The Phase 3 SONIA study of 1,050 patients with HR+, HER2- MBC evaluated progression free survival (PFS) and overall survival (OS) from the initiation of first line treatment through failure of second line treatment. It compared two groups of patients. One group took the current first line standard-of care-treatment consisting of a combination of a CDK4/6 inhibitor with an aromatase inhibitor (followed by Faslodex as second-line treatment after progression). The second group started with an aromatase inhibitor alone, followed by a combination of a CDK4/6 inhibitor with Faslodex after progression on initial treatment.
As disclosed at ASCO 2023, the study determined that there was no statistically significant difference in time to progression and OS through second-line therapy between the two groups. Median OS through second line treatment reached 45.9 months when a CDK4/6 inhibitor was used in the first line, and 53.7 months when a CDK4/6 inhibitor was used in the second line (P = .83). (Anne's note: nearly 8 months' difference in OS sounds pretty significant to me!)
Patients who received a CDK4/6 inhibitor up-front remained on it for a median of 24.6 months until moving to second line treatment, whereas patients who received a CDK4/6 inhibitor in the second line took it for a median of 8.1 months until treatment failure - a 16.5 month difference. Because patients taking the CDK4/6 inhibitor as first line therapy remained on it much longer than patients taking it in the second line setting, they experienced a 42% increase in the incidence of grade 3/4 toxicity and an increase in drug expenditure of approximately $200,000 per patient.
According to Gabe Sonke, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, the SONIA results warrant rethinking of the current "CDK4/6 inhibitor in the first line setting for all" paradigm. And Daniel Stover, MD, of the Ohio State University Comprehensive Cancer Center, agreed that the SONIA trial asks the important question of whether all patients need to start with a CDK4/6 inhibitor as first-line therapy because identifying the ‘right size’ therapy for patients with HR+, HER2- MBC is highly important.
The SONIA study has some limitations. It reflects state-of-the-art treatment when the trial was initiated in 2017 but now may be considered somewhat dated. For example, more than 90% of patients in the study received Ibrance as the CDK4/6 inhibitor, which is currently considered the least attractive CDK4/6 inhibitor to use in the first line because of its relative lack of OS benefit. Moreover, in the second line setting, other treatment options are now available such as Piqray plus Faslodex and Elacestrant, along with other emerging agents and combinations.
In conclusion, as Dr. Sonke further commented, by conducting randomized clinical trials such as SONIA that evaluate shorter treatment courses, lower doses, or less frequent administration, researchers can determine the optimal treatment that minimizes harmful side effects while maintaining the therapeutic benefits. This approach can significantly reduce the toxicity of medications while making effective drugs more accessible to patients who would otherwise find them unaffordable. Furthermore, the costs of these trials can be covered by the savings achieved through the less-expensive treatments used in the study - the SONIA study saved approximately 25 million Euros on drug expenditure during the trial which may entice insurance companies and governments that are paying for patient care to fund these trials since they become self-funding.
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Very interesting, thanks for sharing. Treatment with CDK4/6 can last for a longer time than other treatments in first line, but I wonder too if what comes next may be not so effective after such a strong initial therapy.
Wow! Sounds like practice changing info. If I were just diagnosed with MBC right now knowing how I felt in 2 years of CDK4-6 ( Ibrance and then Verzenio… I would opt for faslodex upfront and wait to progress. It makes me helpful that some woman would have their first few years of MBC feeling like their normal self. No all fatigued snd with GI issues. This is great news for lots of women afte us!
So funny that you ask about diclofenac! I just today had a 2nd opinion at DFCI in boston and just saw Sara tolvaney MD (who this week presented at ASCO) and she told me about the Diclofenac study and recommended I try it… I have some at home so will try right away and happy to tell you how it goes… I will also read the study. She is hopeful I will get a long run on cape.. says that sometimes it works “ exquisitely” well for lobular. And she showed me my recent scan which was much improved. I should write a post about this.. thanks for prodding me! And reminding me to read that diclofenac story.
