And the superiority of Abiraterone before switching to Enalutamide (vs. the opposite sequence) Revisited.

[MateoBeach]

More on dialing in the sequencing of advanced androgen receptor (AR) drugs for mCRPC. Though this is from 2019 I think we have well integrated this into standard practice. Just noting that the side-effects advantages of abiraterone do not have a therapeutic effects downside. Abi before Enza.

sciencedirect.com/science/a...

Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial

Summary

Background

Abiraterone acetate plus prednisone and enzalutamide are both used for the treatment of metastatic castration-resistant prostate cancer. We aimed to determine the best sequence in which to use both drugs, as well as their second-line efficacy.

Methods

In this multicentre, randomised, open-label, phase 2, crossover trial done in six cancer centres in British Columbia, Canada, we recruited patients aged 18 years or older with newly-diagnosed metastatic castration-resistant prostate cancer without neuroendocrine differentiation and Eastern Cooperative Oncology Group performance status 2 or less. Patients were randomly assigned (1:1) using a computer-generated random number table to receive either abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily until PSA progression followed by crossover to enzalutamide 160 mg orally once daily (group A), or the opposite sequence (group B). Treatment was not masked to investigators or participants. Primary endpoints were time to second PSA progression and PSA response (≥30% decline from baseline) on second-line therapy, analysed by intention-to-treat in all randomly assigned patients and in patients who crossed over, respectively. The trial is registered with ClinicalTrials.gov, NCT02125357.

Findings

Between Oct 21, 2014, and Dec 13, 2016, 202 patients were enrolled and randomly assigned to either group A (n=101) or group B (n=101). At the time of data cutoff, 73 (72%) patients in group A and 75 (74%) patients in group B had crossed over. Time to second PSA progression was longer in group A than in group B (median 19·3 months [95% CI 16·0–30·5] vs 15·2 months [95% CI 11·9–19·8] months; hazard ratio 0·66, 95% CI 0·45–0·97, p=0·036), at a median follow-up of 22·8 months (IQR 10·3–33·4). PSA responses to second-line therapy were seen in 26 (36%) of 73 patients for enzalutamide and three (4%) of 75 for abiraterone (χ2 p<0·0001). The most common grade 3–4 adverse events throughout the trial were hypertension (27 [27%] of 101 patients in group A vs 18 [18%] of 101 patients in group B) and fatigue (six [10%] vs four [4%]). Serious adverse events were reported in 15 (15%) of 101 patients in group A and 20 (20%) of 101 patients in group B. There were no treatment-related deaths.

Interpretation

Enzalutamide showed activity as a second-line novel androgen receptor pathway inhibitor, whereas abiraterone acetate did not, leading to a longer time to second PSA progression for the sequence of abiraterone followed by enzalutamide than with the opposite treatment sequence. Our data suggest that using a sequencing strategy of abiraterone acetate followed by enzalutamide provides the greatest clinical benefit.

[tango65]

Quite right!! The pharmaceutical companies are expending very large sums of money in clinical investigations combining the already approved "new" drugs instead of using the money, talent and knowledge to find other drugs which could overcame the resistant to the "new" anti androgens and chemo agents.

[dhccpa in reply to tango65]

Amen

[Herman_PSA_OK]

Greetings everyone! Great discussion about the optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer. Looks like I'm living through this situation currently.

My MO made the comment about his experience with the sequence when he started me on abiraterone acetate plus prednisone a few months ago in addition to my Eligard ADT. Sure, he reads and is up on the studies. Plus what he has experienced in his practice.

Well, last month my PSA stopped dropping from 49.8 PSA when I started to 9.1 two months ago. Last month at my monthly visit to the MO my PSA creeped up to 9.9 PSA in just one month. He suggested sending out my biopsy tissues for genomic testing to see if I had a defective PCa gene or not just in case my PSA has bottomed out and the next SOC path to take.

In two weeks I will be testing again my blood labs and PSA level. Plus we will be reviewing the outcome of my gene report. Looks like I may be starting enzalutamide if PSA continues to rise and I don't have any bad genes. Any comments or suggestions out there. Has anyone ever experience a zig zag of PSA at the mCRPC state? Should I be concerned and what would you do in my shoes?

God Bless!

[MateoBeach in reply to Herman_PSA_OK]

Hi Herman. Reading your profile I see you have a complicated case. Your Doctor sounds to be on top of things now. Presume he is medical oncologist and not urologist. Because of your sickle cell trait and already having marrow suppression must be carefully considered. Often it is beneficial to go to a course of docetaxel chemotherapy after one advanced AR agent fails before going to another such as enzalutamide or apalutamide. But your low counts may preclude this for now. You should be on bone strengthening and protecting agent like Xgeva. Don’t avoid it, request it! A PSMA scan would be helpful to further clarify extent and distribution of mets. This would also tell you if Lu-PSMA treatment may be appropriate. Or if bone only lesions then Ra223 considered. Complements the Xgeva well. Best of strength and some luck to you. -Paul.