ESUO: Progressive prostate cancer therapy in outpatient setting

Dr. Horst Brenneis ESUO board member Urologie im Zentrum Pirmasens (DE)

brenneis-dr@gmx.de

Prof. Helmut Haas Chairman ESUO Heppenheim (DE)

hf.haas-hp@ t-online.de

Even in the early 2000s, progression in prostate cancer was associated with short survival time and poor prognosis. The introduction of taxanes and the second generation of androgen deprivation therapies, e.g. abiraterone, enzalutamide, apalutamide, darolutamid, led to a significant prolongation of survival and a much better prognosis. Since these are partly oral and ambulatory therapies, there has been a shift of these therapies to the outpatient setting. Only the application of nuclear medicine therapies (alpharadin223 and PSMA-lutetium) still require mandatory inpatient treatment.

Oncology Agreement The prerequisite for progressive prostate cancer therapy in Germany is participation in the ’Oncology Agreement’ within the framework of the statutory health insurance. Furthermore, corresponding additional training (additional qualification: ‘drug-based tumour therapy’) and clinical experience should be available. In addition, the office staff (medical assistants) must complete an oncology continuing education course. Both physicians and staff are required to undergo continuous education, e.g. in the CME programme of the EAU. A network of clinics, regional general practitioners and specialists, e.g. via tumour boards, is also essential.

Profound knowledge In addition, profound knowledge of the approval status of especially novel hormonal treatments (NHT) is important, since not all substances are approved in all stages of prostate carcinoma (hormone-sensitive, castration-resistant, metastatic, M0CRPC, M1CRPC). Incorrect prescribing can lead to expensive recourse, at least in Germany.

M0CRPC is defined by PSA increase in combination with testosterone at castration level under androgen deprivation therapy (ADT) and the absence of metastases in conventional imaging (technetium99m bone scan and computed tomography (CT) of the pelvis, abdomen, chest, and head). PSA doubling time can be calculated using a calculator (e.g. www.mskcc.org/nomograms/prostate/psa_ doubling_time).

Androgen receptor inhibitors In patients with nonmetastatic castration-resistant prostate cancer (nmCRPC or M0CRPC) at high risk of progression (defined as prostate-specific antigen [PSA] doubling time ≤ 10 months), new androgen receptor inhibitors (ARI) in combination with continued androgen deprivation therapy (ADT) are considered the new standard of care. Apalutamide, enzalutamide, and darolutamide have been approved on the basis of improved metastasis-free survival (MFS) in the respective large pivotal studies SPARTAN, PROSPER and ARAMIS. After a longer follow-up period, they were able to show a statistically significant and clinically relevant overall survival advantage.

Close patient control All substances are administered orally and easy to handle in office. A close control of the patients is necessary, especially at the beginning of the therapy. In the first phase, blood count, liver and kidney function should be checked every 2 weeks. In the further course, this interval can be extended to 4 weeks. This laboratory control is easily done together with a clinical control when the drug is re-prescribed. We also perform a PSA check at the same interval. Imaging is sufficient every 6-12 months if the PSA course/decline is stable. According to literature and experience of the authors, the substances are well tolerated. In most cases only moderate fatigue occurs. With apalutamide, eczema develops relatively frequently (Rush, see Fig.1,2), which may be perceived as very disturbing by the patient and can force him to discontinue therapy or reduce the dose. Topical or systemic corticosteroids are helpful in this case. It is important to educate the patient well and to inform the primary care physician.

Compliance In daily practice the use of abiraterone requires good patient education regarding the intake of the medication (2 hours before meals) and compliance regarding cortisone substitution.

The author remembers a case of an 81-year-old patient who had already been on abiraterone for over a year. In the course of networking, the general practitioner noticed distinct hypokalaemia. The reason was the independent discontinuation of the corticosteroid therapy in the context of a respiratory tract infection. His wife had advised him to do this because “cortisone is not good for the immune system”.

Such situations are also conceivable in the context of the current COVID-19 situation. Once again, the importance of a good network of physicians must be emphasised. Particularly in rural areas, the necessary laboratory tests (see above) can be performed by a general practitioner close to the patient's home. This can save the patient long journeys.

“…, there has been a shift of these therapies to the outpatient setting.”

Intravenous chemotherapy with taxanes Intravenous chemotherapy with taxanes is the longest established therapy for metastatic prostate cancer. It is approved for both hormone-sensitive and castration-resistant stages. In practice, this requires a team experienced in intravenous chemotherapy. Close monitoring of the patient is required regarding laboratory tests (especially blood count/leukocytes), neuropathy and susceptibility to infection. The patient should be encouraged to have regular weight and blood pressure checks and documentation. Onycholysis can be prevented by cooling the acra. Docetaxel, especially at the 50 mg dosage every 2 weeks, is generally well tolerated. With cabazitaxel, particular attention should be paid to neutropenia. As a preventive measure, a GM-CSF preparation (e.g. filgrastin) can be given 48 hours after infusion.

Personalised medicine A new challenge for practice urology lies in the introduction of personalised medicine in the therapy of CRCP. In early 2021, the first PARPP inhibitor (olaparib) was approved in Europe. The prerequisite for the effect of this substance is the presence of a defect in the DNA repair genes BrCa1 and BrCA2. As condition to use the substance, this genetic defect must be detected either in the tumour tissue (somatic mutation in the primary tumour or metastatic tissue) or as a germline mutation in the peripheral blood. The probability of this defect is estimated at approx.10-15% in the literature. Testing possible genetic alterations requires a detailed discussion and explanation to the patient at the time of arranging the test with the molecular pathologist. In particular, the presence of a germline mutation means a significantly increased risk of BrCa-associated tumours for close relatives of the patient. In this respect, the risk of breast carcinoma in female relatives (sister, daughter) is also important for the urologist. Accordingly, a human geneticist needs to be consulted here specifically.

Qualification for genetic counselling In Germany, a special qualification for genetic counselling is necessary, which can also be acquired by urologists. Monitoring the well-tolerated therapy in the office is possible without any problems. Especially blood count control is necessary due to the risk of anaemia. Because this drug has only been approved recently, the authors do not yet have personal experience in its use.

In summary, the modern therapy of metastatic prostate cancer is possible without problems in an outpatient setting in the office, provided a sufficiently experienced and trained team is present. In palliative situations, it saves hospitalisation and thus improves the patient’s quality of life.

Fig. 1: Eczema developed in the posterior surface of the trunk after apalutamide administration Fig. 2: Eczema developed in the anterior surface of the trunk after apalutamide administration

ANNOUNCEMENT FEBU Part 1 Written Exam

Determine & demonstrate your level of knowledge

Date: Thursday, 23 September 2021 Local time: 14:30 – 16:30 Venues: Pearson VUE test centres

FORMAT The exam consists of 100 single correct answer MCQs.

COMPUTER BASED EXAM The exam is organised in collaboration with Pearson VUE. The candidate takes the exam at one of Pearson VUEs secured test centres.