RP56976 | Microrna Synthesis

Treatment of hormone-na¨ıve metastatic prostate cancer

Zineb Hamiloua, Fred Saada, and Karim Fizazib

INTRODUCTION
Prostate cancer is the most commonly nonskin can- cer in men, representing 19% of all newly reported cases. Patients with newly diagnosed radiographi- cally evident metastatic cancer represent only 5% of new cases in western countries but up until 60% in countries in Eastern Asia [1,2]. Until recently, these patients were treated exclusively with androgen deprivation therapy (ADT) while numerous new treatments improved outcomes of men with meta- static castrate resistant prostate cancer. The last
5 years saw a great shift in the treatment of de novo metastatic hormone-sensitive cancer. Indeed, reports from five randomized controlled phase III trials compared standard of care ADT with ADT and docetaxel (DOC) or abiraterone. DOC, customarily used in castrate resistant prostate cancer became the first agent to demonstrate an overall survival (OS) benefit in metastatic hormone-na¨ıve prostate cancer
(mHNPC) and is now standard of care [3,4&&,5&&].

survival of these patients. Although it was estimated recently at 42 months with ADT alone [8,9], it reached 57.6 and 65 months, respectively, in CHARTED and STAMPEDE and is not yet reached with the addition of abiraterone [4&&,6&&,7&&,10&&]. In this review, we aim to review the evidence behind the use of DOC and abiraterone acetate in mHNPC.

ANDROGEN DEPRIVATION THERAPY WITH OR WITHOUT ABIRATERONE

Trials overview
Two trials with very recent results compared ADT with ADT abiraterone acetate 1000 mg/day pred- prednisolone or prednisone 5 mg/day in mHNPC.

aCentre Hospitalier de l’Universite´ de Montre´al, Montre´al, Que´bec,
b

Canada and De´partement De Me´decine Oncologique, Institut Gustave

More recently, CYP17 inhibitor abiraterone acetate
proved the same benefit and is pending approval for the same indication [6&&,7&&]. These major trials have revolutionized our daily practice when caring for patients with mHNPC. Most importantly, they allowed a significant improvement in the median

Roussy, Universite´ Paris-Saclay, Paris, France
Correspondence to Zineb Hamilou, MD, Centre Hospitalier de l’Univer- site´ de Montre´al, Montre´al, Que´bec, Canada.
Tel: +1 514 890 8000×20696; e-mail: [email protected] Curr Opin Support Palliat Care 2018, 12:334–338 DOI:10.1097/SPC.0000000000000359

www.supportiveandpalliativecare.com Volume 12 ● Number 3 ● September 2018

Treatment of hormone-na¨ıve metastatic prostate cancer Hamilou et al.

The LATITUDE trial randomized 1199 ECOG 0-2 metastatic patients to these two arms. Patients were included if newly diagnosed ( 3 months before random assignment) with high-risk disease defined as having at least two of the following factors: Gleason score at least 8, at least three bone metasta- ses and presence of measurable visceral metastasis [6&&]. Primary outcomes of interest for this trial were both OS and radiographic progression-free-survival (rPFS). Results were presented at ASCO 2018 after an interim analysis conducted with about 50% of expected death events and a median follow-up of
30.4 months: abiraterone acetate addition to ADT significantly improved both primary endpoints with a 38% reduction in the risk of death [hazard ratio, 0.62; 95% confidence interval (CI), 0.51–0.76, P < 0.001], median survival of 34.7 months in the ADT alone arm vs. not reached in the abiraterone acetate ADT arm. Moreover, the LATITUDE trial detected a reduction in the risk for rPFS of 53% (hazard ratio 0.47; 95% CI, 0.39–0.55; P < 0.001) in favor of the abiraterone acetate ADT arm. This trial also demonstrated superiority of abiraterone acetate over ADT alone for all secondary endpoints. STAMPEDE authors presented at the same meeting their results from arm G randomizing
1917 patients to the same combination of ADT abiraterone acetate prednisolone [7&&]. Patients were included if newly diagnosed and metastatic, node positive, or had high-risk locally advanced disease or disease that had previously been treated with radical surgery or radiotherapy that was relaps- ing with high-risk features. Both OS, the primary outcome, and failure-free-survival (FFS) as an inter- mediate primary outcome were met. In the overall population, addition of abiraterone acetate to ADT translated in a significant survival advantage at

