Prostate Cancer: Drug Therapy

Therapeutic target

To prevent further spread of carcinoma and thus prolong survival.

Therapy recommendations

The following recommendations are based on the current S3 guideline (see below-“Introduction”) unless otherwise noted:

  • Prior to radical prostatectomy (surgical removal of prostate with capsule, the end pieces of the vas deferens, and the seminal vesicles), neoadjuvant (treatment that occurs before tumor surgery) hormone ablative therapy (also referred to as ADT = androgen deprivation therapy; hormone therapy that withholds the male sex hormone testosterone) should not be performed for clinically localized stage.
  • After radical prostatectomy, patients with locally advanced prostate cancer without lymph node metastases (PSA in the zero range) should not receive adjuvant (“supplemental/supportive”) hormone ablative therapy (HAT; synonyms: Hormone ablation; English androgen deprivation therapy, ADT; hormone therapy that withholds the male sex hormone testosterone) be performed.
  • Patients with locally advanced prostate cancer who elect radiotherapy should receive hormone ablative therapy in addition to percutaneous radiotherapy. The total duration of HAT should be two to three years. Of this, up to six months may be neoadjuvant. Notice:
    • Tumors with a low-risk profile (PSA < 10 ng/mL, Gleason sum score < 7, and cT1c-cT2a): neoadjuvant and adjuvant HAT with definitive radiotherapy did not confer a benefit in any oncologic end point
    • Tumors with intermediate risk profile (PSA > 10 and < 20 ng/ml and/or Gleason sum score = 7 and/or cT2b): HAT for a total period of six months combined with radiotherapy including a total dose of 72 Gy is considered standard.
    • Tumors with a high-risk profile (PSA > 20 ng/ml or Gleason sum score ≥ 8 and/or ≥ cT3): studies in which the [HAT lasted 18-, 24-, and 36-months, respectively, obtained comparable results
  • Patients with symptomatic metastatic prostate cancer should be recommended androgen deprivation. If androgen deprivation is indicated, it should be performed by medication or surgery.
  • In metastatic prostate cancer, early use of conventional chemotherapy can significantly improve outcomes compared with a conventional approach group (conventional androgen deprivation/suppression of testosterone, in which chemotherapy was not started until tumor progression had occurred): Prolongation of the average survival time of patients from 44.0 to 57.6 months; in patients with extensive metastases (daughter tumors), the average survival time increased from 32.2 to 49.2 months; progression-free survival was increased from 19.8 to 32.7 months
  • If PSA recurrence has occurred after radical prostatectomy (surgical removal of prostate with capsule, the end pieces of the vas deferens, and the seminal vesicles) or radiotherapy (radiation therapy), delaying the start of therapy until symptoms appear does not shorten survival times. PSA recurrence or biochemical recurrence occurs when a very low PSA level after surgery rises above 0.2 nanograms per milliliter and this trend continues with further measurements. There is a tendency to delay therapy for about two years or wait until PSA levels have risen sharply or the first symptoms have appeared.
  • Therapy of metastatic hormone-sensitive prostate carcinoma (mHSPC): combined hormone chemotherapy (first-line therapy); patients in good general condition (ECOG 0-1) with metastatic (M1), hormone-sensitive prostate carcinoma should be recommended chemotherapy with docetaxel in addition to androgen deprivation (drug or surgical).
  • Therapy of androgen-independent or castration-resistant prostate carcinoma: Patients with castration-resistant prostate carcinoma should be educated: A cure cannot be achieved.
  • Patients with castration-resistant, asymptomatic, or low-symptomatic progressive disease without imaging evidence of metastases should be offered a wait-and-see approach while maintaining androgen deprivation.
  • Patients with metastatic, castration-resistant, asymptomatic, or mildly symptomatic and progressive disease under androgen deprivation may be offered a change in treatment with education about benefits and side effects.
  • If a patient with metastatic, castration-resistant, asymptomatic, or low-symptomatic and progressive disease has decided against a wait-and-see approach and to switch treatment, one of the following options should be offered::
    • Chemotherapy with docetaxel
    • Abiraterone
    • Sipuleucel-T (immunotherapeutic)
  • First-line therapy of symptomatic patients: Patients with metastatic, castration-resistant, symptomatic progressive disease and good general condition.
    • Chemotherapy with docetaxel
    • Abiraterone
    • Radionuclide therapy with radium-223 for osseous metastasis (daughter tumors in the bone)Note: According to the Institute for Quality and Efficiency in Health Care (IQWiG), the benefit of the treatment is not proven (the underlying study from 2014 is outdated).
    • Combination with bisphosphonates or denosumab (gG2 anti-RANKL antibody) in osseous metastasisCaution: osteonecrosis (death (necrosis) of bone) of the jawbone and external auditory canal during therapy with bisphosphonates and denosumab.
  • Second-line therapy (no distinction between symptomatic and asymptomatic patients): Patients with castration-resistant, progressive disease and good general condition after chemotherapy with docetaxel should be offered one of the following treatment options, in combination with symptomatic and supportive (adjuvant) therapy if needed:
    • Abiraterone
    • Enzalutamide
    • Cabazitaxel (cytostatic drug from the taxane group).
    • Radionuclide therapy with radium-223 for osseous metastasisNote: According to the Institute for Quality and Efficiency in Health Care (IQWiG), the benefit of the treatment is not proven (the underlying study from 2014 is outdated).
    • Combination with bisphosphonates or denosumab for osseous metastasis.
  • Therapy of osseous metastases: The therapy of osseous metastases is part of the overall oncological concept: patients with osseous metastases should additionally be offered one or more of the following therapy options:
    • Medicinal pain therapy
    • Local irradiation
    • Surgical intervention (usually in combination with radiation).
    • Bisphosphonate or denosumab (monoclonal antibody).
    • Radionuclide therapy
  • To prevent osteonecrosis of the jaw should be prior to the administration of bisphosphonates or denosumab:
    • A dental examination and any necessary dental rehabilitation, as well as.
    • An instruction and motivation of the patient to above-average oral hygiene take place.
    • Notice: In clinical trials in patients with advanced cancers, occurrence of increased incidence of new primary malignancies with denosumab compared with zoledronic acid.
  • See also under “Other Therapy.”

