CASTRATION-RESISTANT PROSTATE CANCER (CRPC) NOVEL CHEMOTHERAPEUTIC AGENTS P. Carlini, Rome

CASTRATION-RESISTANT PROSTATE CANCER (CRPC) NOVEL CHEMOTHERAPEUTIC AGENTS

P. Carlini, Rome

Although a variety of cytotoxic agents have been actively investigated for the treatment of patients with CRPC, most agents tested have demonstrated only

marginal efficacy and, at best, have extended survival only 10–12 months.

Mike Shelley, et al. Cochrane Database Syst Rev 2008

Mike Shelley, et al. Cochrane Database Syst Rev 2008

Mitoxantrone with prednisone is the only other cytotoxic regimen indicated for CRPC based on a palliative benefit

(improvement in the McGill-Melzack bone pain score) rather than a prolongation of OS.

Mitoxantrone

Kantoff PW et al J Clin Oncol 1999;17: 2506–2513.

Tannock IF et al. J Clin Oncol 1996;14:1756 –1764.

Berthold DR et al Ann Oncol 2008;19:1749 –1753.

Rosenberg JE et al Cancer 2007;110:556 –563.

PSA response, as defined above, occurs in approximately 20%– 30% of patients treated with mitoxantrone in the first-line setting and in 15% of patients treated in the second- line setting following docetaxel

FDA Regulatory Approvals in Metastatic CRPC

• Estramustine-1981 Ancient History

• Strontium89-1993 Reduction in new onset of painful bone lesions after XRT + isotope

• Mitoxantrone + prednisone-1996 Reduction in pain

• Samarium153-1997 Reduction in bone pain

• Zoledronic acid-2002 Skeletal related event reduction

• Docetaxel + prednisone-2004 Prolonged survival

• Sipuleucel-T-2010 Prolonged Survival

• Cabazitaxel + prednisone-2010 Prolonged Survival

• Denosumab-2010 Skeletal related event reduction

• Abiraterone + prednisone-2011 Prolonged Survival

• 2012: MDV3100 and radium-223 chloride Prolonged Survival

Two randomised phase 3 trials have demonstrated a significant improvement in overall survival (OS)

for docetaxel- based chemotherapy, compared with the

mitoxantrone-prednisone combination

Petrylak DP et al NEJM 2004; 351: 1513–20.

30 months

Tannock IF et al NEJM 2004; 351: 1502–12

Docetaxel given at the dose of 75 mg/m2 every 21 d is the sole regimen approved by the FDA and EMA for the treatment of mCRPC

Treatment for docetaxel-resistant CRPC is becoming a major unmet need

for patients with advanced prostate cancer because no standard treatment

exists for this clinical situation

Berthold DR et al J Clin Oncol 2005;23:8247– 8252.

MECHANISMS OF RESISTANCE TO DOCETAXEL IN METASTATIC PROSTATE CANCER.

Seruga B et a. NRCO 2011

CELLULAR MECHANISMS OF RESISTANCE TO TAXANES

Seruga B et a. NRCO 2011

SECOND LINE CHEMOTHERAPYOPTIONS

• DOCETAXEL RE-CHALLENGE

• NEW TAXANES :CABAZITAXEL

• NEW CHEMOTHERAPEUTIC AGENTS:

• EPOTHILONES,, NEW PLATINUM- BASED REGIMENS,

• NONTAXANE HALICHONDRIN B ANALOG MICROTUBULE INHIBITOR,

NEW CHEMOTHERAPEUTIC AGENTS

NEW TAXANES: CABAZITAXEL, NAB-PACLITAXEL

EPOTHILONES:IXABEPILONE,PATUPILONE,SAGOPILONE

PLATINUM CHEMOTHERAPY DRUGS:SATRAPLATIN

NONTAXANE HALICHONDRIN B ANALOG MICROTUBULE INHIBITOR: ERIBULIN MESYLATE (E7389)

