Convegno Nazionale AIOM Giovani 2016: News in Oncology Daniele Alesini Istituto Nazionale dei Tumori Regina Elena
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DOCETAXEL: BACK AND FORTH Abiraterone 6 Abiraterone 2 ADT Enzalutamide 3 mpc ADT ADT Docetaxel Enzalutamide Docetaxel 17 Docetaxel 1 Cabazitaxel 4 Alpharadin 5 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 15 1 380 pz OS 58.9 vs 54.2 HR 1.01 95%CI 0.75-1.36 CHAARTED 2 790 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
STAMPEDE 1 2962 pz 1 Lancet. 2016 Mar 19;387(10024):1163-77
HR 0.78 95%CI 0.66-0.93 HR 1.06 95%CI 0.86-1.30 SOC 71.0 SOC+ZA NR SOC+Doc 81.0 SOC+Doc+ZA 76.0 HR 0.94 95%CI 0.79-1.11 HR 0.82 95%CI 0.67-0.97 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. 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
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Single CTC characterization to identify phenotypic and genomic heterogeneity as a mechanism of resistance to AR signaling directed therapies (AR Tx) in mcrpc patients. 179 pts 221 blood samples Howard I. Scher ASCO GU 2016 AR Tx 150 Taxanes 71 15 phenotipically distinct CTC subtypes Ranking based upon their degree of phenotypic heterogeneity
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
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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.
TOPARP: Olaparib in mcrpc 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.
50 Pts 11 PSA 14 CTC 6 rpr 16 Responders (RR 33%) 49 evaluable for response 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.
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FIRSTANA: Cabazitaxel vs Docetaxel in Chemon-naïve mcrpc. Cabazitaxel* 20mg/mq q21 mcrpc PS 0-2 Chemo-naive (1168 pts) Cabazitaxel* 25mg/mq q21 Docetaxel* 75mg/mq q21 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 * And Prednisone 10mg/die
OS (%) FIRSTANA: OS 100 80 60 40 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) 20 0 0 6 12 18 24 30 36 42 48 54 Months
PFS (%) FIRSTANA: PFS 100 80 60 40 20 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) 0 0 3 6 9 12 15 18 21 24 27 30 33 Months Small observed difference in pain progression component of PFS for CBZ 25 vs DOC (p = 0.0354) but likely not clinically significant. 36
FIRSTANA: CONCLUSIONS 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 60 50 40 30 20 10 0 30.9 54/175 DOC + PRED Tumor Response Rate p = 0.731 32.4 61/188 CBZ 20 + PRED p = 0.037 41.6 72/173 CBZ 25 + PRED
FIRSTANA: CONCLUSIONS Different toxicity profiles noted for CBZ vs DOC; however, no new safety concerns. Treatment-Emergent AE, % DOC + PRED (n = 387) CBZ 20 + PRED (n = 369) CBZ 25 + PRED (n = 391) Study investigators suggest that 2 different taxanes may offer similar activity but with different Any grade safety profiles in mcrpc 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
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