Novità in tema di carcinoma della prostata

Daniele Alesini

Istituto Nazionale dei Tumori Regina Elena

Convegno Nazionale AIOM Giovani

“2016: News in Oncology”

“Something Old Something New Something Blue”

Something Borrowed

Cabazitaxel

Alpharadin

Abiraterone

Enzalutamide³

Docetaxel

ADT mPC

Abiraterone

Enzalutamide⁷

Docetaxel

ADT

Docetaxel ADT

DOCETAXEL: BACK AND FORTH

1 N Engl J Med. 2004 Oct 7;351(15):1502-12 2 N Engl J Med. 2011 May 26;364(21):1995-2005 3 N Engl J Med. 2012 Sep 27;367(13):1187-97 4 Lancet. 2010 Oct 2;376(9747):1147-54 5 N Engl J Med. 2013 Jul 18;369(3):213-23 6 N Engl J Med. 2013 Jan 10;368(2):138-48 7 N Engl J Med. 2014 Jul 31;371(5):424-33

GETUG-AF 15¹ 380 pz

OS 58.9 vs 54.2

HR 1.01 95%CI 0.75-1.36

CHAARTED² 790 pz OS 57.6 vs 44.0

HR 0.61 95%CI 0.47-0.80

1 Lancet Oncol. 2013 Feb;14(2):149-58 2 N Engl J Med. 2015 Aug 20;373(8):737-46

STAMPEDE¹ 2962 pz

1 Lancet. 2016 Mar 19;387(10024):1163-77

SOC 71.0

SOC+ZA NR

SOC+Doc 81.0 SOC+Doc+ZA 76.0

Zoledronic Acid showed no evidence of survival improvement and should be not part of standard care for this population.

Docetaxel chemotherapy, given at the time of long-term hormone–therapy initiation, showed evidence of improved survival.

HR 0.94 95%CI 0.79-1.11

HR 0.82 95%CI 0.67-0.97 HR 0.78 95%CI 0.66-0.93

HR 1.06 95%CI 0.86-1.30

“The survival benefit obtained by docetaxel in men with mHSPC is consistent and much larger than when given at the time of mCRPC. Thus six cycles of docetaxel plus ADT should be the new standard of care in men with newly diagnosed metastatic prostate cancer.”¹

1 BMC Medicine (2015) 13:304

“Something Old Something New Something Blue”

Something Borrowed

179 pts

221 blood samples

Taxanes 71 AR Tx

150

15 phenotipically distinct CTC subtypes

Ranking based upon their degree of phenotypic

heterogeneity

Single CTC characterization to identify phenotypic and genomic heterogeneity as a mechanism of resistance to AR signaling directed therapies (AR Tx) in mCRPC patients.

Howard I. Scher ASCO GU 2016

There is a clear increase in phenotypic heterogeneity according to the number of prior lines of therapy.

High phenotypic heterogeneity correlate with shorter survival with AR Tx (OS High vs Low was 9 vs NR, p<0.0001)…but not with Taxanes (11 vs 13, p=0.182)

In a multivariate model in which phenotypic heterogeneity is paired with treatment, Taxanes are strikngly favored over AR Tx on patients with high heterogeneity (HR 0.32, 95% C.I. 0.12- 0.86) but not in those with low heterogeneity (HR 1.09, 95% C.I. 0.54-2.21).

“[This thecnology] allows you to pick out patients that might favor Taxanes instead of AR Tx therapy. That’s important. Our patients need to have the best drugs at the best time, and right now we’re quite empirical in our choices.”¹

1 Study discussant A. Oliver Sartor

“Something Old Something New Something Blue”

Something Borrowed

mCRPC develop numerous mutations that provide malignant cells with the ability to divide, metastasize, escape immune surveillance, and so forth. One of the drivers of this mutation cascade is genetic instability, in part due to the accumulation of mutations that keep the cells from correcting DNA alterations.

These mutations in DNA-repair enzymes can leave the cancer susceptible to additional inhibitors of DNA repair, one of which is PARP, an enzyme found in the nucleus that detects DNA strand breaks and initiates repair.

PARP inhibitor Olaparib has recently been approved for treating BRCA1-2 positive ovarian cancer.

mCRPC

Maximum 2 lines of CHT

CTC ≥ 5 (50 pts)

Olaparib 400mg bid

Until PD

or unacceptable toxicity

Primary endpoint: RR defined as objective response according to RECIST or reduction of PSA

≥50% or CTC <5

Secondary endpoints: rPFS, PFS, OS, Time to PSA Progression >25%, Proportion of Patients with CTC conversion, Safety.