METRONOMIC CHEMOTHERAPY

NEW TAXANES

The Oncologist 2012;17:543–549

CABAZITAXEL

Cabazitaxel: a next generation taxane

Both extracted from needles of the European Yew treeTaxus baccata

XY

X Y

Docetaxel

Cabazitaxel

-OH

-OCH3 -OCH3

-OCCH3

O

99th AACR annual meeting, San Diego, April 2008 (abstract #3227)

These 2 radicals confer very specific properties to cabazitaxel

http://upload.wikimedia.org/wikipedia/commons/6/69/TXbaccata.jpg

Cabazitaxel: selected to overcome taxane resistance

• Some patients do not answer to Docetaxel (acquired or constitutional resistance). This may be due to various mechanisms:

affinity for multidrug resistant (MDR) membrane-associated P-glycoprotein (PgP) efflux pump,

alterations of tubulin, overexpression Bcl-2, Aurora-A …

• Cabazitaxel: Poor affinity for the PgP efflux

pump

greater penetration of the blood brain barrier compared with docetaxel and paclitaxel

Active in vitro and in vivo on tumors resistant to Docetaxel

Mita AC et al, Clin Cancer Res. 2009, 15, 723-730

Taxane

H

R

• Docetaxel and paclitaxel have a strong affinity for the PgP pump

• If the PgP pump is surexpressed, it drives drug out of tumour cell

• Preclinical data Activity against tumor cells and tumor models that are

resistant to, or not sensitive tocurrently available taxanes¹,²

As potent as docetaxel against sensitive cell lines and tumor models¹,²

• Phase I studies Dose-limiting toxicity was neutropenia Antitumor activity in mCRPC including docetaxel-

resistant disease3

Cabazitaxel: preclinical & clinical data

¹ Attard G, Greystoke A, Kaye S, De Bono J. Pathol Biol (Paris). 2006;54(2):72-84.² Pivot X, Koralewski P, Hidalgo JL, et al. Ann Oncol. 2008;19(9):1547-1552.3 Mita AC, Denis LJ, Rowinsky EK, de bono JS et al. Clin Can Res. 2009; Jan 15;15(2):723-30.

De Bono JS et al. Lancet 2010; 376: 1147–54

Primary endpoint: OSSecondary end-points: Progression-freesurvival (PFS), response rate, and safety

Baseline characteristics and treatment history of patients in the intention-to-treat population


Baseline characteristics and treatment history of patients in the intention-to-treat population


Primary endpoint:Overall survival (updated ITT analysis*)


Progression-free survival


De Bono JS et al. Lancet 2010; 376: 1147–54 Oudard S, Future Oncology, 2011

TROPIC Update: at 2 years the same OS (HR 0.70 vs 0.72)

Oudard S, Future Oncology, 2011De Bono JS, The Lancet 2010

OS: 15,1 Vs 12,7 mo

Cut-off Sept 25, 2009)

Intention-to-treat analysis of overall survival in subgroups of patients defined by baseline characteristics.


TROPIC Cabazitaxel: Haematological results


Higher rate of grade ≥ 3 neutropenia than in TAX 327 but patients enrolled in TROPIC had more advanced disease, were heavily pretreated and had weekly hematological testing

*Prophylactic use of G-CSF was permitted except for cycle 1 of treatment at the discretion of the investigator.

*

The incidence of neutropenia varied significantly by region, with rates of neutropenia in North America exceeding those in the Europe

TROPIC Cabazitaxel: Most frequent adverse events



Deaths in patients who received at least one dose of study treatment

30

Conclusions: TROPIC

• Cabazitaxel demonstrated a statistically and clinically significant survival improvement compared with mitoxantrone in study population 15.1 months vs 12.7 months 28% reduced risk of death (HR=0.72, P <.0001) Survival benefit consistent across subgroups

• Secondary endpoints of PFS, RR, and TTP also significantly improved

• Safety profile was manageable Proactive management of side effects recommended

(neutropenia/diarrhea)

Cabazitaxel is the first treatment to show a survival benefit in patients with mCRPC after failure of docetaxel-based therapy

TROPIC post-hoc analyses: impact of cabazitaxel on overall survival at 2 yrs in patients with aggressive

disease

Methods: Patients with poorly differentiated

tumours and/or with visceral metastases

at baseline were analyzed in term of OS

•Aggressive disease was defined as the presence of poorly differentiated tumour histopathology at diagnosis, or presence of visceral metastases.

