LATITUDE Study - final survival analysis

[pjoshea13]

New paper below.

LATITUDE: Abiraterone Acetate [ZYTIGA] + Prednisone with ADT, versus ADT & placebo in newly diagnosed high-risk metastatic patients (at least two of the following: "Gleason score of ≥8, presence of three or more lesions on bone scan, or presence of measurable visceral metastasis except lymph node metastasis".

"This final analysis ... was done after a median follow-up of 51·8 months ... and 618 deaths (275 [46%] of 597 in the abiraterone acetate plus prednisone group and 343 [57%] of 602 in the placebo group)."

"Overall survival was significantly longer in the abiraterone acetate plus prednisone group (median 53·3 months ...) than in the placebo group (36·5 months ...)"

-Patrick

ncbi.nlm.nih.gov/pubmed/309...

Lancet Oncol. 2019 Apr 12. pii: S1470-2045(19)30082-8. doi: 10.1016/S1470-2045(19)30082-8. [Epub ahead of print]

Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial.

Fizazi K1, Tran N2, Fein L3, Matsubara N4, Rodriguez-Antolin A5, Alekseev BY6, Özgüroğlu M7, Ye D8, Feyerabend S9, Protheroe A10, Sulur G2, Luna Y2, Li S11, Mundle S12, Chi KN13.

Author information

1

Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, France. Electronic address: [e-mail].

2

Janssen Research and Development, Los Angeles, CA, USA.

3

Instituto de Oncologia de Rosário, Rosário, Argentina.

4

National Cancer Center Hospital East, Chiba, Japan.

5

12 de Octubre University Hospital, Madrid, Spain.

6

PA Hertsen Moscow Cancer Research Institute, Moscow, Russia.

7

Cerrahpaşa Medical Faculty, Istanbul University Cerrahpaşa, Istanbul, Turkey.

8

Fudan University Shanghai Cancer Center, Shanghai, China.

9

Studienpraxis Urologie, Nürtingen, Germany.

10

Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

11

Janssen Research and Development, Spring House, PA, USA.

12

Janssen Research and Development, Raritan, NJ, USA.

13

BC Cancer Agency-Vancouver Centre, Vancouver, BC, Canada.

Abstract

BACKGROUND:

In the interim analyses of the LATITUDE study, the addition of abiraterone acetate plus prednisone to androgen deprivation therapy (ADT) led to a significant improvement in overall survival and radiographic progression-free survival compared with placebos plus ADT in men with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (mCSPC). Here, we present long-term survival outcomes and safety of abiraterone acetate plus prednisone and ADT from the final analysis of the LATITUDE study.

METHODS:

This is a multicentre, randomised, double-blind, phase 3 trial done at 235 sites in 34 countries. Eligible patients (men aged ≥18 years) had newly diagnosed, histologically or cytologically confirmed prostate cancer with metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and at least two of the three high-risk prognostic factors (Gleason score of ≥8, presence of three or more lesions on bone scan, or presence of measurable visceral metastasis except lymph node metastasis). Patients were randomly assigned (1:1) to receive abiraterone acetate (1000 mg) once daily orally plus prednisone (5 mg) once daily orally and ADT (abiraterone acetate plus prednisone group) or matching placebos plus ADT (placebo group); each treatment cycle was 28 days. Randomisation was done by a centralised interactive web response system in a country-by-country scheme using permuted block randomisation, stratified by presence of visceral disease and ECOG performance status. The coprimary endpoint of overall survival was assessed in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT01715285 and is complete.

FINDINGS:

Between Feb 12, 2013, and Dec 11, 2014, 1209 patients were screened, of whom ten were ineligible because of study site violations. 1199 patients were randomly assigned to either the abiraterone acetate plus prednisone group (n=597) or placebo group (n=602). After the results of the first interim analysis (cutoff date Oct 31, 2016), the study was unmasked to patients and investigators, and patients in the placebo group were allowed to cross over to receive abiraterone acetate and prednisone plus ADT treatment as per a protocol amendment (Feb 15, 2017) in an open-label extension phase of the study (up to 18 months from the protocol amendment). This final analysis (data cutoff Aug 15, 2018) was done after a median follow-up of 51·8 months (IQR 47·2-57·0) and 618 deaths (275 [46%] of 597 in the abiraterone acetate plus prednisone group and 343 [57%] of 602 in the placebo group). Overall survival was significantly longer in the abiraterone acetate plus prednisone group (median 53·3 months [95% CI 48·2-not reached]) than in the placebo group (36·5 months [33·5-40·0]), with a hazard ratio of 0·66 (95% CI 0·56-0·78; p<0·0001). The most common grade 3-4 adverse events were hypertension (125 [21%] in the abiraterone acetate plus prednisone group vs 60 [10%] in the placebo group vs three [4%] in the 72 patients who crossed over from placebo to abiraterone acetate plus prednisone) and hypokalaemia (70 [12%] vs ten [2%] vs two [3%]). Serious adverse events of any grade occurred in 192 (32%) of 597 patients in the abiraterone acetate plus prednisone group, 151 (25%) of 602 in the placebo group, and four (6%) of 72 in the crossover group. The most common treatment-related serious adverse event was hypokalaemia (four [1%] patients in the abiraterone acetate plus prednisone group and none in the other groups). Treatment-related deaths occurred in three (<1%) patients each in the abiraterone acetate plus prednisone group (gastric ulcer perforation, sudden death, and cerebrovascular accident) and the placebo group (sudden death, cerebrovascular accident, and pneumonia), with none in the crossover group.

INTERPRETATION:

The combination of abiraterone acetate plus prednisone with ADT was associated with significantly longer overall survival than placebos plus ADT in men with newly diagnosed high-risk mCSPC and had a manageable safety profile. These findings support the use of abiraterone acetate plus prednisone as a standard of care in patients with high-risk mCSPC.

