)RFDOWKHUDS\7DEOH ,QGLFDWLRQV
UDWLQJ Patients with metastatic PCA should
immediately receive ADT 6WURQJ
There is no indication to systematically SUHVFULEHDVRFDOOHGÀUVWJHQHUDWLRQ DQWLDQGURJHQDWWKHÀUVWLQMHFWLRQRI/+5+
agonist
6WURQJ
There is no indication for treatment E\FDVWUDWLRQFRPELQHGZLWKDÀUVW generation antiandrogen
6WURQJ
There is no indication for treatment ZLWKDÀUVWJHQHUDWLRQDQWLDQGURJHQ in monotherapy
6WURQJ
IAD is a treatment option for patients who are informed of the uncertainties it presents, and who are voluntary, asymptomatic, either in BCR after local treatment, or with locally advanced disease, or with great caution for pauci-metastatic patients. IAD can only be administered if there is a good response to the induction therapy (PSA < 4 ng/ml) at 6-9 months. Treatment is resumed based on empirical data in case of symptoms, or on PSA levels.
6WURQJ
7DEOHRandomised trials evaluating docetaxel + ADT in hormone-sensitive metastatic PCA.
5HVXOWVRIWKHWKUHHUDQGRPLVHGWULDOVWKDWHYDOXDWHGFKHPRWKHUDS\GRFHWD[HOFRPELQHGZLWKDQGURJHQ GHSULYDWLRQLQKRUPRQHVHQVLWLYHPHWDVWDWLFSURVWDWHFDQFHU
Trial GETUG-AFU 15
[413] CHAARTED
[415] STAMPEDE
[289]
Total population (n) 385
M+ patients included (%) 100 100 61
M+ population:
% synchronous/metachronous
95/5
M+ population: % high/low
volume 48/52 65/35 NK
Median follow-up (months) 84
ADT + docetaxel versus ADT Overall survival HR (IC95%)
+5²S S 0.81 (0.69-0.95) p = 0.009
ADT: androgen deprivation therapy NK: not known
take into consideration certain characteristics of the trials.
3DWLHQWVZLWKDVPDOOWXPRXUYROXPHGLGQRWEHQHÀWIURP the addition of docetaxel in the analysis of the subgroup of the CHAARTED study [415]. The meta-analysis of CHAARTED and GETUG-AFU 15 concluded that the results were identical
>@&RQYHUVHO\WKHUHWURVSHFWLYHDQDO\VLVRIWKH67$03('(
VWXG\IRXQGDFRPSDUDEOHEHQHÀWLQDOOSDWLHQWJURXSVERWK high and low-volume [412]. Patients with secondary meta-static disease after local treatment were under-represented in all three studies, so it is not possible to draw any conclu-sions in this population.
Abiraterone acetate
Two studies have evaluated a combination of ADT with abi-raterone acetate for hormone-sensitive metastatic prostate cancer. (Table 45)
The phase III study LATITUDE [390] included 1,199 patients with high-risk prostate cancer, metastatic from the outset (on bone scintigraphy with technetium, CT scan or MRI) and hormone-sensitive and randomised them between ADT combined with a placebo (n = 602) and ADT combined with abiraterone acetate (1,000 mg/day) and prednisone (5 mg/
GD\Q
+LJKULVN SDWLHQWV ZHUH GHÀQHG E\ DW OHDVW RI WKH IROORZLQJFULWHULD,683JUDGHWKHSUHVHQFHRIPRUH than 2 lesions on bone scan, the presence of at least one PHDVXUDEOHYLVFHUDOOHVLRQ3DWLHQWVZHUHVWUDWLÀHGDFFRUGLQJ to the presence or absence of visceral metastasis and their general health (PS 0.1 vs. 2).
The majority of patients in both arms had an ISUP grade
DQGUHVSHFWLYHO\:LWKDPHGLDQIROORZXSRI 51.8 months, patients treated with the combination of ADT SOXVDELUDWHURQHDFHWDWHKDGDQRYHUDOOVXUYLYDOEHQHÀWRI 16.8 months compared to the placebo group (51.3 months vs.
36.5 months; HR:0.66, p < 0.0001). All secondary endpoints
ZHUHVLJQLÀFDQWO\LPSURYHGE\WKHFRPELQDWLRQZLWKDEL-raterone acetate: time to PSA progression, progression of painful symptoms, time to a new bone event, initiation of FKHPRWKHUDS\RURWKHUVSHFLÀFWUHDWPHQW
STAMPEDE [329] is a multi-stage, multi-step trial.
