Prostate cancer is the most common male tumor in Western countries and is the second leading cause of cancer-related death in Switzerland. In particular, metastatic castration-resistant prostate cancer (mCRPC) is a challenge that can now be addressed therapeutically in a variety of ways. The current data situation on the new active substances was discussed at the Prostate Symposium in St. Gallen in November.
“What is the promise of the new drugs and developments in the field of metastatic prostate cancer?” was the question posed by Aurelius Omlin, MD, of the Cantonal Hospital of St. Gallen. “It wasn’t long ago that chemotherapy with docetaxel was the only treatment option that offered an overall survival benefit to patients with castration-resistant (progression despite suppressed testosterone) metastatic prostate cancer (mCRPC).
This changed only in the last four years, when the efficacy of the following drugs was demonstrated in prospective randomized trials: immunotherapy with sipuleucel-T, tubulin-binding chemotherapy analogous to docetaxel with cabazitaxel, the new hormone synthesis inhibitor abiraterone, the radionuclide radium-223, and the new androgen receptor antagonist enzalutamide (Table 1).”
Cabazitaxel: Is approved in Switzerland after failure of chemotherapy with docetaxel. In combination with prednisone, shows significant advantage in overall survival over combination with mitoxantrone [1].
Abiraterone: Is approved in Switzerland after and as the only one of the new substances also before chemotherapy with docetaxel. In combination with prednisone, it shows a significant advantage in overall survival compared with placebo plus prednisone, following first-line docetaxel therapy [2]. When combined with prednisone, it also significantly improves progression-free survival as first-line therapy compared with placebo plus prednisone and shows a trend in overall survival [3].
Enzalutamide: Not yet approved in Switzerland, but expected in 2014. After chemotherapy, it shows a significant advantage over placebo in overall survival [4].
Radium-223: Is currently available in Switzerland under an Expanded Access Program.
Monitoring and sequential deployment
“PSA levels can rise with the new therapies during the first twelve weeks, so PSA measurement should be taken with caution during this time. After that, however, it should be done every three to four weeks,” says Dr. Omlin. Monitoring also includes:
- CT and scintigraphy every twelve weeks
- MRI Long-Spine for extensive bone involvement: baseline and when clinically indicated (pain, neurologic deficits).
No prospectively collected data are currently available on the sequential use and possible cross-resistance of the new substances. However, there are smaller studies with limited power investigating docetaxel after abiraterone, for example: Docetaxel activity was lower than expected post-abiraterone and there was no significant PSA or soft tissue response in eight patients who had also not responded to abiraterone or had progressed during therapy with abiraterone. [5]. Enzalutamide showed significant benefit sequentially after docetaxel and abiraterone in a few patients [6]; similarly, abiraterone appears to have a moderate effect after docetaxel and enzalutamide [7]. Currently, predictive factors that would allow individualized therapy selection are lacking.
“Overall, then, there are many new therapeutic options with improved survival rates, which makes the management of side effects and the prevention of complications (bone events) all the more important in return. In any case, therapy monitoring is challenging, in some cases cross-resistance of the new therapies is to be expected and, what should also not be forgotten: the costs of the new therapies are considerable,” Dr. Omlin concluded his presentation. “Because of the increasing options and complexity, patients with castration-resistant prostate cancer should be discussed across disciplines and, if possible, included in clinical trials to achieve further progress in the treatment of this disease.”
How to treat for bone metastases?
PD Dr. med. Dr. Friedemann Honecker from ZeTuP in St. Gallen spoke on the topic of bone metastases and bone-directed treatment: “More than 90% of all patients with mCRPC develop bone metastases. This is associated with significant mortality and morbidity. Such majority osteoblastic metastases cause an increased rate of bone events (“skeletal related events”, SRE). Possible complications include: Pain, immobilization, pathologic fractures, hypercalcemia, or nerve/spinal compression.”
Since on the tumor side the messengers PTHrP, RANKL, TGF-β, FGF, MET and VEGF, and on the bone side TNF-α and ET-1 are significantly involved in skeletal metastasis, they also represent potential targets for targeted therapy.