3 years (83 vs. 76%; hazard ratio.0.63; 95% CI
0.52– 0.76; P < 0.001). Specifically, the 1002 men with mHNPC treated with ADT abiraterone ace- tate had greater survival advantage (hazard ratio 0.61; 95% CI 0.49–0.75; CI 0.49– 0.75; P < 0.001). The STAMPEDE trial also detected a reduction in the risk of FFS of 69% (hazard ratio; 0.31; 95% CI
0.26– 0.37; P < 0.05) in the metastatic population (median, 30 months with ADT alone vs. 43.9
months with abiraterone acetate and prednisolone). A recent systematic review reported a combined analysis of both trials: mHNPC patients treated with abirateroneacetate ADT had a 38% reductioninthe risk of death (hazard ratio 0.62; 95% CI 0.53–0.71;
P 0.55 10–10) and 55% reduction in the risk of
clinical or rPFS (hazard ratio 0.45; 95% CI 0.40–0.51; P 0.66 10–36). In addition, OS benefit was greater in younger men (<65, 65–75, >75: interaction haz-
ard ratio ¼ 1.24; 95% CI 1.02–1.52; P ¼ 0.033) [11].

Adverse events (grade ≤3)
In the LATITUDE trial, serious adverse event (SAE) rates were similar between the two arms: 10 vs. 12% of patients in the ADT alone and abiraterone aceta- te ADT arm discontinued treatment because of side effects [6&&]. Hypertension, increases in amino- transferase levels and respiratory disorders were increased in abiraterone acetate ADT arm and were the most common grades 3 and 4 SAEs (5, 6,
5%, respectively). Grades 3 and 4 hyperkaliemia was present in only 1% of abiraterone acetate ADT- treated patients vs. 0.3% in ADT alone arm.

ANDROGEN DEPRIVATION THERAPY WITH OR WITHOUT DOCETAXEL

Trials overview
Three randomized trials showed benefit of early use of DOC after a follow up of merely 10 years. GETUG- AFU 15 launched in 2004 randomized 385 men with metastatic prostate cancer to receive ADT alone or ADT DOC (75 mg/m2 every 3 weeks, up to nine cycles). In 2013, it concluded in a nonsignificant increase in median OS of 4.7 months, together with a significant improvement in the secondary end- point of progression-free survival: 23.5 months (20.5– 31.9) vs. 15.4 months (12.5– 19.8); hazard
ratio 0.72, 95% CI 0.59–0.94; P 0.015) [3,5&&].
By 2014, CHAARTED phase III, became the first trial supporting survival improvement with DOC in metastatic hormone-sensitive prostate cancer. It randomized 790 patients between ADT alone or ADT DOC (75 mg/m2 every 3 weeks, up to six cycles). Originally, patients had to be considered

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‘high-risk’, that is, with one or more visceral metas- tases and/or four bone metastases with at least one appendicular localization. However, an amendment added after the inclusion of the first 53 patients allowed the inclusion of low-risk patients. Patients were stratified prospectively according to this vari- able. After 28.9 months of follow-up, first results revealed a benefit in favor of ADT DOC with a median survival of 57.6 months in comparison with 44 months (hazard ratio 0.61; 95% CI 0.47–0.80; P < 0.001). This 13.6 months survival improvement
was largely driven by the high-risk group with a 17-
month increase in OS. In contrast, there was no difference in OS in the low-risk group but the median survival had not been reached at the time of analysis. In 2016, long-term efficacy data were presented at ESMO 2016 and confirmed the OS augmentation, although the difference was smaller (median: 57.6 vs. 47.2 months; hazard ratio 0.73; P .0018) [10&&]. These final results stressed that OS benefit was restricted to the high-risk subgroup (51.2 vs. 34.4 months; hazard ratio 0.63; 95% CI
0.50– 0.79; P < 0.001) in contrast to the low-risk (median survival not reached vs. 63.5 months; haz-
ard ratio 1.04; 95% CI 0.70– 1.55; P 0.86).
Finally, the multiarm multistage STAMPEDE trial included 3000 patients with high-risk locally advanced and mHNPC between 2005 and 2014 [4&&]. This trial came to the same conclusions as CHAARTED proving better survival with the addi- tion of DOC in the overall localized and metastatic patients (hazard ratio 0.78; 95% CI 0.66–0.93; median survival, 81 months; P 0.006). Specifically, in the cohort of patients with mHNPC, median survival was 15.0 months longer compared with ADT alone (45 vs. 60 months; hazard ratio 0.76,
95% CI 0.62– 0.92; P 0.005).
In the same year, a meta-analysis confirmed a survival benefit to DOC addition in men with met- astatic prostate cancer starting therapy for the first time [12&&]. It included 3206 patients from the three trials aforementioned and showed an absolute improvement of around 9% at 4 years (95% CI, 5– 14 years). Although these results were derived from 93% of all men (remaining data was pending at the time of analysis), they still provide robust evidence that DOC should be a standard of care for these patients.
A second meta-analysis by Tucci et al. [13] con- cluded to DOC addition benefit also (hazard ratio 0.73; 95% CI 0.60– 0.90; P ¼ 0.002).