Comparison of the ADT plus abiraterone acetate arm with the ADT alone arm reinforces the LATITUDE results. The popu-ODWLRQSDWLHQWVZDVYHU\KHWHURJHQHRXVLQFOXGLQJ0 N+ patients and with locally advanced tumours (with at least two of the three severity criteria: stage T3/T4, ISUP grade
36$OHYHOQJPO3DWLHQWVLQUHODSVHDIWHUUDGLFDO surgery or radiotherapy with high risk factors (PSA > 4 ng/ml with a doubling time of less than 6 months, PSA > 20 ng/ml, lymph node or metastatic recurrence, or androgen depriva-tion for less than one year with a free interval of more than one year) were also included. A total of 52% were metastatic.
Prostate radiotherapy was desired for M0 patients. Three-TXDUWHUVRIWKHSDWLHQWVKDGDQ,683JUDGH$WRWDORI 96% and 93% of the patients were hormone-sensitive. The main endpoint was overall survival. With a median follow-up RIPRQWKVWKHUHZHUHVLJQLÀFDQWO\IHZHUGHDWKVLQWKH ADT plus abiraterone arm: 184 deaths vs. 262 (HR = 0.63,
&, S7KHKD]DUGUDWLRZDVLQ metastatic patients.
The intermediate primary endpoint was failure-free VXUYLYDOGHÀQHGE\UDGLRJUDSKLFFOLQLFDORUELRORJLFDOSUR-JUHVVLRQRUGHDWK7KHUHZHUHVLJQLÀFDQWO\IHZHUIDLOXUHVLQ the ADT + abiraterone arm: 248 vs. 535 events (HR = 0.29;
95% CI, 0.25-0.34; P < 0.001). The hazard ratio was 0.31 in metastatic patients.
In the arms with and without abiraterone acetate, grade 3-5 hypertension at rates of 5% and 1%, hypokalaemia rates of 1% and 0.003%, lower limb oedema rates of 1% and 0%, DQGWUDQVDPLQDVHHOHYDWLRQUDWHVRIDQGUHVSHFWLYHO\
were observed.
New generation antiandrogens
Enzalutamide and apalutamide were also evaluated in this situation. (Table 46)
(1=$0(7 [418] is a phase III randomised study that compared an ADT combined with either enzalutamide or a ÀUVWJHQHUDWLRQDQWLDQGURJHQELFDOXWDPLGH7KHSULPDU\
endpoint was overall survival. Patients could have received prior local treatment and therefore have metachronous metastases. Chemotherapy with docetaxel was also allowed.
Enzalutamide was prescribed concomitantly with chemo-therapy. A total of 1,125 men with a median age of 69 years were randomised. After a median follow-up of 34 months, DVLJQLÀFDQWLPSURYHPHQWLQRYHUDOOVXUYLYDOZDVQRWHGLQ WKHHQ]DOXWDPLGHDUPDW\HDUVYV+5 S 7KLVEHQHÀWZDVIRXQGLQSDWLHQWVZLWKDORZRU high tumour volume and in patients with secondary metastasis or metastasis as of the initial diagnosis. It is important to note WKDWLQWKHSDWLHQWVRIWKHSRSXODWLRQSUHYLRXVO\
treated with docetaxel, no improvement in survival was observed and more toxicity was reported. Discontinuation due to adverse events was more common in the enzalutamide group.
$5&+(6 [419], a phase III randomised study that compared an ADT associated with either enzalutamide or SODFHERLQSDWLHQWVZLWKDPHGLDQDJHRI\HDUV 3DWLHQWVZHUHVWUDWLÀHGDFFRUGLQJWRWXPRXUYROXPHDQG 7DEOHRandomised trials evaluating abiraterone
acetate + ADT in hormone-sensitive metastatic PCA.
5HVXOWVRIWKHWZRUDQGRPLVHGWULDOVHYDOXDWLQJ DELUDWHURQHDFHWDWHFRPELQHGZLWKDQGURJHQ
GHSULYDWLRQLQKRUPRQHVHQVLWLYHPHWDVWDWLFSURVWDWH FDQFHU
Trial LATITUDE
[390]
STAMPEDE [329]
Total population (n) 1,199
M+ patients included (%) 100 52 M+ population: %
synchronous/metachronous 100/0 95/5 M+ population: % high/low
volume
100/0 56/44
Median follow-up (months) 51.8 40 ADT + ABI versus ADT
Overall survival HR (IC95%)
0.66 p < 0.0001
0.63 p < 0.001 ADT: Androgen deprivation therapy
prior administration of docetaxel. The study was positive on the primary endpoint of radiographic progression-free survival (HR: 0.39; p = 0.001), regardless of tumour volume or docetaxel exposure.