For example, denosumab, an anti-RANKL antibody, is already being used specifically to treat bone metastases. It is particularly effective in reducing SRE risk. In a phase III study, a relative reduction of approximately 18% was achieved compared with zoledronate (Fig. 1) [8].
However, the bisphosphonate zoledronate also significantly prevented SREs compared with placebo [9]. “Adverse reactions to bisphosphonates include flu-like symptoms (acute phase reaction) in 10-20% of cases, renal side effects (decrease in creatinine clearance), hypocalcemia (decrease in serum calcium level), and osteonecrosis of the jaw (multifactorial event). In any case, creatinine clearance should be checked before each infusion; if it increases, the dose should be adjusted. The infusion duration should not be shortened, but withheld or extended. The recommendation to the patient that he should drink 1-2 l of water on the infusion day is sensible,” explained Dr. Honecker.
Radium-223 even showed a positive effect on overall survival in symptomatic patients with bone metastases, and approval in Switzerland is therefore currently under review. Lastly, the already approved compound abiraterone also shows good efficacy with regard to the occurrence of SRE as well as palliation of bone pain.
Cabozantinib, a VEGFR2/MET inhibitor, is particularly promising among the very new and as yet unapproved agents and induced in phase II studies in partly pretreated patients a very clear response of bone metastases in skeletal scintigraphy in 60-70% and pain relief in a good 50%. The compound is currently in Phase III trials. Further to be observed are the sometimes severe side effects, especially with cabozantinib.
Radium-223
Finally, Dr. Joachim Müller, Kantonsspital St. Gallen, went into more detail about the radionuclide radium-223 (trade name new Xofigo®): “It is the first clinically available alpha particle-emitting radiopharmaceutical for the nuclear medicine therapy of osseous metastases in mCRPC.
Compared to beta emitters (strontium-89, samarium-153, rhenium-188), which have long been used and allow palliative pain therapy but do not prolong survival, alpha emitters show some physical advantages: they transfer their energy to the tissue via the shortest possible path, so neighboring areas such as the adjacent bone marrow receive no or only a very low dose of radiation.”
The well-known Phase III ALSYMPCA [10] trial recently led to FDA approval. Overall survival was significantly prolonged compared with placebo, as was the time interval to the first skeletal event. Side effects were only mild and included diarrhea and nausea. Grade 3-4 hemotoxicity is rare: Neutropenia 2%, thrombocytopenia 3%, anemia 6%.
Possible combinations with other drugs have not yet been determined.
Source: 5th Interdisciplinary Prostate Cancer Symposium, November 7, 2013, St. Gallen.
Literature:
- De Bono JS, et al: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. The Lancet 2010; 376(9747): 1147-1154. doi:10.1016/S0140-6736(10)61389-X.
- De Bono JS, et al: Abiraterone and Increased Survival in Metastatic Prostate Cancer. N Engl J Med 2011; 364: 1995-2005. doi: 10.1056/NEJMoa1014618.
- Ryan CJ, et al: Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy. N Engl J Med 2013; 368: 138-48. doi: 10.1056/NEJMoa120909.
- Scher HI, et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012 Sep 27; 367(13): 1187-97. epub 2012 Aug 15.
- Mezynski J, et al: Antitumor activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance? Ann Oncol 2012 Nov; 23(11): 2943-7. doi: 10.1093/annonc/mds119. Epub 2012 Jul 5.
- Schrader AJ, et al: Enzalutamide in Castration-resistant Prostate Cancer Patients Progressing After Docetaxel and Abiraterone. Eur Urol 2013 Jul 2. pii: S0302 2838(13)00657-X. doi: 10.1016/j.eururo.2013.06.042. [Epub ahead of print].
- Noonan KL, et al: Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol 2013. doi: 10.1093/annonc/mdt138 First published online: April 12, 2013.
- Fizazi K, et al: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011 Mar 5; 377(9768): 813-22. doi: 10.1016/S0140-6736(10)62344-6. epub 2011 Feb 25.
- Saad F, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002 Oct 2; 94(19): 1458-68.
- Parker C, et al: Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. N Engl J Med 2013; 369: 213-23. doi: 10.1056/NEJMoa1213755.
InFo Oncology & Hematology 2013; 1(1): 33-36.
