Background
Methods
Ethics statement
Study population and treatment
Data collection and outcomes measures
Statistical analysis
Results
Characteristics of patients
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 presentationa, 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) |
Clinical efficacy
PSA response
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 AAa (%) | 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) |
Duration of AA treatment and post-AA treatment
Overall survival and progression-free survival
Pain control
Adverse events
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 |
Univariate and multivariate analysis
Chemo-naïve 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. |
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. |
Discussion
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 | 6.7a
| 16.5b
| 6.4a
| 8.5c
|
5.6d
| ||||
PSA response, % | 62.1 | 62 | 50.0 | 29 |
Pain control, % | 57.9e
| – | 68.8e
| 44f
|