This is a statement that deeply resonates: "By conducting randomized clinical trials such as SONIA that evaluate shorter treatment courses, lower doses, or less frequent administration, researchers can determine the optimal treatment that minimizes harmful side effects while maintaining the therapeutic benefits."
It's great that existing therapies are beginning to be evaluated in view of balancing both toxicity and efficacy!
A great read. Thanks for sharing, it’s all very interesting. Funnily enough I recall starting with Faslodex a wee bit before iBrance and after a month of both thinking , well how do we know which one is mostly working? And it seemed a bit dumb to me to start them both basically at the same time! Well lo and behold, my thinking was on target!
Thanks for sharing. I have been on Ibrance and anastrozole for over 5.5 years after my 2nd endometrial cancer recurrence. I was in remission when I started and remain in remission now. My dose was dropped from 125 mg to 100 mg in the third year due to poor recovery of blood counts on the week off. I've talked to three different oncs about taking an Ibrance vacation. 2 say maybe, 1 says no way - it's working. There simply is not enough long-term research available to really tell us either way. So, I am staying on this regimen, until it no longer works. Though there is some research that says taking a "vacation" and restarting later may work too. None of it is really conclusive.
Thank you for sharing this article and good to see you post here. Hope you are doing well. It is interesting to me that now they are starting new high risk early stage breast cancer patients on Verzenio to hopefully prevent them from progressing to MBC. So I would also wonder what would come next for those patients if they progress. Sending hugs and prayers.
Thanks so much for your post, Anne! I was happy to read that you are still active! Your book, ("The Insider's Guide to Metastatic Breast Cancer: A Summary of the Disease and Its Treatments" Book by Anne Loeser) is such an excellent resource I hope everyone on this site has at least an online copy.
Best of Wishes, Cindy
P.S. I found the comments made by the reviewer of the article you summarized also of interest.
I’d forgotten about Diclofenac. My oncologist wants me to scale back on opioids and use something else. I’ve got some Diclofenac that I can trial and see if it is effective for bone mets pain. Voltaren has to be taken with food but that’s not hard to do. I used to take it for severe period pain and it worked for that so maybe it’s another option for met pains.
This makes so much sense. Too bad that ship has sailed for those of us further along. I have fulvestrant and Ibrance as 1st line. It worked incredibly, from mets all over to NEAD, but we thought it was the fulvestrant. (Still, I am trying to get my onc to retry Ibrance: I had minimal side effects from full dose of Ibrance, but am suffering with the lowest dose of verzenio, and it is not working that well.)
One point, though. I am sure you know that statistical significance is a measure of reliability -- whether the results were due to chance, and not effect size (how much difference it made). That the difference between the groups was not significant is good news. It doesn't matter which path you follow. That the difference between the groups was ns means that it could have been due to chance; it was not a reliable difference. Choosing two other groups might have come out differently. We don't know the sample sizes from this description. It the number of participants was small, the difference could become significant with a bigger sample.
Thanks for the information. My oncologist started me on faslodex alone as a first line treatment. Recently, after a bit over 2 years of stability, I had some progression so ibrance has now been added to my treatment. I am hoping for good results from that...fingers crossed 🤞.
I am new to all this having only been diagnosed MBC in April this year, but through this site I have found your book and I suspect it will become my "go to" when I have questions. I have been a nurse for 48 years, the last 8 being at our local hospice, so I tend to ask my onc oodles of questions when I see her. Was interested in the article you posted about maybe only having Fulvestrant in the beginning. She has started me on Ibrance and Fulvestrant so I will ask her. I'm lucky, after a rocky start, which seemed to be connected to the Covid I had in my first week of treatment, I seem to be having very few side effects. Haven't had follow up CT yet, that's in 3 weeks, will be interesting to see what's happening inside. Once again, thank you very much for your wonderful informative book. My hopes, thoughts and prayers are with you.
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Positive immunotherapy trial results
Ibrance/Arimidex stopped working 😥
Long timer-choice between Faslodex + Picray or Tamoxifen 
New lesions and change of treatment.
