Dr. Neal Shore MD, FACS @AtlanticUrology #ESMO20 #prostatecancer Tolerability and treatment response in the phase 3 ARAMIS trial - Nonmetastatic, Castration-Resistant Prostate Cancer and ...

Dr. Neal Shore MD, FACS @AtlanticUrology #ESMO20 #prostatecancer Tolerability and treatment response in the phase 3 ARAMIS trial - Nonmetastatic, Castration-Resistant Prostate Cancer and ...

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Dr. Neal Shore MD, FACS, CPI, of the Atlantic Urology Clinics and Director at the Carolina Urologic Research Center, discusses Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide and ESMO abstract tolerability and treatment response to darolutamide (DARO) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) in the phase 3 ARAMIS trial.

Prostate Nonmetastatic, Castration-Resistant Darolutamide Cancer and Survival

Darolutamide is an inhibitor of the androgen receptor that is structurally distinct and approved for the treatment of non-metastatic, castration-resistant prostate cancer. The median metastasis-free survival was substantially longer with darolutamide (40.4 months) than with placebo (18.4 months) in the expected primary analysis of a phase 3 trial. At the time of the primary study , the data for the measurement of overall survival was immature.

We randomly assigned 1509 men in this double-blind, placebo-controlled experiment, in A 2:1 ratio for the administration of darolutamide (955 patients) or placebo (554 patients) while androgen deprivation therapy proceeded. After positive outcomes of the primary endpoint study were found, the treatment allocations were unblinded and patients in the placebo group were eligible to cross over to undergo open-label darolutamide therapy. At the time of this recommended final examination, which was scheduled to be completed after approximately 240. There were deaths, total survival, and all other secondary endpoints were measured.

The median time for follow-up was 29.0 months. All 170 patients who were already receiving placebo crossed over at the time of the unblinding of the data to receive the Darolutamide; 137 patients who stopped their placebo prior to unblinding received at least one additional life-prolonging medication. The overall 3-year survival in the darolutamide group was 83 percent (95 percent confidence interval [CI], 80 to 86) and 77 percent (95 percent CI, 72 to 81) in the placebo group. The risk of death in the darolutamide group was substantially lower, by 31 percent than in the placebo group. (fatality hazard ratio, 0.69; 95 % CI, 0.53 to 0.88; P=0.003). The major advantage of darolutamide was also correlated with all other secondary endpoints, including the time of first symptomatic skeletal event and the time of first cytotoxic chemotherapy use. In the two classes, the frequency of adverse effects following the start of treatment was similar; no new safety signals were found.

Among men with nonmetastatic, castration-resistant prostate cancer, the percentage of patients who were alive at 3 years of age was significantly higher for darolutamide than for placebo. In the two classes, the frequency of adverse effects was comparable. (Funded by Bayer HealthCare and Orion Pharma; number NCT02200614 from ARAMIS ClinicalTrials.gov.)


Tolerability and treatment response to darolutamide (DARO) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) in the phase 3 ARAMIS trial.

Androgen receptor inhibitors (ARIs) that are authorized for nmCRPC treatment are
Associated with such adverse effects (AEs) at different amounts, e.g.,
Tiredness, falls, injuries, rash, hypertension, and mental disability.
Dose modification and discontinuation due to AEs were higher vs. placebo (PBO) in phase 3 studies of apalutamide and enzalutamide.2,3
Dose reductions for managing AEs, enforcement habits, and lack of loyalty to treatment may decrease medication efficacy.
DARO, a structurally distinct ARI approved for the treatment of nmCRPC, substantially prolonged phase 3 ARAMIS trial survival results: 6,77
DARO has a favorable safety profile, with limited additional risk of AEs associated with other ARIs and comparable AE discontinuation rates relative to PBO.7.7.
The low risk of AEs linked to the central nervous system could be due to DARO.7-99 low blood-brain barrier penetration.
DARO also shows low risk for drug-drug drug interactions with drugs typically used by males with nmCRPC.10
Here, the tolerability of DARO treatment documented in the phase 3 ARAMIS trial is identified and the correlation between treatment response and delayed progression of the disease in men with nmCRPC is investigated.

In addition to androgen deprivation therapy (ADT) in men with nmCRPC, ARAMIS was a double-blind, randomized, multicentre, global phase 3 study to determine the effectiveness and safety of DARO vs PBO.
Treatment-emergent AEs were evaluated according to the Standard Terminology Guidelines for Adverse Effects, version 4.03 of the National Cancer Institute; AEs and dose changes were evaluated every 16 weeks.
On 30 November 2018, following the positive results of the primary review for metastasis-free survival (MFS), the study was unblinded.
The analyses recorded here were performed on primary data (3 Sep 2018) and double-blind time final analyses (30 Nov 2018).
The relation between the baseline decline of prostate-specific antigen (PSA) in response to DARO treatment and MFS was assessed using the Cox proportional hazard mode.



• The median care period was 14.8 months for DARO and 11.0 months for PBO.
The maximum expected dose of DARO was well tolerated (600 mg twice daily).
In both treatment arms, the number of dosage changes was identical.
(145/954=15.2% with DARO versus 54/554=9.7% with PBO) (Figure 3).
Changes in doses involved dosage interruptions or delays and decreases in doses.
Dose changes were mainly due to AEs: 184/219=84.0 percent of darolutamide arm events and 57/78=73.1 percent of placebo arm events.
Nearly all patients with dose increases have been successfully re-escalated to the full scheduled dose (133/145=91.7% with DARO and 48/54=88.9% with PBO).
The incidence of discontinuation of the study drug due to AEs was comparable between DARO and PBO (8.9 percent vs 8.7 percent) and remained unchanged between the double-blind period's primary and final studies.


• The prescribed twice-daily dosage of DARO 600 mg was well tolerated and almost all ARAMIS patients were able to take their maximum scheduled dose.
• In addition to the low dose reduction rates, medication discontinuation rates attributable to AEs remained unchanged and were close to placebo in the ARAMIS final double-blind time study, demonstrating the favorable tolerability of DARO.
Long-term DARO therapy extends longevity and slows the progression of disease in men with nmCRPC.
More than 80% of DARO randomized patients showed > 50 percent maximum decrease from baseline in PSA. Modelling pharmacodynamics.
A positive correlation between a maximum decline in PSA from baseline and longer MFS was expected.
Darolutamide has a highly favorable tolerability and safety profile, and it would be of great clinical benefit to have real-world experience comparing ARIs.

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