Apalutamide

Apalutamide is an orally administered, pure androgen receptor antagonist of the 2nd generation. It binds to the receptor more strongly than e.g. bicalutamide and does not develop an agonistic effect if androgen-receptor overexpression occurs during treatment.

Apalutamide is approved for the treatment of adult men with non-metastatic castration-resistant prostate cancer (nm-CRPC) who are at high risk of developing metastases. Apalutamide is considered castration-resistant when the carcinoma is progressive despite massive suppression of gonadal testosterone synthesis (increase in prostate-specific antigen). apalutamide is also approved for the treatment of adult men with metastatic hormone sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT).

Apalutamide is a selective androgen receptor (AR) inhibitor that binds directly to the ligand-binding domain of the receptor. This prevents the docking of its natural ligand (testosterone) and the transcription mediated by it. Apalutamide reduces the proliferation of tumour cells, increases apoptosis and thus has an antitumoral effect. The main metabolite N-desmethylapalutamide still shows partial activity in vitro.

According to the guidelines, in the past, in the case of prostate carcinoma with mildly symptomatic disease without evidence of metastases, a wait-and-see approach was recommended while maintaining conventional androgen deprivation therapy. For these patients, non-steroidal androgen receptor inhibitors such as apalutamide represent a new option that significantly delays the time to metastasis and prolongs survival.

In the pivotal SPARTAN study in M0CRPC patients at high risk of metastasis, apalutamide significantly prolonged metastasis-free survival by more than 2 years compared to placebo (+ ADT each).

In the so-called TITAN study, the efficacy and tolerability of 240 mg of apalutamide daily in addition to androgen deprivation therapy (ADT) was assessed in comparison to placebo plus ADT (n= 1052 patients with metastatic hormone sensitive prostate cancer = mHSCP). 10.7 % of the patients had already been pretreated with the cytostatic drug docetaxel. 62.7 % of the patients had a high-volume prostate carcinoma (defined as the presence of visceral metastases and/or 4 or > 4 bone lesions, at least one of which was outside the spine and/or pelvic bone). After 24 months, a statistically significant benefit was documented with apalutamide compared to placebo, both in radiologically progression-free survival and overall survival. There were no substantial differences in the side effect profile between the placebo and verum arms (Chi KN et al. (2019).

Fatigue, skin rash as well as weight loss, arthralgias and falls are the most common side effects.

Significant side effects were fractures and hypothyroidism. The rate of adverse events leading to discontinuation of therapy in studies was 10.6 percent.

Apalutamide is a potent enzyme inducer, for example of CYP3A4, -2C19 and -2C9, and drug transporters such as PGP are induced. It can therefore influence the efficacy of numerous drugs. Simultaneous use with warfarin and coumarin-like anticoagulants should be avoided.

It should also be noted that androgen deprivation therapy can prolong the QT interval of the heart. This requires careful consideration if apalutamide is to be used simultaneously with drugs that can prolong the QT interval or trigger torsade-de-points (e.g. antiarrhythmics, methadone, moxifloxacin or antipsychotics such as haloperidol).

Erleada®

The first approval of apalutamide for the therapy of non-metastatic castration-resistant prostate cancer (nm-CRPC or M0CRPC) with a high risk of metastasis was granted in January 2019.

With 60,000 new cases per year, one in four malignant tumours diagnosed in men involves prostate carcinoma. As long as the prostate carcinoma is localized, androgen deprivation therapy (ADT, hormone blockade, chemical castration) is usually given in addition to radiation treatment. If the blood level of the marker protein PSA continues to rise, the tumour is considered resistant to castration. In this situation, tumour cells can produce increased amounts of androgens themselves or, after amplification and mutation of the androgen receptor gene or through altered cofactors of the androgen receptor, can also use very low androgen concentrations for increased tumour growth.

1. Chi KN et al (2019) Updated results from a randomized phase II study of cabazitaxel (CAB) versus abiraterone (ABI) or enzalutamide (ENZ) in poor prognosis metastatic CRPC. J Clin Oncol 37(suppl): abstract 5006
2. Chi KN et al (2019) Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 381: 13-24
3. Technical information Erleada®, status January 2019
4. Moul JW et al(2015) Hormones naïve prostate cancer: predicting and maximizing response intervals. Asian J Androl 17: 9290-9235
5. Scher HI et al(2015) Prevalence of Prostate Cancer Clinical States and Mortality in the United States: Estimates Using a Dynamic Progression Model. PLoS One 10: d0139440
6. Smith MR et al (2018) Relationship of time to metastasis (TTM) and site of metastases in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): Results from the phase 3 SPARTAN trial. J Clin Oncol 36 (suppl; abstr 5033) & Poster Session, ASCO 2018, Abstract 5033: meetinglibrary. asco.org/record/163132/abstract.
7. Smith MR et al (2018) Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med 378: 1408-1418