Adverse events (grade ≤3)
The most common adverse side effects in patients treated with chemotherapy and ADT are infectious.

Incidence of febrile neutropenia reached 15% in STAMPEDE and of neutropenia 12%. No amend- ment in the trials was suggested as to growth-factor support. Neuropathy, the other characteristic side effect of DOC, was reported only in 3% of the patients. Finally, up to 7% of patients complained of grades 3 and 4 fatigue.

DISCUSSION
The addition of both DOC or abiraterone to ADT in men with newly diagnosed metastatic prostate can- cer offers a significant survival benefit in compari- son with treatment with ADT alone. Nonetheless, some questioning arises from these data.

Volume distribution
The issue of volume distribution in newly diagnosed mHNPC became a source of controversy [14]. Out of the three trials that discussed upfront chemother- apy, only CHAARTED stratified patients according to this variable. On one hand, positive trial STAM- PEDE included patients without restriction for vol- ume of disease. Second, two meta-analyses, with a nonnegligible number of almost 3000 patients also proved DOC addition benefit. On the other hand, while OS was increased for those classified as high- risk in CHAARTED, patients at low risk did not seem to profit from this therapy. A retrospective analysis from the GETUG-15 trial leaned toward the same conclusion without reaching statistical significance (hazard ratio 0.78, P 0.14 vs. hazard ratio 1.02, P 0.9 for high risk and low risk, respectively) [8]. Lastly, a recent meta-analysis of the aggregate data from both CHAARTED and GETUG-AFU15 studies reaffirmed these results: adding DOC in patients with high-volume disease has a consistent effect in improving median OS (ADT: 34.4 and 35.1 months vs. ADT DOC 51.2 and 39.8 months in CHAARTED and GETUG-AFU15, respectively; haz-
ard ratio 0.68; P < 0.001). Patients with low volume disease showed much longer OS, without DOC con-
ferred advantage (ADT: not reached and 83.4; ADT DOC: 63.5 and not reached in CHAARTED and GETUG-AFU15, respectively; 1.03) [15].
As a result, although CHAARTED was designed with the strength to prove OS in the total popula- tion, DOC use is patients with low-volume disease is not as strongly recommended as in patients with high volume as per recently published ASCO clinical practice guidelines [16]. In contrast, both European Urology guidelines and National Compre- hensive Cancer Network do not consider burden of disease and strongly recommend upfront chemo- therapy to all fit M1 patients. To our opinion, given

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Treatment of hormone-na¨ıve metastatic prostate cancer Hamilou et al.

low-volume patients’ better prognosis, decisions need to be individualized as to patient’s fitness to chemotherapy. Undoubtedly, febrile neutropenia is a main concern with an incidence ranging from 6 to 12% in the three trials aforementioned and in this context, use of granulocyte-stimulating factor is strongly recommended [17].
Volume distribution issue is also pertinent when considering abiraterone for patients with mHNPC. STAMPEDE and LATITUDE trials were both conclu- sive trials, with a similar design but in a different population. STAMPEDE evaluated abiraterone ace- tate ADT efficacy in a broad population of meta- static and nonmetastatic patients. In the overall population, abiraterone acetate added to ADT reduced the risk of death by 37% (hazard ratio 0.63; 95% CI 0.52– 0.76; P < 0.001) and by 39% in
the metastatic population (hazard ratio 0.61; 95% CI
0.49– 0.75; P < 0.05). LATITUDE focused on a spe- cific subgroup of high-risk metastatic patients defined as aforementioned and as a reminder announced a similar 38% reduction in the risk of death (hazard ratio 0.62; 95% CI 0.51– 0.76; P < 0.001). Consequently, although data are conclu- sive for high-risk patients, abiraterone acetate ADT should not be restricted to them since benefit in the overall mHNPC population was demonstrated.

