what to do after docetaxel, cabazitaxel, enzalutamide, abiraterone. how to manage relapsed refractory ca prostate.

1. What to do after Docetaxel, Cabazitaxel,
Abiraterone, Enzalutamide?
Dr Chandan K Das MD,DM
Assistant Professor Medical Oncology, Regional Cancer Center, PGIMER, Chandigarh

2. Overview
 Targeting the androgen : ADT
 Chemotherapy :
Docetaxel/Mitoxantrone/Carboplatin
 PARP inhibitor: Olaparib
 Immunotherapy: Pembrolizumab
 Metabolic radiotherapy: LuPSMA Therapy

3. Prostate cancer therapy

4. Prostate cancer therapy

5. Molecular
Subtyping of
Relapsed
Refractory
CRPC
80%
10-15% 5%

6. ADT

7. Diethylstilbestrol- Dexamethasone
 ORR DEX+DES (68%) and DEX (64%)
 PFS (median=8.1 months for both)
 OS (19.4 vs 18.8 months)
Shamash J, Powles T, Sarker SJ, et al. A multi-centre randomised phase III trial of dexamethasone vs dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred diethylstilbestrol. Br J Cancer. 2011;104:620-8.

8. Steroids

9. Dexamethasone vs Prednisolone
 PSA response 41% versus 22%
(p = 0.08)
 Median time to PSA progression
9.7 mo versus 5.1 mo on
prednisolone (hazard ratio: 1.6;
95% confidence interval, 0.9–2.8)
Dexa>Prednisolone
Venkatraman et al Eur Urol April 2015 Volume 67, Issue 4, Pages 673–679

10. Docetaxel
Rechallenge

11. Docetaxel
Rechallenge
 Docetaxel rechallenges are considered to be an option for
patients with CRPC who responded to first-line docetaxel
therapy
 The strategy was developed for patients progressing after
first-line discontinuation when no new active drugs were
available
 A number of demonstrated that rechallenge strategy is
 Safe,
 Feasible,
 Well-tolerated, and
 Improves disease control
 The current availability of new second-line drugs that
increase patient survival means that the need for
rechallenges has been questioned

12. Docetaxel Rechallenge: AUO AP33/02
 N=75; Patients with HRPC and PSA or clinical progression
 Treatment:
 Weekly docetaxel with estramustine X 3 cycles (Sequence 1) followed by monthly follow-up
 Treatment restarted if PSA levels doubled or if progression was suspected for other reasons
(Sequence 2/3/4)
 Primary endpoint: Best response (clinical and/or PSA) to treatment
Results:
 Sequences 2/3/4 were started in 40/23/7 patients
 PSA Response (≥50% reduction in PSA from baseline, lasting ≥ 4 weeks)
 Sequence 2: 80%/Sequence 3: 57%/Sequence 4: 29%
 mOS of retreated patients: 18.9 months
Rechallenged docetaxel and estramustine is well tolerated and shows a high response rate in the 2nd
and 3rd sequence of treatment
Miller K et al., J Clin Oncol, 2005;23:Abstract #4613.

13. Docetaxel re-treatment in docetaxel-
pretreated CRPC
 N=45
 Patients initially responding to docetaxel and then experiencing disease progression after a period
of biochemical remission of at least 5 months
 Primary Endpoint: Biochemical partial response (>50% PSA Decline)
 Secondary endpoint: ORR, Toxicity, PFS and OS
Results:
 Partial PSA response: 24.5% (n=11)
 Objective response: 4/11 (25%)
 mPFS: 5 months
 mOS: 13 months
Conclusion
 Docetaxel re-treatment preserves anti-tumour activity and is well tolerated in a selected population of
pretreated patients with CRPC.
Di Lorenzo G et al., BJU Int, 2011;107:234–9.

