
• In vitro studies of androgen dependent prostate cancer cell lines: Increased
sensitivity to taxane-mediated cell death in response to androgen
stimulation of the androgen receptor.
• In one series, androgen-dependent LNCaP prostate cancer cells showed
decreased survival when cultured with steroid hormones and paclitaxel
(25% survival) versus cells depleted of steroid hormone and then cultured
with paclitaxel (55-60% survival).
• The mechanism for this finding was outlined as likely increased caspace-
dependent apoptosis in the presence of p53 activation and cellular
proliferation.(9)
7. Hess-Wilson JK, Daly HK, Zagorski WA, Montville CP, Knudsen KE. Mitogenic action of the androgen receptor sensitizes prostate
cancer cells to taxane-based cytotoxic insult. Cancer research. 2006;66(24):11998-2008.• In a separate trial in LNCaP-bearing immunodeficient mice, tumor
volume and tumor apoptosis were measured in response to :
• castration alone, docetaxel alone, both interventions administered
concurrently, and both interventions administered in different
sequences.
• Docetaxel administered prior to castration yielded the longest delay
in tumor growth of the studied interventions including a statistically
significant improvement as compared to castration followed by
docetaxel. (p=0.0003)
Tang Y, Khan MA, et al. Docetaxel followed by castration improves outcomes in LNCaP prostate cancer-bearing severe
combined immunodeficient mice. Clinical cancer research : an official journal of the American Association for Cancer Research.
2006;12(1):169-74Breast Cancer
• Hormone-receptor positive breast adenocarcinoma is also responsive to
hormonal manipulation and cytotoxic chemotherapy.
• As opposed to prostate cancer, the established paradigm in breast cancer
is administering cytotoxic chemotherapy independently from hormonal
manipulation.
• A randomized phase III trial of 1558 postmenopausal women – treated
with chemo followed by daily tamoxifen for 5 years
• 9 years follow-up- sequential therapy showed a strong trend toward
improved DFS with HR of 0.84 (95% CI 0.70-1.01; p = 0.061).
7. Osborne CK, Kitten L, Arteaga CL. Antagonism of chemotherapy-induced cytotoxicity for human breast cancer cells by
antiestrogens. Journal of clinical oncology : 1989;7(6):710-7.1.Human Trials
• Hussain et al. Treated 39 men with normal testosterone and rising
PSA post prostatectomy or radiation with up to six cycles of
docetaxel 70 mg/m2 every three weeks.(14)
• Chemotherapy was followed by total androgen blockade (LHRH agonist
and bicalutamide for 12-20 months).
• Serum PSA decreased > 50% in 48.5% and > 75% in 20% of patients
with docetaxel alone,
• Only one patient had increased PSA at the end of the docetaxel
therapy.
12. Hussain A, Dawson N, Amin P, Engstrom C, Dorsey B, Siegel E, et al. Docetaxel followed by hormone therapy in men experiencing increasing
prostate-specific antigen after primary local treatments for prostate cancer. Journal of clinical oncology : official journal of the American
Society of Clinical Oncology. 2005;23(12):2789-96.Hussain et al. continued… • The majority of patients had PSA progression after stopping ADT • 5/33 (15%) patients - undetectable PSA at a median of 18.9 months after stopping ADT. • 7 of the men on this study had radiographic evidence of metastatic disease at enrollment • 3 were in the group who continued to have undetectable PSA for a lengthy period of time despite regaining non-castrate level testosterone post-ADT.
A PHASE II STUDY OF DOCETAXEL BEFORE MEDICAL CASTRATION WITH DEGARELIX IN PATIENTS WITH
NEWLY DIAGNOSED METASTATIC PROSTATIC ADENOCARCINOMA.
N = 50 patients
Enrolling men with newly diagnosed treatment naïve metastatic prostate cancer of all volume
statuses.
>>>
S
8
CT
Primary Endpoint – Proportion of men who maintain a PSA < 0.2 ng/ml at 40 weeks on
study(7 months ADT)
Additional Endpoints – Toxicity, PSA response to Docetaxel alone, time to development of
castration resistance, overall survival, correlating genomics with response.Study Design • Single-arm phase II interventional trial treating n=50 patients • Newly diagnosed metastatic hormone sensitive prostate cancer with 4 cycles Docetaxel 75 mg/m2 without castration followed by 2 cycles docetaxel concurrent with degarelix and then continuing degarealix alone out to 12 months. • MUSC and the Ralph H. Johnson Charleston V.A. Medical Center. • Recently opened at University of Maryland, • Goal - enroll all patients in 24 months.
Accrual Ongoing • 27 patients enrolled to date at the Medical University of South Carolina(21), Ralph H. Johnson Charleston VAMC(5), and University of Maryland(1) • 74% with high volume disease(CHAARTED criteria) • 60% Caucasian, 40% African American
Issues • Is it a good idea to use these agents up front. • Will we negate the benefit of subsequent therapies – earlier resistance or • Perhaps delay the need for their introduction. • Docetaxel response rate was lower and survival much less in CRPC. • Docetaxel much better tolerated in fitter younger pts. • Should it be reserved for high volume metastatic disease. • Cost must be a factor for all these strategies.
You can also read