•Visceral metastases are defined as the presence of lung, liver, adrenal or pancreatic lesions.

Oudard S. at al. ESMO 2012 abs 933P

Overall survival by differentiation at diagnosis

• Patients with poorly differentiated tumour histopathology showed significantly improved OS with CbzP compared with MP


Overall survival by duration of hormonal therapy

Cabazitaxel was associated with a significant survival advantage over MP in all subgroups, suggesting that duration of prior hormonal therapy does not affect the OS benefit associated with cabazitaxel


Heidenreich A et al European Urology 9 August 2012

In patients likely to poorly respond to abiraterone (eg, high Gleason score, rapid progression to CRPC with primary ADT, or progression during docetaxel therapy), cabazitaxel might be the first option in the second- line setting.

For patients with less-aggressive mCRPC, cabazitaxel and abiraterone are reasonable treatment options.

NAB-PACLITAXEL

Journal of Urology 2009; 181, 1672 1677

2 cycles of 150 mg/in2 nab-paclitaxel weekly for 3 weeks during each4-week cycle, followed by radical prostatectomy with bilateral lymphadenectomy.

Journal of Urology 2009; 181, 1672 1677

Post-chemotherapy prostate specific antigen was decreased in 18 of 19 (95%)

Intracytoplasmic vacuolizationoccasional Intranuclear Inclusions.

First-line Therapy : NAB-PACLITAXEL

Kolevska et al 2009: 100 mg/m2 was administered IV QW for 3 weeks of a 4-week cycle. ( 35pts) PSA response was achieved in 9 (25%) Clinical Benefit (response + SD) of 68%.

Amato et al. 2012 in combination with leuprolide and bicalutamide(46 pts)

After two years of therapy, tumor regression was achieved in 78% of patients with a median reduction of PSA level of >90%.

EPOTHILONES:IXABEPILONE

EPOTHILONES (1)

The epothilones represent a novel class of cytotoxic agents that stabilizes microtubules, leading to cell cycle arrest at the G2/M phase of the cell cycle and triggering death, especially in rapidly growing cellsLee FY et al Clin Cancer Res 2001;7:1429 –1437

Detailed structural studies have identified a taxane binding site on the -tubulin surface localized on the luminal (inner) surface of microtubules.

Nogales E et al. Nature 1995;375:424–427

EPOTHILONES (2)

Epothilones also circumvent the overexpression of the multidrug resistance genes or proteins such as MDR-1 and MRP-1Goodin S et al. J Clin Oncol 2004;22:2015–2025.

These agents have also been shown to inhibit tumor growth in taxane-resistant cell lines, suggesting a lack of crossresistance between the two drug classes

Lee FY et al. Cancer Chemother Pharmacol 2009;63:201–212.

Altmann KH. Curr Pharm Des 2005;11:1595–1613 Sepp-Lorenzino L et al. Prostate Cancer

ProstaticDis 1999;2:41–52.

IXABEPILONE: Trials (1)

IXABEPILONE: Trials (2)

EPOTHILONES: PATUPILONE

PATUPILONE

Patupilone 2.5 mg/m2 weekly for 3 weeks of a 4-week cycle.

Annals of Oncology 20: 492–497, 2009

EPOTHILONES: SAGOPILONE

SAGOPILONE

Graff J et al. abstract 5141. J Clin Oncol 2008;26:284s.

SAGOPILONE

Beer TM et al.British Journal of Cancer (2012) 107, 808–813.

Chemotherapy-naıve patients with metastatic CRPC:

Sagopilone (one cycle: 16 mgm2 intravenously over

3 h q3w) plus prednisone (5 mg twice daily)

PSA response rate was 37%.Median overall PFS was 6.4 months.