7,7$1 [420] is a phase III, double-blind, randomised study that compared an ADT with either apalutamide or placebo.
Patients could have received local treatment or docetaxel.
The main co-endpoints were radiographic progression-free survival and overall survival. After a median follow-up of PRQWKVWKHÀUVWLQWHULPDQDO\VLVUHYHDOHGDVLJQLÀFDQW EHQHÀWLQUDGLRJUDSKLFSURJUHVVLRQIRUWKHDSDOXWDPLGHJURXS (HR: 0.48; p < 0.001) and an overall survival at 24 months for DSDOXWDPLGHRIYHUVXVIRUWKHSODFHER+5 S 7KHUHZDVQRVXUYLYDOEHQHÀWLQSDWLHQWVSUH-viously treated with docetaxel. Grade 3 side effects were found in 42.2% of the patients on ADT plus apalutamide. A skin UDVKZDVREVHUYHGLQRIWKHVHSDWLHQWV$SDOXWDPLGH did not deteriorate quality of life, (particularly on fatigue scores) [421].
Bone-targeting drugs
The importance of preventing the complications of bone metastases by bone resorption inhibitors was demonstrated in the castration resistant phase, but never in the cas-tration sensitive phase [289]. They are recommended at the hormone-sensitive stage, only in the management of osteoporosis on rheumatological advice.
Local treatment Surgery
Very little prospective data is currently available. Therefore, surgery cannot be recommended in this situation, except in clinical trials.
Prostate radiotherapy
Two randomised trials evaluated the impact of prostate radiotherapy on overall survival in patients with metastatic disease from the initial diagnosis.
The HORRAD trial [422] included all patients with meta-static disease from the initial diagnosis, regardless of the clinical features. All the patients received an ADT, and KDOI WKH SRSXODWLRQ UHFHLYHG SURVWDWH LUUDGLDWLRQ *\
in 35 fractions). In 10 years, 446 patients were included;
PRVWKDGPRUHWKDQPHWDVWDVHVDQGKDGDQ,683 JUDGH:LWKDPHGLDQIROORZXSRIPRQWKVQRVLJQL-ÀFDQWGLIIHUHQFHLQPHGLDQVXUYLYDOZDVLGHQWLÀHGEHWZHHQ the two arms (45 months in the RT group and 43 months in the control group). In the subgroup analysis, the hazard ratio was 0.68 in favour of the radiotherapy arm for patients with OHVVWKDQPHWDVWDVHVEXWLWUHPDLQVQRQVLJQLÀFDQW
The STAMPEDE trial [423] randomised patients with metastatic disease on the initial diagnosis into groups trea-ted with ADT with or without prostate irradiation. There ZHUHWZRHQGSRLQWVDQHIÀFDF\HQGSRLQWUHSUHVHQWHGE\
overall survival, and an activity endpoint, represented by relapse-free survival, including PSA progression. It should be emphasized that staging consisted of a bone scintigraphy DQG D WKRUDFLF DEGRPLQRSHOYLF VFDQ 7KH VWUDWLÀFDWLRQ criteria were management site, age, lymph node invol-vement, general health status, and use of non-steroidal DQWLLQÁDPPDWRU\GUXJV5DGLRWKHUDS\FRXOGEHGHOLYHUHG according to two regimens, 36 Gy in 6 fractions or 55 Gy LQIUDFWLRQVRI*\DVOLJKWO\ORZHUGRVHOHYHOWKDQ currently recommended. Only the prostate was irradiated.
0HWDVWDWLFORDGDVGHÀQHGE\&+$$57('ZDVHYDOXDWHG on a centralised imaging review. An analysis according to the irradiation modalities and most of all according to the WXPRXUORDGZDVSUHVSHFLÀHGLQWKHSURWRFRO%HWZHHQ 7DEOHRandomised trials evaluating novel antiandrogens + ADT in hormone-sensitive metastatic PCA.