Further notes

  • Examination of cell-free tumor DNA in the blood (= “liquid biopsy/tissue collection) may show resistance to abiraterone and enzalutamide.

Hormone therapy (hormone ablative therapy).

Indications

  • Locally advanced prostate carcinoma in which the patient has opted for radiotherapy.
  • Metastatic tumor
  • Inoperable tumor
  • Adjuvant therapy after radical prostatectomy.

Further notes

  • Androgen deprivation therapy (ADT) leads to an increased risk of cardiac mortality in patients with existing heart failure or post-myocardial infarction status (7% of men who received ADT had died of cardiac death within 5 years vs. 2.01% of men without ADT)
  • Hormone ablative therapy (GnRH agonist therapy in this case) versus hormone deprivation therapy by bilateral orchiectomy (testicular removal): no difference when comparing cardiovascular risks in men with drug or surgical therapy, respectively (hazard ratio [HR]: 1.02; 95% confidence interval between 0.96 and 1.09)
  • Neoadjuvant hormone therapy (NHT) to reduce tumor mass before radical prostatectomy is probably not indicated for low-risk carcinomas. After NHT, invasion into the lymphatic system was found significantly more frequently in RP tissue samples than without NHT (64.3% vs. 26.3%). The more rapid occurrence of biochemical recurrence and shortened survival can thus be explained. NHT thus promotes cancer progression via upregulation of lymphangiogenesis.
  • When the limits of androgen deprivation therapy are reached (doubling of PSA in less than ten months), the oral androgen receptor inhibitors enzalutamide and apalutamide can still protect patients from mostly painful metastases for more than two years.
  • The Institute for Quality and Efficiency in Health Care (IQWiG) attributed considerable additional benefit to apalutamide with regard to symptomatic progression. This was defined as the “occurrence of skeletal-related events (e.g., pathological fractures/bone fractures), pain progression (increase in pain) or worsening of disease-related symptoms, or the emergence of clinically significant symptoms due to locoregional tumor progression (progression of tumor disease at the site of tumor origin) “.
  • The androgen receptor blocker apalutamide, previously used in patients with metastatic prostate cancer only after failure of androgen deprivation, improved 2-year overall survival (apalutamide group at 82.4%; placebo group 73.5%) and radiographic progression-free survival (after 2 years: Apalutamide group 68.2%, placebo group 47.5%) significantly prolonged than with placebo plus ADT. Has since been demonstrated for enzalutamide as well….
  • The androgen receptor blocker daralutamide prolongs metastasis-free survival in patients with nonmetastatic castration-resistant prostate cancer compared with placebo.
  • Olaparib, from the series of so-called PARP (poly-ADP-ribose polymerase) inhibitors, can temporarily halt tumor growth in male prostate cancer: Survival time was extended from 15.11 months with standard treatment to 18.5 months in the olaparib group (hazard ratio 0.64; 0.43 to 0.97). A prerequisite for an effect is a failure of the “DNA damage response” due to BRCA1/2 mutations, for example.

Chemotherapeutic agents

No dosages are given below, because there are constant changes in the field of chemotherapeutic agents.

  • Are used in secondary therapy (moderate success).
  • Commonly used → docetaxel → paclitaxel → estramustine phosphate → mitoxanthrone.