LATITUDE - Final report.

[pjoshea13]

New LATITUDE final paper [1]

I posted the final account several months ago, as reported at ASCO [2].

& now we have the English version [1]. e.g.

From [2]:

"The final analysis continues to demonstrate a significant OS advantage of combining AA+P to ADT in NDx-HR mCNPC pts. These efficacy findings and AE profiles are consistent with IA1 and IA2 and reinforce AA+P as a standard of care in NDx-HR mCNPC pts."

From [1]:

"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."

-Patrick

[1] thelancet.com/journals/lano...

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

Prof Karim Fizazi, MD

NamPhuong Tran, MD

Luis Fein, MD

Nobuaki Matsubara, MD

Alfredo Rodriguez-Antolin, MD

Boris Y Alekseev, MD

et al.

Summary

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.

***

[2] healthunlocked.com/advanced...

[NPfisherman]

Thanks for posting...My MO put me on AA=P quickly...my question will be whether stereotactic radiation improves outcomes when added to AA =P---which appears likely...My MO said he would not even give me an OS estimate until after next PSA--I have been undetectable on PSA for 6 months--next test in August...

All the best,

Fish

[elvismlv123]

does anyone know how bad prednisone is? its a killer drug on any playing field.

someone is smoking something in the back room.

[j-o-h-n in reply to elvismlv123]

I thought prednisone was an antifreeze for you car...

Good Luck, Good Health and Good Humor.

j-o-h-n Thursday 05/09/2019 11:46 AM

[elvismlv123 in reply to elvismlv123]

Thats Prestone but it might be made by the same lab that makes prednisone.The long term use of Prednisone can kill you. Antifreeze just keeps your blood from freezing up.

My doc said today that Prednisone is a miracle drug and I have no reason to oppose him. Its a limited use drug to achieve a short term positive end result.In other words they have no farging idea what it does or how it works or what damage it does either.

[JimVanHorn]

Prednisone is a steroid that is used to simulate the effects of Adrenalin. Many other drugs like methyl prednisolone, prednisolone, dexamethasone all mimic the effects of adrenalin. Each drug has similar side effects and these effects are dose and length of therapy dependent. They have been used for 50 years or more. Some of the high doses over long periods of time have irreversible side effects, like elephant hump on back and moon face, but in lower doses this does not occur. They help the body heal faster. They have a synergistic effect with some medications (meaning that each drug separately would not be as effective as both together and could be three times the effect).

[middlejoel]

So the trial added AA + P to ADT. My question is about the term ADT. That could mean a variety of drugs or combination of them. What did they used in the trial?

Joe

[pjoshea13 in reply to middlejoel]

Joel,

A lot of people still use "ADT" to mean old-style ADT with no add-ons. I was once criticized for doing so, although Tall-Allen did the same thing a week later.

"ADT" should include any drug where the target is the androgen receptor. Perhaps we could use "ADT-basic" & "ADT+", but researchers need to lead the way.

I believe that the paper uses ADT in the same way that it has been used for decades - castration - i.e. gonad inhibition only.

-Patrick

[middlejoel in reply to pjoshea13]

Patrick,

Thanks for the reply. I think that my problem was that I was reading too much into the Latitude trial's description. I was reading as forming a combination by adding Zytiga plus Prednisone plus ADT. Since Zytiga is an ADT drug, that didn't make sense.

joe