Progress in Prostate Cancer (at Last!)

It is difficult (but not impossible) to reflect on the fact that one of the key reasons I went into medical oncology was the seminal study by Bonadonna, published in 1976,[1] that showed a dramatic reduction in cancer recurrence in women with breast cancer and positive axillary nodes who received CMF (cyclophosphamide, methotrexate, fluorouracil) chemotherapy. Subsequently, tens of thousands of women participated in clinical trials to further refine which drugs (including many new ones), which clinical presentations (eg, node-positive or node-negative, hormone and growth factor receptor status, menopausal status. . . ) benefited most from different treatments. Medical oncologists, surgeons, and radiation oncologists collaborated in advancing our understanding of how best to treat these patients, resulting in multidisciplinary clinics that are now a standard of care in most medically advanced countries.

What went wrong with prostate cancer? Certainly, there were some efforts to replicate the breast cancer experience. Indeed, The National Prostate Cancer Project studied single agents in the late 1970s, with hints of improvement in progression-free survival.[2] Yet, it was 17 YEARS (!) before the CMF regimen (“combination chemotherapy”) was found to have minimal activity in advanced prostate cancer in a small clinical trial.[3] Following this, mitoxantrone, as a single agent, was found to improve quality of life in metastatic prostate cancer,[4] and my colleagues and I started a study to evaluate 2 years of androgen deprivation therapy (ADT) with or without mitoxantrone in high-risk post-surgery patients.[5] However, it wasn’t until a truly active class of chemotherapy agents, the taxanes, became available that real progress could be forecast.[6] Nevertheless, the numbers of patients participating in trials remained abysmal compared with breast cancer. Cooperation between medical, surgical (urologic), and radiation oncologists has lagged in the United States as physicians have debated “who really knows this disease best?” rather than striving for collaborative improvement in care.

Potentially, we are finally at the end of this dark tunnel. The American Society of Clinical Oncology (ASCO)/American Society for Therapeutic Radiology and Oncology (ASTRO)/Society for Urologic Oncology (SUO) annual genitourinary cancer symposium started off with a few hundred participants and now attracts thousands of physicians and scientists from around the world. Moreover, we are seeing the fruits of improved collaboration in the form of the CHAARTED trial,[7] as well as the new data emerging from the STAMPEDE trial.[8] This European trial has multiple arms, and in the data presented at the ASCO annual meeting, chemotherapy with docetaxel has again been shown to improve survival for men with metastatic disease compared with ADT alone.[9] Also, the study will soon have mature data on the use of such treatment in the adjuvant setting following surgery/radiation; we look forward to the results.

One of my colleagues has urged caution regarding the temptation to rush to establish early use of docetaxel as a new standard of care, pointing out the potential benefit of adding the newer second-line hormonal agents (abiraterone, enzalutamide, orteronel, galeterone, etc), which have fewer side effects. This seems like sound advice, particularly since one of the mechanisms of action of docetaxel may indeed be inhibition of translocation of the androgen receptor (AR) to the nucleus of cancer cells-in other words, docetaxel might be, in part, simply a more toxic way of inhibiting the AR signaling pathway.

The article by Drs. Graff and Beer in this issue of ONCOLOGY[10] reviews the improvements to be expected from many of the newer agents with relation to skeletal events. These advances, while modest, illustrate the growing armamentarium available to improve both the quality and duration of life for men living with advanced disease.

The good news in all of this is that after watching the Komen Foundation and women “race for the cure,” we are no longer “crawling for the cure” in prostate cancer. Thanks to the efforts of the Prostate Cancer Foundation and Movember, men of good will (especially those inclined to grow mustaches and raise awareness and funds each year) and their physicians are newly energized to make progress. It is an altogether satisfying situation to observe as I near the end of my oncology career!

Financial Disclosure:Dr. Glodé serves on the advisory boards of Bayer and Janssen.

References:

1. Bonadonna G, Brusamolino E, Valagussa F, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976;294:405-10.

2. Schmidt JD, Gibbons RP, Murphy GP, Bartolucci A. Evaluation of adjuvant estramustine phosphate, cyclophosphamide and observation only for node-positive patients following radical prostatectomy and definitive irradiation. Prostate. 1996;28:51-7.

3. Wozniak AJ, Blumenstein BA, Crawford ED, et al. Cyclophosphamide, methotrexate, and 5-fluorouracil in the treatment of metastatic prostate cancer. A Southwest Oncology Group study. Cancer. 1993;71:3975-8.

4. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996;14:1756-64.

5. Dorff TB, Flaig TW, Tangen CM, et al. Adjuvant androgen deprivation for high-risk prostate cancer after radical prostatectomy: SWOG S9921 study. J Clin Oncol. 2011;29:2040-5.

6. Glodé LM. The case for adjuvant therapy for prostate cancer. J Urol. 2006:176(Suppl):S30-S33.

7. Sweeney C, Chen YH, Carducci MA, et al. Impacat on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): an ECOG-led phase III randomized trial. J Clin Oncol. 2014;32(Suppl 5):abstr LBA2.

8. National Institutes of Health/National Cancer Institute. STAMPEDE: systemic therapy in advancing or metastatic prostate cancer: evaluation of drug efficacy: a multi-stage multi-arm randomized controlled trial. Available from: http://www.cancer.gov/about-cancer/treatment/clinical-trials/search/view?cdrid=455088&version=HealthProfessional. Accessed May 20, 2015.

9. James ND, Sydes MR, Mason MD, et al. Docetaxel and/or zoledronic acid for hormone-naïve prostate cancer: first overall survival results from STAMPEDE (NCT00268476). American Society of Clinical Oncology Annual Meeting 2015. May 29–Jun 2, 2015. Chicago, IL. Abstr 5001.

10. Graff JN, Beer TM. Reducing skeletal-related events in metastatic castration-resistant prostate cancer. Oncology (Williston Park). 2015;29:416-23.