Which to offer: abiraterone or docetaxel
We currently have two options available for our patients with mHNPC. To our opinion, both drugs constitute standard of care if used according to their respective indications. Only indirect comparison is available to guide us in this decision. First, STAM- PEDE authors presented a comparative analysis between patients randomized to ADT abiraterone abiraterone acetate in arm G and to ADT DOC in arm C [18]. No statistical significant difference in survival was found (hazard ratio 1.16 CI 0.82– 1.65) in the locally advanced and metastatic population. At the same meeting, an indirect comparison deter- mining the relative effect of ADT abiraterone acetate prednisone vs. ADT DOC in mHNPC was presented. Treatment with ADT abiraterone acetate prednisone improved both OS (hazard ratio: 0.846; CI: 0.629, 1.141) and rPFS (hazard ratio:
0.706; CI: 0.490, 1.021) with ADT abiraterone ace- tate being more effective with Bayesian probabilities of 86.7 and 96.8%, respectively [19].
With no head to head efficacy comparison avail- able, factors like duration of treatment, drug toxicity and patient’s choice can determine the option selected. Chemotherapy addition is completed in 4 months in contrast to treatment ad progression for abiraterone. Second, as described above, the most

common grades 3 and 4 adverse events occurring in patients treated with DOC on the CHAARTED, STAMPEDE-Docetaxel, and GETUG-AFU 15 trials were neutropenia (12, 12, and 32%, respectively),
febrile neutropenia (6, 15, and 7%, respectively), and fatigue (4% in CHAARTED and 7% in GETUG-AFU 15). Abiraterone has the advantage of being better tolerated with no infectious and neuropathic risk. Abiraterone acetate prescription still calls for a rigorous follow-up routine of miner- alocorticoid side and cardiovascular side effects as well as liver function tests. In the preceding meta- analysis, grades 3 and 4 acute cardiac and hepatic toxicity as well as vascular events were increased with abiraterone acetate addition (Peto odds ratio
(OR) 2.93 CI 1.74– 4.93, P < 0.001; Peto OR 3.09
CI 2.12– 4.50, P < 0.001 and OR 0.28 CI 1.71–3.03,
P < 0.001, respectively) while no statistically signifi- cant excess of death was found (P 0.23) [11].
Finally, an indirect treatment comparison of abir- aterone acetate and prednisone and DOC on patient-reported outcomes in mHNPC compared data from CHAARTED and LATITUDE: abiraterone acetate prednisone ADT showed improved alle- viation of pain and health-related quality of life over DOC (Bayesian probability ranging from 92.3 to 100%) [20&&].

PERSPECTIVE
Several studies evaluating combination therapies are ongoing. PEACE-1 trial (NCT01957436) com- pares the clinical benefit of ADT ( DOC) with or without local radiotherapy, with or without abiraterone acetate prednisone in mHNPC. As such, it will be the first trial to disclose results about upfront DOC abiraterone acetate ADT in this population. Other androgen receptor-axis inhibitors are currently tested in mHNPC: Enzalu- tamide in two phase III trials, ENZAMET (NCT02446405) and ARCHES (NCT02677896), dar-
olutamide (ODM-201) ADT DOC in ARASENS trial (NCT02799602), and apalutamide in TITAN trial (NCT02489318). The multiarm multistage STAMPEDE trial has begun accrual for experi- mental arm J: standard of care enzalutamide abiraterone. Finally, SWOG S1216 randomized patients to a combination to ADT þ orterenol vs.
ADT þ bicalutamide (NCT01809691).

CONCLUSION
Treatment of patients with mHNPC has entered a promising era. DOC and abiraterone offer now two strong standard of care options, seem to confer the same advantage by indirect comparison, but

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retain their own pros and cons. Although DOC is strongly recommended for patients with a high burden of disease and is a treatment limited in time, abiraterone seems to be an option for a broader population, has better tolerability and improves more patient-reported outcomes. As of today, each patient needs to be managed individu- ally in the matter of adding one or the other to standard ADT.
Surely, the treatment landscape of mHNPC is rapidly evolving. Efforts to understand disease biol- ogy modification is urgently needed. This early and combined use of therapies might just modify our management of patients with castrate-resistant disease.

Acknowledgements
None.

Financial support and sponsorship
None.

Conflicts of interest
Z.H.: participation to advisory boards/honorarium for Bayer, Pfizer. Participation in clinical trials supported by pharmaceuticals without honorarium perceived. F.S.: Consultant and research activities with Astrazeneca, Astellas, Amgen, Janssen, Bayer, Sanofi. K.F.: Participa- tion to advisory boards/honorarium for Amgen, Astellas, Astrazeneca, Bayer, Clovis, Curevac, Essa, Genentech, Janssen, MSD, Orion and Sanofi.

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Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest

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Indirect comparison of abiraterone and DOC addition to androgen deprivation therapy in mHNPC.RP56976