14. Docetaxel rechallenge after an initial
good response in patients with mCRPC
 N=290 (Good responders to 1st line docetaxel)
 Docetaxel rechallenge: 223
 Non-taxane therapy: 47
A PFI of >6 months and added
estramustine predicted a good PSA
response and symptomatic response
on docetaxel rechallenge
Only a PFI of >6 months predicted
longer OS
Docetaxel rechallenge is a management option for responders to docetaxel with a PFI of >6 months, but did
not prolong survival
Oudard S et al., BJUI (2015), 115 (5), pg 744-752

15. Docetaxel Rechallenge Experiences in
CRPC
Caffo O et al., European Oncology & Haematology, 2012;8(1):36–41

16. Factors Predicting a Response to a Rechallenge
PSA response
to the
previous
docetaxel
(50 %
reduction)
Taxane free
period 6-12
month

17. Mitoxantrone
+
prednisone

18. Mitoxanthrone:
mCRPC
Post Docetaxel
 Earlier trials showed that mitoxantrone +
prednisone gave superior pain control and QoL
compared to prednisone alone.
 There was no improvement in survival but the
trials were too small to detect small differences
(Tannock et al, JCO 1996)
 Mitoxantrone remains a reasonable option and is
very well tolerated
 More recent trials have shown higher response
rate (PSA and pain) and improved survival with
docetaxel and prednisone, albeit with increased
toxicity
 Tannock et al, NEJM 2004
 Petrylak et al, NEJM

19. TAX 327 study- Overall Survival
Months
Median
survival Hazard
(mos) ratio P-value
Combined: 18.2 0.83 0.03
D 3 wkly: 18.9 0.76 0.009
D wkly: 17.3 0.91 0.3
Mitoxantrone 16.4 – –
ProbabilityofSurviving
0 6 12 18 24 30
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Docetaxel 3 wkly
Docetaxel wkly
Mitoxantron
e
(Tannock et al, NEJM, 2004;351:1502-12

20. TAX 327 study: Secondary endpoints
Docetaxel
q 3wk
Docetaxel weekly Mitoxantrone
q 3wk
Pain Response
Rate
34.6%
p=0.01
31.2%
p=0.08
21.7%
PSA Response
Rate
45.4%
p=0.0005
47.9%
p<0.0001
31.7%
Tumor Response 12%
p=0.11
8%
p=0.59
7%
QOL Response
rate
21.9%
p=0.009
22.6%
p=0.005
13.1%
(Tannock et al, NEJM, 2004;351:1502-12
p values are for comparison with mitoxantrone group

21. TROPIC study: Mitoxantrone Arm
15.112.7Median OS (months)
0.59–0.8395% CI
<.0001P Value
0.70Hazard Ratio
CBZPMP

22. TROPIC Study: Important secondary results
De Bono et al., Lancet 2010; 376: 1147–54
Efficacy MP CBZP p-value Comment
Tumor response (%) 4.4 14.4 0.0005
PSA response (%) 17.8 39.2 0.0002 MP consistent with other studies
Pain response (%) 7.8 9.2 0.63 Disappointing !
Toxocity MP CBZP Comment
Toxic death 7 (1.9%) 18 (4.9%) Concerning!
Neutropenic sepsis 1.3% 7.5%
Diarrhea (≥ grade III) 0.3% 6.2% Major impairment to quality of life

23. Carboplatin

24. Small cell/Neuroendocrine Change

25. Small cell/Neuroendocrine CRPC
Baseline
1%
Post
Treatment
10-15%

26. Platinum-based chemotherapy for variant CRPC
small-cell/anaplastic prostate carcinoma (SCPC)
 N=120
 1st line: Carboplatin and docetaxel (CD)
 2nd line: Etoposide and cisplatin (EP)
 Progression-free after 4 cycles of
 CD: 65.4%
 EP: 33.8%
 mOS: 16 months
 Bulky tumor mass was significantly associated with poor outcome
 LDH strongly predicted for OS and rapid progression.
 Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid
progression
These results suggest that CEA is useful for selecting therapy in men with castration-resistant prostate
cancer
Aparicio AM et al., Clin Cancer Res. 2013 Jul 1;19(13):3621-30

27. Carboplatin + etoposide in heavily
pretreated CRPC patients
 Carboplatin + etoposide has modest efficacy in docetaxel-pretreated CRPC
 N=15
 Primary endpoint: PFS at 12 weeks
Results
 mPFS: 11 weeks
 mOS: 18 weeks
 Measurable disease : 7 patients
 PR: 2
 SD: 2
 PD: 3
 Preliminary findings support the hypothesis that carboplatin plus etoposide may yield some clinical benefit
in a population of patients who failed all currently approved therapeutic options for prostate cancer.
Buonerba C et al., Future Oncol. 2014 Jun;10(8):1353-60

28. Olaparib

29. Olaparib BRCA+ & BRCAness CRPC
 50 patients prior treatment with docetaxel, abiraterone or enzalutamide,cabazitaxel.
 ORR 33 %;
 HRD(BRCA1, BRCA2, ATM, RAD51, and CHEK2) :33% ORR:(88%)
Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697-708.