Preplanned whole-exome sequencing and transcriptome studies from fresh-frozen tumor-biopsy samples obtained before treatment.

TOPARP: Olaparib in mCRPC

50 Pts

49 evaluable for response Responders 16

(RR 33%)

11 PSA 14 CTC

6 rPR

16 BioM positive

7 BRCA2 5 ATM 3 FANCA+

BRCA1/CHEK2 1 HDAC2

RESPONSE:

BioM + 14/16 (88%)

BioM – 2/33 (6%)

Defects in DNA repair machinery accounts for approximately 25-30% of sporadic mCRPC.

Obtaining fresh tumor-biopsy samples from mCRPC patients is feasible and can increase our undrestanding of treatment responses.

Platinum-based chemotherapy is generally not used for the treatment of mCRPC but responses to a platinum analogue (Satraplatin) have been reported.

It is conceivable that DNA repair defects may be associated with platinum sensitivity in mCRPC as in ovarian cancer.

“Something Old Something New Something Blue”

Something Borrowed

mCRPC PS 0-2 Chemo-naive

(1168 pts)

Cabazitaxel*

25mg/mq q21

Docetaxel*

75mg/mq q21

Cabazitaxel*

20mg/mq q21

* And Prednisone 10mg/die

Until PD

or unacceptable toxicity

Primary endpoint: OS

Secondary endpoints: safety, composite PFS*, tumor response, PSA response, pain response, time to skeletal-related events, HRQoL, PK/PG

Exploratory: circulating free DNA level

FIRSTANA: Cabazitaxel vs Docetaxel in Chemon-naïve mCRPC.

36

0 6 12 18 24 30 42 48 54

Months 100

80 60 40 20 0

OS (%)

DOC + PRED CBZ 20 + PRED CBZ 25 + PRED

Median OS, Mos (95% CI)

DOC + PRED 24.3 (22.18-27.60) CBZ 20 + PRED 24.5 (21.75-27.20) CBZ 25 + PRED 25.2 (22.90-26.97) CBZ 20 vs DOC

HR: 1.009 (95% CI: 0.85-1.197; p = 0.9967) CBZ 25 vs DOC

HR: 0.97 (95% CI: 0.819-1.160; p = 0.7574)

FIRSTANA: OS

FIRSTANA: PFS

Months

36 0 3 6 9 12 15 18 21 24 27 30 33 100

80 60 40 20 0

PFS (%)

DOC + PRED CBZ 20 + PRED CBZ 25 + PRED

Median PFS, Mos (95% CI)

DOC + PRED 5.3 (4.86-5.78) CBZ 20 + PRED 4.4 (3.91-5.09) CBZ 25 + PRED 5.1 (4.60-5.72) CBZ 20 vs DOC

HR 1.062 (95% CI: 0.913-1.236; p = 0.4218) CBZ 25 vs DOC

HR: 0.989 (95% CI: 0.849-1.152; p = 0.8035)

Small observed difference in pain progression component of PFS for CBZ 25 vs DOC

(p = 0.0354) but likely not clinically significant.

Study did not show superiority in OS of either dose of CBZ vs DOC

PFS, OS statistically comparable across treatments; CBZ 25 demonstrates superior tumor response…

FIRSTANA: CONCLUSIONS

Tumor Response Rate

DOC + PRED

CBZ 20 + PRED

CBZ 25 + PRED 60

50 40 20 10 0

30.9

54/175

32.4

61/188

41.6

72/173

p = 0.731

p = 0.037

30

Different toxicity profiles noted for CBZ vs DOC; however, no new safety concerns.

Study investigators suggest that 2 different taxanes may offer similar activity but with different safety profiles in mCRPC…

Treatment-Emergent AE, % DOC + PRED (n = 387)

CBZ 20 + PRED (n = 369)

CBZ 25 + PRED (n = 391)

Any grade 97.2 95.9 96.2

Grade 3/4 46.0 41.2 60.1

Serious 32.6 34.4 47.6

Leading to discontinuation 33.9 25.2 31.7

Select any grade occurring in

≥ 5% of pts

 Febrile neutropenia

 Neutropenic infection

 Diarrhea

 Stomatitis

 Hematuria

 Peripheral neuropathy

 Peripheral edema

 Alopecia

 Nail disorder

8.3 4.9 37.0 13.7 3.6 25.1 20.4 39.0 9.0

2.4 1.6 32.5

4.9 20.3 11.7 9.8 8.9 0.3

12.0 6.1 49.9

6.6 25.1 12.3 7.7 13.0

0.8

FIRSTANA: CONCLUSIONS

Grazie per l’attenzione

«Possis nihil Urbe Roma visere maius»