5HVXOWVRIWKHWKUHHUDQGRPLVHGWULDOVHYDOXDWLQJQHZDQWLDQGURJHQV(Q]DOXWDPLGHDQG$SDOXWDPLGHFRPELQHG ZLWKDQGURJHQGHSULYDWLRQLQKRUPRQHVHQVLWLYHPHWDVWDWLFSURVWDWHFDQFHU
Trial ARCHES [419] ENZAMET [418] TITAN [420]
Drug Enzalutamide Enzalutamide Apalutamide
Total population (n) 1,150 1,125 1,052
M+ patients included (%) 100 100 100
M+ population:
% synchronous/metachronous 58/42
M+ population:
% high/low volume
62/38 52/48
Median follow-up (months) 14.4 33.9 22
Combined with docetaxel:
Moment
% pts
Before 18
During 45
Before 11 ADT + NGHT
versus ADT HR (IC95%)
Radiographic progression-free survival 0.39 (0.30-0.50)
p < 0.001
Overall survival p = 0.002
Overall survival p = 0.005 ADT: Androgen deprivation therapy; NGHT: new generation hormonal therapy
2013 and 2016, 2,061 patients were included, of which 819 (40%) had a small tumour volume. With a median follow-up RIPRQWKVQRVLJQLÀFDQWGLIIHUHQFHLQRYHUDOOVXUYLYDOZDV LGHQWLÀHGEHWZHHQWKHWZRDUPVDW\HDUVYV+5 S EXWWKHUHZDVDVLJQLÀFDQWLPSURYHPHQWLQ SURJUHVVLRQIUHHVXUYLYDOYV+5S On the other hand, only patients with a low tumour burden KDGDVLJQLÀFDQWEHQHÀWLQRYHUDOOVXUYLYDODW\HDUV YV+5S 7KLVWULDOZLWKDVLJQLÀFDQW number of patients makes it possible to recommend pros-tate irradiation in case of metastatic disease on the initial GLDJQRVLVZLWKDVPDOOWXPRXUYROXPHGHÀQHGRQERQH scintigraphy and CT scan.
Local treatment of metastases
In case of oligometastatic disease, each metastasis can be treated by surgery, interventional radiology or stereotactic radiotherapy. There is little prospective data that evaluates this strategy.
The STOMP trial [424] included 62 patients with bio-chemical recurrence (PSA > 50 ng/ml) in the form of an oligometastatic disease (less than 3 metastases detected on a Choline PET/CT scan) after local treatment. Patients were randomised between simple monitoring and local treatment of all the metastases. Treatment of all the metastases delayed the initiation of hormonal treatment E\DQDYHUDJHRIPRQWKVDQRQVLJQLÀFDQWGLIIHUHQFH For all other parameters, there was no difference between the two groups.
The SABR-COMET trial [425] is a phase II trial that randomised 99 patients with oligometastatic disease (1 to 5 metastases) of different origins, mainly breast, lung and colorectal and 16 patients with prostate cancer, to systemic treatment alone or combined with stereotactic irradiation.
$EHQHÀWLQSURJUHVVLRQIUHHVXUYLYDODQGRYHUDOOVXUYLYDO was observed for irradiated patients, but the predominance of prostate cancers in the irradiation group (14 vs 2) might explain the differences observed.
The ORIOLE study [426] randomised 54 patients with less than 3 asymptomatic metastases on conventional imaging (CT scan, MRI and bone scintigraphy) between stereotactic radiotherapy of metastases and observation (2:1 randomi-sation). All the subjects had relapsed after local treatment.
3URJUHVVLRQZDVGHÀQHGDVDFRPSRVLWHHQGSRLQWELRORJLFDO (PSA nadir + 2 ng/ml), radiological, clinical, initiation of ADT, RUGHDWK6WHUHRWDFWLF57VLJQLÀFDQWO\GHFUHDVHGWKHSUR-portion of patients who were progressive at 6 months (19 vs 61%; p = 0.005). Progression-free survival was 5.6 months in the observation arm and was not achieved with a median follow-up of 18 months (p = 0.002). The study also aimed to identify factors related to the effectiveness of stereotactic RT. Therefore, all irradiated patients were also treated with PSMA-PET, which revealed additional metastases in 16 of the 36 patients in the RT group. The proportion of patients with progressive disease at 6 months was 1/19: 5% when there were no additional lesions found on PSMA-PET compared to 6/16:
38% when there were additional lesions (p = 0.03). Nuclear imaging would improve patient selection for stereotactic RT.
Overall, these phase II trials do not allow a clear conclu-VLRQWREHGUDZQFRQFHUQLQJWKHHIÀFDF\RIORFDOWUHDWPHQW of metastases, even for metachronous metastases. No recommendation can be made.