30. Pembrolizumab

31. KEYNOTE-199: Pembrolizumab in
Post-Docetaxel mCRPC
Patients with
metastatic CRPC and
ECOG PS 0-2;
5 planned cohorts
For 35 cycles or until PD,
unacceptable toxicity, or
investigator/patient decision
Pembrolizumab
200 mg Q3W
de Bono JS, et al. ASCO 2018. Abstract 5007.
≥ 1 prior targeted endocrine therapy, 1-2 prior CT regimens
including docetaxel (current analysis)
Cohort 1: measurable disease, PD-L1 positive (n = 131)
Cohort 2: measurable disease, PD-L1 negative (n = 67)
Cohort 3: bone metastases, no measurable disease, any PD-L1 status (n = 60)
Receiving enzalutamide, no prior CT, any PD-L1 status:
Cohort 4: measurable disease
Cohort 5: bone metastases, no measurable disease

32. KEYNOTE-199: OS/DCR
de Bono JS, et al. ASCO 2018. Abstract 5007.

33. KEYNOTE-199: Conclusions
 In a small population of patients with docetaxel-refractory metastatic
CRPC, pembrolizumab showed antitumor activity in a subset of
patients
 Acceptable safety profile observed
 Investigators suggest additional biomarker evaluation needed to
identify patients who may benefit from pembrolizumab
 Evidence of antitumor activity with pembrolizumab in patients with DNA repair
gene defects
de Bono JS, et al. ASCO 2018. Abstract 5007.

34. PSMA-
Targeted
radionuclide
therapy

35. Ga PSMA vs FDG PET
Kratochwil et al. Cancer J Nuclear Medicine 2016.
 PSMA: Prostate Specific
Membrane Antigen
 Transmembrane protein.
 Nearly universally expressed by
prostate epithelial cells.
 Upregaluted in prostate cancer,
with increase grade and
castration-resistance.

36. Anti-PSMA antibody
Liu et al. Cancer Res 1998.

37. Lu 177 PSMA vs Radium-223

38. 177Lu PSMA: Overview of currently published trials
Emmett et al., J Med Radiat Sci. 2017 Mar; 64(1): 52–60.

39. 100 consecutive patients treated with Lu-
177-labeled PSMA for mCRPC
 N=100
 Treatment dose: I.V. 177Lu-PSMA-I&T, 6- to 8-weekly with an activity of 7.4GBq up to 6 cycles
Results:
 PSA decline
 ≥30%: 40%
 ≥50%: 32%
 ≥90%: 9%
 Median PSA-PFS: 3.4 month
 median OS: 12.2 months
 Grade 3/4-non-hematologic toxicities were not observed.
 Radioligand therapy with 177Lu-PSMA I&T appears to be safe and active in late-stage mCRPC.
Heck MM et al., Journal of Clinical Oncology 36, no. 6_suppl (February 20 2018) 206-206.

40. LuPSMA trial: [177Lu]-PSMA-617
 Single-arm, single-centre, phase 2 trial
 mCRPC patients with PD after standard treatments
 N=30
 Treatment dose: mean administered radioactivity was 7·5 GBq per cycle
Results:
 PSA decline of 50% or more: 17/30 (57%)
 No treatment-related deaths.
 most common toxic effects (Grade 1) related to [177Lu]-PSMA-617: 87%
Radionuclide treatment with [177Lu]-PSMA-617 has high response rates, low toxic effects,
and reduction of pain in men with metastatic castration-resistant prostate cancer who have
progressed after conventional treatments.
Hofman M et al., The Lancet Oncology Volume 19, No. 6, p825–833, June 2018

41. Take home message
Relapsed Refractory CRPC
TFI>6month
Docetaxel
Rechallenge
PS 0-4
BSC/ADT/Dexa
TFI<6month
Mitoxantrone
Small cell/NE
Change
Carboplatin
MSI+
Pembrolizumab

42. When the world says: “Give Up”
Hope whispers...
‘Try it one more time’