FUNDING:

Janssen Research & Development.

Copyright © 2019 Elsevier Ltd. All rights reserved.

PMID: 30987939 DOI: 10.1016/S1470-2045(19)30082-8

[GP24]

I liked Fred Saad's comment regarding this publication:

thelancet.com/journals/lano...

[snoraste]

The initial report in 2017 had the HR of OS at 0.62, vs 0.66 here. Not a huge change, and I'm not surprised. What would be more interesting to me (and is missing from LATTITUDE) is cancer specific mortality comparisons.

[TEBozo]

"EXCEPT FOR LYMPH NODE METASTASES?"

[pjoshea13 in reply to TEBozo]

Lymph node mets are excluded from high-risk factors.

-Patrick

[Ahk1 in reply to pjoshea13]

Patrick,

I was offered two days ago by MO to participate in a similar trial at MSK ( 3 arms, one of them is zaytiga, adt and prednisone). I have been struggling to make a decision on this as no Mets have been identified as of yet, mri says one met suspicion and psma says no Mets so I am thinking I am on the border line with my stats as of now. What do you think? Is it worth it to join? Thanks

[pjoshea13 in reply to Ahk1]

I can't give advice, of course.

I have spent 15 years avoiding mainstream ADT & ADT extensions, based on:

i) they are not curative, so the "hit it hard" point of view doesn't resonate with me.

ii) for men who would otherwise expect to live for more than 10 years, say, their mean-times-to-failure are woefully short.

ii) they select for cells that are more difficult to manage. Johann de Bono, who was involved in the development of Zytiga & Xtandi has fretted about the lack of options when resistance occurs.

On the other hand, if studies were to show that early use for low-risk cases, such as yourself, could lead to significantly longer survival, I would have to rethink. But for now, I think the BAT approach of rapidly cycling from castrate to high testosterone, offers an attractive alternative to long-term ADT, with its treatment-induced aggressive PCa.

Ultimately, IMO, effective treatments will emerge, & they will include secondary agents to counter resistance.

-Patrick

[6357axbz in reply to pjoshea13]

Patrick, is yours a low risk case?

[pjoshea13 in reply to 6357axbz]

By the definition given above, I am not "high-risk".

I do have metastatic disease, but a solitary bone met at L5 was radiated 4 years ago. I haven't had many scans in 15 years, but I do have one coming up next week.

When I was on a 3-month cycle for high-T/no-T, by the 3rd month of the testosterone [T] phase, my PSA doubling time was 3 months. Many would not consider that as low-risk, yet as the years slip by, it feels like a stable chronic condition. But, alas, I'm not smarter than the cancer ...

-Patrick

[6357axbz in reply to pjoshea13]

Is being on a 3 month high-t/low-t cycle some sort of ADT treatment?

[pjoshea13 in reply to 6357axbz]

I wanted to be on intermittent ADT [IADT] with a far shorter on-phase than the usual 12-month minimum.

I also wanted full restoration of testosterone during the off-phase.

I put my modified ADT approach in effect some years before I started reading about BAT, which crams the entire cycle into one month. I switched over late last year.

One can imagine variations in both protocols, but the theme is interference with the kind of adaptation that leads to CRPC.

-Patrick

[6357axbz in reply to pjoshea13]

You’ve had a terrific response! Apparently you’re way ahead of the curve. Do you know anyone else with a similar cancer and response IADT? Are you still HS?

Please let us know your upcoming scan results if you’re comfortable. Bone and CT?

[pjoshea13 in reply to 6357axbz]

I was fortunate to have treatment failure at a time when I was young & the options were few & unattractive. I felt empowered, somehow. If I had been diagnosed 10 years later, I might have been seduced by the newer options.

Initially, I regulated my estrogen:testosterone & was good for 5 years or so. But, ultimately, I had to switch to my version of IADT.

I don't know anyone else who tried it. And I have not been promoting it. But I have become increasingly concerned about the fact that resistance to the new drugs creates cells that are much more difficult to manage than Lupron-resistant cells, say.

As of now, there is no standard protocol that offers hope of a cure. Therefore, it isn't important to "hit it hard", IMO. More important to keep it tame & find a way of living with it that can be sustained for 10, 15, 20 years or longer.

I continue to be hormone resistant.

I am only having a bone scan next week. I'll report back.

-Patrick

[6357axbz in reply to pjoshea13]

Thanks Patrick. Hoping for the best for you next week.

[TEBozo in reply to 6357axbz]

Dr. Lebowitz, LA doc protocol

[Ahk1 in reply to pjoshea13]

THanks Patrick,

On a side note. You said “early use for low-risk cases, such as yourself”. Why do you think I am low-risk?

[pjoshea13 in reply to Ahk1]

Because you don't meet the definition of "high-risk" as defined in my original post.

-Patrick

[Ahk1 in reply to pjoshea13]

I’m sorry, I don’t see this post. Can you point it out for me please?

[Ahk1 in reply to pjoshea13]

Oh, sorry. I got it. Thanks

[GeorgeGlass in reply to Ahk1]

I haven't tried to push my doctor for zytiga because I am still not clear on whether adding zytiga at the beginning is much better than adding it when Lupron starts to fail on its own. They didn't compare those two options.

[TEBozo]

No advice but a "me too" as I had 3 hot lymph nodes removed and found 3 more with PSMA Scan done at UCLA on 3.27.19. Mark Scholz MD group (Prostate Oncology Specialists-Marina del Rey) recommends Zytiga and prednisolone but Dallas surgeon says just ADT and IMRT. Keep Zytiga in my "back pocket" he says.