Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer

The Unanticipated Real-World Clinical Experience

Darren M. C. Poon; Kuen Chan; S. H. Lee; T. W. Chan; Henry Sze; Eric K. C. Lee; Daisy Lam; Michelle F. T. Chan

BMC Urol. 2016;16(12)

Conclusions

The present study reported the unanticipated short survival after AA in chemo-naïve patient outside clinical trial setting. The overall survival was particularly short in those with visceral diseases, and further clinical trial for AA in this subgroup of patients is warranted. In contrast, AA was well tolerated and efficacious in mCRPC patients with prior chemotherapy. AA resulted in comparable pain control in both groups of patients. PSA response, in particular present within the first 3 months after AA, could serve as a prognostic biomarker for survival outcome and may have a potential role in selecting patients for additional or alternative treatment earlier in future clinical trial.

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Abbreviations
AA: abiraterone acetate; ADT: androgen deprivation therapy; AR: androgen receptor; mCRPC: metastatic castration-resistant prostate cancer; PCWG-2: Prostate Cancer Clinical Trials Working Group; PSA: prostate-specific antigen; PSA-DT: PSA doubling time.

Acknowledgement
The authors wish to thank Ms Lee-Wai Yee, Dr. Leung-Sing Fai and Dr. Michael Kam for their input and contributions to the study.

Ethics Approval and Consent to Participate
The study was approved by the institutional review board of the authors' institutions (Joint Chinese University of Hong Kong – New Territories East Cluster Clinical Research Ethics Committee/Ref no: CRE-2015.481). Informed consent has been exempted by the review board as most of the patients in this study were dead when the data was collected.

Table 1. Patient's characteristics
	Chemo-naïve (n = 58)	Post-chemo (n = 52)
Age, years
Median	77	66
Range	56–92	39–85
≥75 (%)	37 (63.8)	11 (21.2)
ECOG performance status, No. (%)
0–1	36 (62.1)	45 (86.5)
2	18 (31.0)	7 (13.5)
3	4 (6.9)	0
4	0	0
Gleason score at time of initial diagnosis (%)
<8	24 (41.4)	19 (36.5)
≥8	16 (27.6)	29 (55.8)
Unknown	18 (31.0)	4 (7.7)
Median PSA (range), ug/l	212 (6.22–3095)	191 (4.2–4694)
Median PSA doubling time (range), months	2.1 (0.5–9.0)	2.3 (0.7–13.4)
Symptomatic at presentation^a, No. (%)	19 (32.8)	16 (30.8)
Baseline Hb (g/dl), median (range)	12 (5.2–15.5)	11.7 (5.7–14.9)
Baseline ALP (IU/l), median (range)	116.5 (40–2960)	119 (45–1857)
Disease location, No. (%)
Bone only	35 (60.3)	28 (53.8)
Bone	55 (94.8)	50 (96.2)
Lymph node	22 (37.9)	20 (38.5)
Lung	2 (3.4)^b	3 (5.8)
Liver	3 (5.2)^b	5 (9.6)
Co-morbidities, No (%)
Diabetes Mellitus	16 (27.6)	8 (15.4)
Hypertension	32 (55.2)	20 (38.5)
Hyperlipidemia	0	4 (7.7)
Atrial fibrillation	1 (1.7)	1 (1.9)
Congestive heart failure	1 (1.7)	0
No. of previous cytotoxic regimen (%)
1	0	44 (84.6)
2	0	7 (13.5)
3	0	1 (1.9)
Disease progression prior AA (%)
Biochemical progression only	42 (72.4)	35 (67.3)
Clinical or radiographic progression	16 (27.6)	17 (32.7)

Abbreviations: ECOG Eastern Cooperative Oncology Group, PSA prostate specific antigen, Hb hemoglobin, ALP alkaline phosphatase, AA abiraterone acetate
^apresence of pain prior abiraterone acetate and require WHO level II or above analgesics
^bOne patient with both liver and lung metastases

Table 2. Treatment details
	Chemo-naïve (n = 58)	Post-chemo (n = 52)
Median duration of AA treatment, month (range)	6.8 (0.6–21.5)	7.1 (0.5–25.0)
PSA response (%)
≥50 % PSA decline from baseline	36 (62.1)	26 (50.0)
≥90 % PSA decline from baseline	16 (27.6)	8 (15.4)
Median time to PSA nadir, month (range)	3.1 (0.9–15.0)	2.8 (0.5–15.3)
PSA flare (%)
No. of patients	17 (29.3)	15 (28.8)
Presence of eventual PSA response (≥50 % PSA decline from baseline)	12 (70.6)	10 (66.7)
Pain alleviation during or after AA^a (%)	11 (57.9 %)	11 (68.8 %)
Reasons of discontinuing AA (%)
Disease progression	24 (41.4)	36 (69.2)
Treatment-related complication	3 (5.2)	1 (1.9)
Patient's decision	3 (5.2)	2 (3.8)
Unknown	1 (1.7)	0
Continuation of AA beyond PD
No. of patients (%)	13 (22.4)	18 (34.6)
Median time, month (range)	2.8 (1.0–5.8)	2.0 (1.2–16.2)
Subsequent therapy after PD (%)
Docetaxel	5 (8.6)	2 (3.8)
Cabazitaxel	2 (3.4)	7 (13.5)
Mitoxantrone	0	1 (1.9)
Ketoconazole	0	1 (1.9)

