Ti Timi ming of ADT T and ch chemotherapy Thomas Keane M.D. - - PowerPoint PPT Presentation

Ti Timi ming of ADT T and ch 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 Today

. .

New concept

• could these agents be applied to Hormone Sensitive Prostate Cancer a
• Which agents and when ??

Discus ussion n Topi pics

• 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

STRATIFICATION Extent of Mets

• High vs Low

Age ≥70 vs < 70yo ECOG PS

• 0-1 vs 2

CAB> 30 days

• Yes vs No

SRE Prevention

• Yes vs No

Prior Adjuvant ADT ≤12 vs > 12 months R A N D O M I Z E ARM A: ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles ARM B: ADT (androgen deprivation therapy alone) Evaluate every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks Evaluate every 12 weeks Follow for time to progression and

• verall survival

Chemotherapy at investigator’s discretion at progression

Sweeney C et al. ASCO 2014; Abstract LBA2.

• ADT allowed up to 120 days prior to randomization
• Intermittent ADT dosing was not allowed
• Standard dexamethasone premedication but NO DAILY PREDNISONE
• Original design n=568 for high volume disease
• Adjustments for allowance of low volume

disease and projected OS based on S9346 data n=780

E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen Ablation for Metastatic Prostate Cancer

Sweeney C et al. ASCO 2014; Abstract LBA2.

• N=790 men accrued 07/28/06 -

11/21/12

• Planned interim analysis at 53%

information met 10/13

• 01/16/14 median followup 29

months

• 136 (110 high volume) deaths

ADT alone vs. 101 (82 high volume) deaths ADT+D

• 83.6% vs. 83.2% of deaths

from prostate cancer

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

OS (Months)

12 24 36 48 60 72 84

Probability HR=0.61 (0.47-0.80) p=0.0003 Median OS: ADT + D: 57.6 months ADT alone: 44.0 months

Primary endpoint – Overall survival

Sweeney C et al. ASCO 2014; Abstract LBA2.

E3805 CHAARTED: ChemoHormonal Therapy vs. Androgen Ablation for Metastatic Prostate Cancer

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

OS (Months)

12 24 36 48 60 72 84

Probability

p=0.0006 HR=0.60 (0.45-0.81) Median OS: ADT + D: 49.2 months ADT alone: 32.2 months >4 bone lesions and >1 lesion in any bony structure beyond the spine/pelvis OR visceral disease

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

OS (Months)

12 24 36 48 60 72 84

Arm ALIVE DEAD MEDIAN TOTAL

Probability

p=0.1398 HR=0.63 (0.34-1.17) Median OS: ADT + D: Not reached ADT alone: Not reached

High volume Low volume

OS by extent of metastatic disease at start of ADT

CHAARTE TED -4 Y 4 YEAR ME MEDIAN F N FOLL LLOW U 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
• f 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

* Pairwise comparisons to control SOC study arm were calculated for each research arm.

• Docetaxel, and not ZDA, improves overall survival compared to SoC
• Docetaxel + ZDA improves survival but offers no obvious benefit over

docetaxel alone

James ND et al. Proc ASCO 2015;Abstract 5001.

SoC Doc + SoC ZDA + SoC Doc + ZDA + SoC 77 mo 80 mo 72 mo 0.76 (0.003) 0.93 (0.44) 0.81 (0.02) 37 mo 21 mo 37 mo Median overall survival 67 mo Hazard ratio (p-value) Ref* Median failure-free survival 21 mo Hazard ratio (p-value) Ref* 0.62 (<0.1 x 10-10) 0.62 (<0.1 x 10-10) 0.93 (0.26)

First overall survival analysis of patients enrolled in the following 4 study arms:

• Standard of care (SOC; n = 1,184)
• Docetaxel (Doc) + SOC (n = 592)
• Zoledronic acid (ZDA) + SOC (n = 593)
• Doc + ZDA + SOC (n = 593)

Gravis et al. Lancet Oncol. 2013; 14:149-58.

Overall Survival Biochemical PFS

HR=1.01 (0.75-1.36) p=0.955 Median OS: ADT + D: 58.9 months ADT alone: 54.2 months HR=0.72 (0.57-0.91) p=0.005 Median OS: ADT + D: 22.9 months ADT alone: 12.9 months

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 (<15); ADT+D (<16) ADT 79/174 (45.5); ADT+D 92/145 (62.8)

• 1. Glass TR et al. J Urol 2003; 169:164-9; 2. Eisenberger M et al. N Engl J Med 1998; 339:1036-42; 3. Millikan RE et al. J Clin Oncol 2008; 26: 5936-42.

Summary y of Factors that may y have Con Contributed t to D

• Different R

Results b between GE GETUG-AF AFU 15 a U 15 and CHAAR CHAARTE TED

• 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

Gr Grade 3 3-5 5 Hematologic Toxicity y from TAX327 327 in mC mCRPC PC vs vs. GET ETUG UG-AFU U 15 vs. CHAARTED ED

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

Tannock IF et al. N Engl J Med 2004; 351:1502-12.

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?

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

Franke RM et al. J Clin Oncol 2010; 28:4562-67; *Bruno R et al. J Clin Oncol 1998; 16:187-96.

50% decrease in docetaxel clearance associated with >430% increase in odds of grade ¾ neutropenia*

What are the Implications of these PK Difference ces?

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?

Qu Question

• n ?

?

• 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 Be Befor

• re Medical

Castration?

The Rationale????

Does one exist

Prostate 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):169-74

Br Breast Ca 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.

Hum Human an Trials ials

• 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 A PHAS HASE II II STUDY Y OF DO DOCETAX AXEL L BEFORE RE MEDIC DICAL AL CAS ASTRA RATIO ION N WIT ITH H DE DEGARE ARELIX LIX IN IN PATIE IENT NTS WIT ITH H NE NEWLY Y DIA DIAGNO NOSED D METAS ASTATIC IC PROSTATIC IC ADE ADENO NOCAR ARCINO INOMA. 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.

St Study D 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.

Ac 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

Is Issues ues

• 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.