Nubeqa® (darolutamide) dla pacjentow z non-mCRPC (FDA)

[zosia bluszcz]

About Nubeqa® (darolutamide)
Nubeqa® (darolutamide) is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription.1
Nubeqa is approved for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC).1
A Phase III study in metastatic hormone-sensitive prostate cancer (ARASENS) is ongoing. Information about this trial can be found at http://www.clinicaltrials.gov.
https://markets.businessinsider.com/new ... 1028400843





ASCO-GU 2019 – Bayer and Orion have their work cut out with darolutamide
February 14, 2019

When entering a prostate cancer market about to see the genericisation of Zytiga, Johnson & Johnson carved out a novel use – non-metastatic disease – for its follow-on drug Erleada.
This strategy was copied by Pfizer/Astellas’s Xtandi, and it could soon result in a third entry, darolutamide from Bayer and Orion.
However, results from darolutamide’s pivotal Aramis study, presented today at the Asco-Genitourinary Cancers symposium, show how hard it will be for the newcomers to compete. The efficacy data are virtually identical to those reported in Erleada and Xtandi’s respective Spartan and Prosper studies, meaning that the drugs’ safety profiles will be more important in determining their use.

Writing in today’s New England Journal of Medicine, where the Aramis data were simultaneously published, the trial’s investigators made much of darolutamide’s potential for lower toxicity. This, they argue, was due to the molecule’s distinct structure, which results in low blood/brain barrier penetration and low binding affinity for GABAA receptors.
On the question of efficacy, however, they accepted that: “The metastasis-free survival with darolutamide is similar to that in ... Prosper and Spartan.”

Tabel 1
Cross-trial efficacy comparisons in non-metastatic, castration-resistant prostate cancer

Among adverse events of note, the authors highlighted fatigue, asthenia (abnormal physical weakness), falls and fractures as less common in Aramis than in rival studies. Cross-trial comparisons are by definition unsound, but in the absence of head-to-head data they are all that prescribers will have to go on.
Also importantly, patients with a history of seizure were not allowed to enter the Spartan and Prosper studies – something that did not apply to Aramis, thanks to darolutamide’s lack of proconvulsive potential in animal trials.
In Aramis there were just two seizures on darolutamide and one in the control group.

Table 2
Cross-trial comparison of selected adverse events reported

A separate consideration, of course, is whether non-metastatic prostate cancer is a genuine setting for these types of drugs, or whether it is one that has been invented to get around the loss of patent protection for Zytiga, which is approved only in metastatic and hormone-sensitive settings.
Some might ask, for instance, whether patients can accurately be classified as non-metastatic or whether this is just a shortcoming of conventional imaging techniques, meaning that they might actually be metastatic and could be prescribed Zytiga according to this drug’s label.

The question is whether there is a window between patients becoming castration-resistant and developing metastases and, if so, how big this window might be. The Aramis authors argue that “delaying the development of metastases ... is a key therapeutic goal”.

It is also unclear how big a market this might amount to.
Erleada was approved a year ago, but J&J has not disclosed its sales and only says it is "pleased" with the drug’s launch progress.
Pfizer does not split out Xtandi sales by metastatic and non-metastatic disease, but on its fourth-quarter analyst call boasted: “In just six months our market share is quadruple that of Erleada.”

Darolutamide is expected to sell $819m in 2024, according to EvaluatePharma’s sellside consensus. Now that the Loxo-derived Vitrakvi has been launched darolutamide is Bayer’s biggest pipeline hope.
Even if Zytiga and its generic alternatives do not enter into the equation, Bayer and Orion will still have a hard task competing against the more established prostate cancer players, J&J and Pfizer/Astellas. Whether darolutamide can achieve forecast sales numbers will therefore depend on pricing and marketing muscle at least as much as on its safety profile.

https://www.evaluate.com/vantage/articl ... rk-cut-out





FDA Approves Bayer's Nubeqa® (darolutamide), a New Treatment for Men with Non-Metastatic Castration-Resistant Prostate Cancer
July 30, 2019