Abbreviations: PSA prostate specific antigen, AA abiraterone acetate, PD disease progression
^aWithdrawal or reduction of level II or III analgesics according to WHO analgesics ladder

Table 3. Adverse events during treatment
	Chemo-naïve (%)				Post-chemo (%)
	Grade 1	Grade 2	Grade 3	Grade 4	Grade 1	Grade 2	Grade 3	Grade 4
Peripheral edema	6 (10.3)	0	3 (5.2)	0	2 (3.8)	1 (1.9)	0	0
Elevation of liver enzymes	7 (12.1)	0	0	0	3 (5.8)	0	1 (1.9)	0
Hypokalemia	15 (25.9)	1 (1.7)	2 (3.4)	0	9 (17.3)	2 (3.8)	2 (3.8)	0
Hypertension	9 (15.5)	7 (12.1)	4 (6.9)	0	17 (32.7)	3 (5.8)	3 (5.8)	0
Fatigue	1 (1.7)	0	0	0	1 (1.9)	0	0	0
Arthralgia	0	0	0	0	1 (1.9)	0	0	0
Diarrhoea	0	0	0	0	1 (1.9)	0	0	0
Dyspepsia	1 (1.7)	0	0	0	0	0	0	0

Table 4. Univariate and multivariate analysis of overall survival and progression-free survival – Chemo-naive group
Factors	Univariate analysis						Multivariate analysis
	Progression-free survival			Overall survival			Progression-free survival			Overall survival
	P value	HR	95 % CI	P value	HR	95 % CI	P value	HR	95 % CI	P value	HR	95 % CI
Time from ADT to CRPC (<10 vs ≥ 10 months)	0.0306	2.191	1.057–4.542	0.0002	4.566	1.913–10.898	0.816	1.104	0.49–2.489	0.0336	2.656	1.061–6.648
ECOG (2–3 vs 0–1)	0.273	1.51	0.718–3.176	0.0034	3.392	1.426–8.071	N.A.	N.A.	N.A.	0.0001	4.907	1.648–14.612
Age (<75 vs ≥75)	0.2687	0.664	0.319–1.381	0.8875	1.068	0.43–2.653	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
Gleason score ( ≥8 vs <8)	0.9539	1.023	0.471–2.225	0.9549	0.973	0.376–2.515	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
Visceral met (yes vs no)	0.0088	4.7	1.313–16.82	0.0007	6.907	1.881–25.357	0.0126	5.891	1.43–24.267	0.0015	4.8	1.026–22.465
Symptomatic (yes vs no)	0.6554	1.183	0.565–2.476	0.1193	1.966	0.826–4.682	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
PSA doubling time (<2 months vs ≥2 months)	0.1667	1.651	0.804–3.393	0.4794	1.573	0.568–3.319	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
Baseline PSA ( ≥200 vs <200 ug/l )	0.0014	3.26	1.513–7.021	0.0365	2.558	1.028–6.364	0.0686	2.15	0.933–4.954	0.6339	1.313	0.428–4.038
Baseline ALP ( ≥120 vs <120 IU/l)	0.1464	1.69	0.825–3.466	0.0535	2.459	0.987–6.13	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
Baseline Hb (<12 vs ≥12 g/dl)	0.1618	1.676	0.805–3.488	0.023	2.712	1.109–6.631	N.A.	N.A.	N.A.	0.0409	2.696	0.912–7.7971
PSA response (yes vs no)	<0.0001	0.135	0.061–0.299	0.0001	0.176	0.067–0.459	<0.0001	0.186	0.079–0.439	0.0001	0.104	0.025–0.387
PSA flare (yes vs no)	0.0623	0.471	0.209–1.06	0.0652	0.373	0.125–1.111	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
Continuation of AA beyond progression (yes vs no)	N.A.	N.A.	N.A.	0.9863	0.992	0.382–2.574	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
Post-AA treatment (yes vs no)	N.A.	N.A.	N.A.	0.3604	0.51	0.117–2.219	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.

