Bone Resorption Inhibitor + Abiraterone - Overall Survival

[pjoshea13]

New study below [1].

"This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019."

NOTE: BRI - Bone Resorption Inhibitor; OS = Overall Survival; SRE - Skeletal-Related Event

"Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months ...)"

"The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months ...)"

"The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months ...)"

"and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29 ...)"

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/342...

JAMA Netw Open

. 2021 Jul 1;4(7):e2116536. doi: 10.1001/jamanetworkopen.2021.16536.

Association of Concomitant Bone Resorption Inhibitors With Overall Survival Among Patients With Metastatic Castration-Resistant Prostate Cancer and Bone Metastases Receiving Abiraterone Acetate With Prednisone as First-Line Therapy

Edoardo Francini 1 , Francesco Montagnani 2 , Pier Vitale Nuzzo 3 , Miguel Gonzalez-Velez 4 , Nimira S Alimohamed 5 , Pietro Rosellini 6 , Irene Moreno-Candilejo 7 , Antonio Cigliola 6 , Jaime Rubio-Perez 8 , Francesca Crivelli 2 , Grace K Shaw 3 , Li Zhang 9 , Roberto Petrioli 6 , Carmelo Bengala 10 , Guido Francini 6 , Jesus Garcia-Foncillas 8 , Christopher J Sweeney 3 , Celestia S Higano 11 , Alan H Bryce 4 , Lauren C Harshman 3 , Richard Lee-Ying 5 , Daniel Y C Heng 5

Affiliations collapse

Affiliations

1 Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

2 Department of Oncology, Ospedale degli Infermi, Biella, Italy.

3 Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

4 Genomic Oncology Clinic, Mayo Clinic, Phoenix, Arizona.

5 Division of Medical Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada.

6 Department of Medical and Surgical Sciences and Neuroscience, University of Siena, Siena, Italy.

7 Medical Oncology Unit, Hospital HM Sanchinarro Start, Madrid, Spain.

8 University Hospital Fundacion Jimenez Diaz, Autonomous University of Madrid, Madrid, Spain.

9 DFCI at Geisinger Medical Center, Danville, Pennsylvania.

10 Medical Oncology Unit, Misericordia Hospital, Grosseto, Italy.

11 Fred Hutchinson Cancer Research Center, University of Washington, Seattle.

PMID: 34292336 DOI: 10.1001/jamanetworkopen.2021.16536

Abstract

Importance: Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown.

Objective: To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy.

Design, setting, and participants: This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019.

Exposures: Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy.

Main outcomes and measures: The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used.

Results: Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P < .001). The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months; HR, 0.51; 95% CI, 0.38-0.68; P < .001). The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months; HR, 1.27; 95% CI, 1.00-1.60; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; 95% CI, 1.57-3.35; P < .001). In the multivariable analysis, concomitant BRIs use was independently associated with longer OS (HR, 0.64; 95% CI, 0.52-0.79; P < .001).

Conclusions and relevance: In this study, the addition of BRIs to abiraterone acetate with prednisone as first-line therapy for the treatment of patients with mCRPC and bone metastases was associated with longer OS, particularly in patients with high-volume disease. These results suggest that the use of BRIs in combination with abiraterone acetate with prednisone as first-line therapy for the treatment of mCRPC with bone metastases could be beneficial.

[cesces]

"Bone resorption inhibitors (BRIs)"

That's the stuff that can harm your jaw, is that correct?

[pjoshea13 in reply to cesces]

... the price one pays for the extra 8.8 months. & these were men with mCRPC.

[cesces in reply to pjoshea13]

Sort of a hard decision.

Are there any precautions you can take with BRIs?

Are there any pre-use indicators that it will or will not have those adverse side effects.

My recollection is that the bad side effects can take place years later, so it isn't possible to stop taking it when you first see the side effects. By then the damage is already done.

[pjoshea13 in reply to cesces]

BRIs have a long wash-out period (my dentist says that they never wash out.) My wife's oncologist says that 3 months after getting the drug one can safely have serious dental work. & then a wait of 3 months before getting the next dose.

Do not start BRIs without first seeing your dentist & assessing risk of future heavy-duty dental work. Perhaps get it out of the way before starting a BRI - but wait 3 months in that case.

-Patrick

[DrRobin in reply to cesces]

I think you can know osteonecrosis is occurring when your blood calcium goes up (pain also). I am on Xgeva and the drug pamphlet says to watch your calcium levels.

[pjoshea13 in reply to cesces]

"Zoledronic acid, the most potent of the bisphosphonates, and denosumab, a monoclonal antibody directed against the receptor activator of nuclear factor κB ligand (RANKL), are osteoclast-mediated bone resorption inhibitors (BRIs) that are approved for the prevention of SREs in patients with CRPC and bone metastases and are recommended by international guidelines for use in this disease setting.8-12 However, neither of these agents alone was associated with a survival benefit among men with CRPC and bone metastases in phase 3 randomized clinical trials.13 Nevertheless, post hoc analyses of prospective studies suggested that the combination of BRIs with the androgen biosynthesis inhibitor abiraterone acetate with prednisone or the bone-targeting radionuclide radium-223 may provide a survival benefit compared with placebo." [1].

See: Antiresorptive agent-related osteonecrosis of the jaw in prostate cancer patients with bone metastasis treated with bone-modifying agents [2].

-Patrick

[1] jamanetwork.com/journals/ja...

[2] pubmed.ncbi.nlm.nih.gov/328...

[cigafred]

"Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months ...)""The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months ...)"

So in both groups of patients, {average] OS was less than time to [average] first skeletal event? [Or if it is median not average, I guess it works, but the distribution is weird.] And all this with a median follow-up of 23.5 months?

[pjoshea13 in reply to cigafred]

Yes, it does look odd at first, but the risk of SRE increases with survival time. An SRE would be less likely in the first half to die.

It gives the impression the BRI increases the risk of an SRE, but, presumably, the men on a BRI had a greater risk of SRE.

The short follow-up time to reach median OS is a feature of mCRPC studies unfortunately.

-Patrick

[TeleGuy in reply to pjoshea13]

They kind of drop the statement about the BRI group having a shorter time to first SRE with no commentary. I wonder if, since this is a retrospective study, that those on BRI meds were already deemed to be at risk.

[PhilipSZacarias]

Good paper. The question has to be asked whether the estradiol in combination with abiraterone might be able to inhibit bone resorption as well, maybe with less side effects? Cheers, Phil