The U.S. Food and Drug Administration (FDA) today approved Nubeqa® (darolutamide), an androgen receptor inhibitor (ARi), for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC). The FDA approval is based on the Phase III ARAMIS trial evaluating Nubeqa plus androgen deprivation therapy (ADT), which demonstrated a highly significant improvement in the primary efficacy endpoint of metastasis-free survival (MFS), with a median of 40.4 months versus 18.4 months for placebo plus ADT (p<0.0001).
MFS is defined as the time from randomization to the time of first evidence of blinded independent central review (BICR)-confirmed distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first.
Nubeqa was approved under the FDA’s Priority Review designation, which is reserved for medicines that may provide significant improvements in the safety or effectiveness of the treatment for serious conditions.
(…)
In the ARAMIS trial, both arms showed a 9 percent discontinuation rate due to adverse reactions.1
The most frequent adverse reactions requiring discontinuation in patients who received Nubeqa included cardiac failure (0.4 percent), and death (0.4 percent). Adverse reactions occurring more frequently in the Nubeqa arm (≥2 percent over placebo) were fatigue (16 percent versus 11 percent), pain in extremity (6 percent versus 3 percent) and rash (3 percent versus 1 percent).
Nubeqa was not studied in women and there is a warning and precaution for embryo-fetal toxicity.

Overall survival (OS) and time to pain progression were additional secondary efficacy endpoints.1 OS data were not yet mature at the time of final MFS analysis. The MFS result was supported by a delay in time to pain progression, defined as at least a 2-point worsening from baseline of the pain score on Brief Pain Inventory-Short Form or initiation of opioids, in patients treated with Nubeqa as compared to placebo. Pain progression was reported in 28 percent of all patients on study.

Bayer has filed for approval of Nubeqa in the European Union (EU), Japan, and with other health authorities. Nubeqa is developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company.

https://www.pcf.org/news/fda-approves-b ... 0190730fda



Bayer bags FDA nod for early prostate cancer drug darolutamide
http://www.pmlive.com/pharma_news/bayer ... de_1295937

[kinaszle]

Hej Kinaszle, dołaczam Twoj post do wątku dot. darolutamidu, ktory zalożylam 2 dni temu.
-zb



30 lipca 2019 r. - Amerykańska Agencja ds. Żywności i Leków (FDA) zatwierdziła preparat Nubeqa® (darolutamid), inhibitor receptora androgenowego (ARi), do leczenia pacjentów z rakiem prostaty opornym na kastrację (nmCRPC).
Zatwierdzenie FDA opiera się na badaniu ARAMIS fazy III oceniającym terapię Nubeqa plus terapia pozbawiona androgenów (ADT), która wykazała bardzo znaczącą poprawę w pierwotnym punkcie końcowym skuteczności przeżycia bez przerzutów (MFS), z medianą 40,4 miesiąca w porównaniu do 18,4 miesiąca dla placebo plus ADT (p <0,0001). 1 MFS jest zdefiniowany jako czas od randomizacji do czasu pierwszego dowodu ślepej niezależnej centralnej oceny (BICR) potwierdzonej odległych przerzutów lub śmierci z jakiejkolwiek przyczyny w ciągu 33 tygodni po ostatni możliwy do oceny skan, w zależności od tego, co nastąpi wcześniej.
Preparat Nubeqa został zatwierdzony na podstawie oznaczenia FDA dotyczącego priorytetu przeglądu, który jest zarezerwowany dla leków, które mogą zapewnić znaczną poprawę bezpieczeństwa lub skuteczności leczenia poważnych chorób.

„Pacjenci na tym etapie raka gruczołu krokowego zwykle nie mają objawów choroby. Nadrzędnymi celami leczenia w tym otoczeniu jest opóźnienie rozprzestrzeniania się raka prostaty i ograniczenie uciążliwych skutków ubocznych terapii” - powiedział dr n. Med. Matthew Smith, Doktor, dyrektor programu chorób nowotworowych układu moczowo-płciowego, Massachusetts General Hospital Cancer Center. „To zatwierdzenie stanowi ważną nową opcję dla społeczności chorych na raka

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[leonardo556]

Post przeniesiony z wątku Leonardo, uzupełniony o cytaty z zalinkowanych artykułów.
-zb


Trafiłem na dwa interesujące artykuły porównujące antyandrogeny nowej generacji:


Darolutamide For Castration-Resistant Prostate Cancer

Abstract
The treatment landscape of advanced prostate cancer continues to evolve rapidly, with newer and more active drugs being used in earlier phases of the disease based on improved overall survival.
After adoption of docetaxel for metastatic castration-sensitive disease, large trials with next-generation androgen receptor-signaling inhibitors (abiraterone, enzalutamide and apalutamide) have demonstrate significant improvements in survival and important secondary endpoints.