The most commonly reported adverse events:Peripheral Neuropathy (94.3%), Fatigue (54.7%)

and pain in the extremities (47.2%).

PLATINUM- BASED REGIMENS

Satraplatin

• Third-generation Platinum complex that exhibits in vitro cytotoxicity comparable to cisplatin

• Orally available• Exhibits activity in cisplatin-resistent cell lines

– the DNA-adducts of satraplatin are not recognized by mismatch repair mechanism that acts on cis and carboplatin

• Based on favorable profiles and preclinical data of activity in HRPC cell lines, phase II studies were undertaken

Sternberg. BJU Int;96: 990-4, 2005

Phase II/III trials of Satraplatin in HRPC

Sternberg CN et al Oncology 2005;68:2–9

•Target accrual was 350 patients, but only 50 enrolled due to production

•Primary endpoints included overall survival and time to pain progression

•Secondary endpoints included pain intensity, response rate, time to overall disease progression, ORR, duration of responses, QOL, and safety

EORTC 30972

Sternberg CN et al. Oncology; 68: 2-9, 2005

Satraplatin

• Toxicities were low with more frequent hematologic toxicities observed in the combination arm

• Based on the results of the phase II studies and the EORTC study, a large Phase III trial was planned to extend the results of the EORTC study and determine the OS benefit– Termed SPARC (Satraplatin and Prednisone Against

Refractory Cancer)

Sternberg CN et al. Oncology; 68: 2-9, 2005

Sternberg CN et al JCO 2009;5431-38

SPARC


•Primary endpoints were OS and PFS

•Secondary Endpoints were Time to Pain Progression,PFS

PFS OS


SPARC

Oh WK et al. Cancer 2007;109:477–86

Platinum chemotherapy drugs historically have been considered inactivein CRPC, although a review of the data suggested otherwise.

Carboplatin, in particular, induced very high response rates when it was combined with estramustine and a taxane, but it also appeared to have activity in patients who progressed after docetaxel

CARBO (AUC=4) +ETOPOSIDE 1OO MG/MQ FOR 3 DAYS,Q21

CARBO (AUC=5) +ETOPOSIDE 8O MG/MQ FOR 3 DAYS,Q21

PSA decline > 50% was achieved in nine patients (23%).Median PFS was 2.1 months (range 0.6–9.6)Median OS was 19 months (range 2.1–27.7).

Eribulin Mesylate (E7389)

Is a synthetic analog of the marine sponge-derived natural product, halichondrin B, which may overcome resistance to docetaxel.Inhibits microtubule dynamics by suppressing microtubule polymerization and sequesters tubulin into nonfunctional aggregatesThe median age of patients was 71 years and median number of cycles was 4.

PSA decreases of 50% were achieved in 22.4% and 8.5% of taxane-naive and taxane-pretreated patients

Grade 3/4 adverse event was neutropenia, seen in 22.4% of chemo-naive and 40% of taxane-pretreated men and peripheral neuropathy occurred in none of the taxane-naive patients and 6.0% of taxane-pretreated patients.

Clin Cancer Res 2009;15(15) August 1, 2009

A confirmed PSA decrease of ≥50% from baseline was observed in 9 of 28 patients (32%).

Median PFS and OS were 3 months and 21 months respectively

500mg/m2 CTX i.v. bolus on day 1 and, from day 2, 50mg/day CTX p.o. plus 200mg/twice a day CXB p.o.

and 1 mg/day DEX p.o. until disease progression

Fontana A et al. Clin Cancer Res 2009;15(15) August 1, 2009

Twenty-eight patients (68%docetaxel-resistant)

Median Age 74.5 yrs

Clin Cancer Res 2009;15(15) August 1, 2009

Documents

CASTRATION-RESISTANT PROSTATE CANCER (CRPC) NOVEL CHEMOTHERAPEUTIC AGENTS P. Carlini, Rome