Abbreviations: HR hazard ratio, 95 % CI 95 % confidence interval, ADT androgen deprivation treatment, CRPC castration-resistant prostate cancer, ECOG Eastern Cooperative Oncology Group, Symptomatic presence of pain prior abiraterone acetate and require WHO level II or above analgesics, PSA prostate-specific antigen, ALP alkaline phosphatase, Hb haemoglobin, PSA response, ≥50 % drop of PSA from baseline, PSA flare, PSA upsurge but not to the extent of biochemical progression, AA abiraterone acetate, N.A. not applicable

Table 5. Univariate and multivariate analysis of overall survival and progression-free survival – Post-chemo group
Factors	Univariate analysis						Multivariate analysis
	Progression-free survival			Overall survival			Progression-free survival			Overall survival
	P value	HR	95 % CI	P value	HR	95 % CI	P value	HR	95 % CI	P value	HR	95 % CI
Time from ADT to CRPC (<10 vs ≥ 10 months)	0.4867	0.788	0.4–1.549	0.0649	0.476	0.213–1.063	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
ECOG (2–3 vs 0–1)	0.4084	0.648	0.229–1.832	0.7205	1.248	0.371–4.198	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
Age (<75 vs ≥75)	0.2988	0.649	0.285–1.478	0.0136	0.303	0.103–0.886	N.A.	N.A.	N.A.	0.3685	0.559	0.155–2.008
Gleason score (≥8 vs <8)	0.0528	1.922	0.98–3.77	0.0236	2.559	1.117–5.846	N.A.	N.A.	N.A.	0.0186	2.658	1.13–6.251
Visceral metastasis (yes vs no)	0.1972	1.793	0.727–4.42	0.3474	1.592	0.598–4.237	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
Symptomatic (yes vs no)	0.7678	1.112	0.549–2.253	0.637	1.227	0.524–2.87	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
PSA doubling time (<2 months vs ≥2 months)	0.251	1.459	0.762–2.794	0.0319	2.337	1.054–5.18	N.A.	N.A.	N.A.	0.0289	3.006	1.278–7.07
Baseline PSA (≥200 vs <200 ug/l)	0.3603	1.356	0.703–2.615	0.422	1.367	0.636–2.938	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
Baseline ALP (≥120 vs <120 IU/l)	0.6113	0.848	0.448–1.605	0.7189	1.151	0.536–2.471	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
Baseline Hb (<12 vs ≥12 g/dl)	0.2146	1.538	0.774–3.056	0.0811	2.143	0.892–5.149	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
PSA response (yes vs no)	0.0007	0.336	0.174–0.648	0.0001	0.207	0.089–0.493	0.0007	0.403	0.203–0.797	0.0001	0.213	0.076–0.592
PSA flare (yes vs no)	0.0130	0.38	0.172–0.838	0.2531	0.609	0.257–1.438	0.0987	0.505	0.222–1.149	N.A.	N.A.	N.A.
Refractory to prior chemotherapy (yes vs no)	0.3883	1.376	0.663–2.857	0.2234	1.659	0.729–3.773	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
Continuation of AA beyond progression (yes vs no)	N.A.	N.A.	N.A.	0.064	0.481	0.218–1.060	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.
Post-AA treatment (yes vs no)	N.A.	N.A.	N.A.	0.3224	0.65	0.275–1.535	N.A.	N.A.	N.A.	N.A.	N.A.	N.A.

Abbreviations: HR hazard ratio, 95 % CI 95 % confidence interval, ADT androgen deprivation treatment, CRPC castration-resistant prostate cancer, ECOG Eastern Cooperative Oncology Group, Symptomatic presence of pain prior abiraterone acetate and require WHO analgesic class II or III analgesics, PSA prostate-specific antigen, ALP alkaline phosphatase, Hb haemoglobin, PSA response, ≥50 % drop of PSA from baseline, PSA flare PSA upsurge but not to the extent of biochemical progression, AA abiraterone acetate, N.A. not applicable

Table 6. Clinical outcome in the present study and the AA pivotal trial
Survival outcome	Present study (Chemo-naïve)	COU-AA-302 study	Present study (Post-chemo)	COU-AA-301 study
Median OS, months	18.1	34.7	15.5	15.8
Median PFS, months	6.7^a	16.5^b	6.4^a	8.5^c
Median PFS, months	6.7^a	16.5^b	6.4^a	5.6^d
PSA response, %	62.1	62	50.0	29
Pain control, %	57.9^e	–	68.8^e	44^f

Abbreviations: OS overall survival, PFS progression-free survival, PSA response ≥50 % decline of PSA from baseline, PSA prostate-specific antigen
^aProstate Cancer Clinical Trials Working Group (PCWG-2) definition
^bRadiographic PFS
^cBiochemical PFS
^dRadiographic PFS
^eWithdrawal or reduction of level II or III analgesics according to WHO analgesics ladder
^fReduction of ≥30 % in the brief pain inventory-short form (BPI-SF) worst pain intensity score over the last 24 h observed at two consecutive evaluations 4 weeks apart without any increase in analgesic usage score; only patients experiencing a pain score ≥4 at baseline were included