For non-metastatic castration-resistant prostate cancer, recent phase III placebo-controlled trials with enzalutamide, apalutamide and darolutamide all demonstrated benefits in improving metastasis-free survival.
This review aims to summarize the clinical development of darolutamide, a novel next-generation androgen receptor antagonist, including preclinical data, clinical studies and the potential of darolutamide for the treatment of advanced prostate cancer.
To date, darolutamide efficacy and tolerability has been demonstrated in the ARAMIS trial, which demonstrated an improvement in metastasis-free survival compared to placebo for non-metastatic castration-resistant prostate cancer patients with a rapid PSA doubling time.
Ongoing studies will further evaluate the role of darolutamide in metastatic castration-sensitive prostate cancer in combination with docetaxel (ARASENS trial) and also in other stages of the disease.

Current Treatment Landscape Of Recurrent And Advanced Prostate Cancer

Figure 1 Prostate cancer clinical states model..jpg

Figure 1
Prostate cancer clinical states model.

Notes: Data created to include the corresponding agents that are FDA approved in each state. Data from Scher et al.35 Green boxes refer to the castration-sensitive state whereas the orange boxes refer to castration-resistant state. Green texts refer to castration-sensitive state whereas orange texts refer to castration-resistant state.

Abbreviations: ADT, androgen deprivation therapy; nmCRPC, non-metastatic castration-resistant prostate cancer; mCRPC, metastatic castration-resistant prostate cancer; MSI-H, microsatellite instability.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816030/


Wybrane informacje:

- skuteczność enzalutamidu, apalutamidu i darolutamidu jest podobna,
- skutki uboczne są zdecydowanie najniższe dla darolutamidu (tabela 3.),
- darolutamid w znikomym stopniu pokonuje barierę krew/mózg,
- darolutamid nie powoduje wzrostu poziomu testosteronu,
- darolutamid nie aktywuje zmutowanego AR (cokolwiek miałoby to oznaczać), *)
- darolutamid powoduje mniej interakcji lekowych w porównaniu z innymi antyandrogenami.

W tabeli porównawczej znalazł się także starszy bikalutamid. Ku wielkiemu zadowoleniu dowiedziałem się, że lek ten także nie pokonuje bariery krew/mózg. Jest jednak tylko częściowym antagonistą AR i nie hamuje translokacji jądrowej (cokolwiek miałoby to oznaczać). *)

Bardzo ucieszyła mnie również wiadomość że trwa badanie fazy II EORTC porównujące ADT z monoterapią darolutamidem u mężczyzn z rakiem prostaty nieleczonym wcześniej hormonalnie.

W podsumowaniu autorzy artykułu zwracają uwagę, że trwające badania [kliniczne] z udziałem darolutamidu i przyszłe strategie skojarzone rzucą dodatkowe światło na zastosowanie tego leku, a także na zapewniające optymalną synergię kombinacje .


[Skasowany fragment tekstu dot. monoterapii bicalutamidem znajduje się obecnie w wątku Leonardo. -zb]


Drugi artykuł potwierdza przewagę darolutamidu w zakresie bezpieczeństwa i skutków ubocznych:


ASCO 2020:
Safety Outcomes of Darolutamide Versus Apalutamide and Enzalutamide in nmCRPC: Matching-Adjusted Indirect Comparisons
(...)
For this study, patient-level data from the ARAMIS (darolutamide versus placebo, n=1,509), SPARTAN (apalutamide versus placebo, n=1,207) and PROSPER (enzalutamide versus placebo, n=1,401) trials were used.

Safety outcomes assessed included:

* Any grade adverse events
* Any serious adverse events
* Adverse events leading to treatment discontinuation
* Adverse events leading to/associated with death
* Individual adverse events of special interest in nmCRPC selected by clinical experts or considered to have CNS relevance

For the general safety outcomes, no statistically significant differences were observed between darolutamide and apalutamide after matching.
However, darolutamide showed a numeric advantage over apalutamide on adverse events leading to treatment discontinuation and adverse events leading to death, whereas apalutamide showed a numeric advantage over darolutamide on any serious adverse events.
Among individual adverse events, darolutamide generally exhibited favorable results compared to apalutamide, showing advantages for mental-impairment disorder, diarrhea, nausea, fatigue, and severe fatigue, as well as reaching statistical significance for falls, rash and fracture.

https://www.urotoday.com/conference-hig ... isons.html




____________________________
*) Praca domowa dla Leonardo

Androgen receptor signaling and mutations in prostate cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3006239/
-zb