The survival of men with biochemical recurrent (BCR) prostate cancer is long and there remains debate over if and when to start androgen deprivation therapy (ADT) in the BCR setting. While early treatment with ADT is used by some, there is no clear consensus on which patients are most likely to benefit and no randomized trials that prove this offers a survival benefit or significant improvement in quality of life. Furthermore, early use of ADT for BCR prostate cancer results in non-metastatic castration resistant prostate cancer, for which, until recently, there was no FDA approved treatment. There have now been 3 large, placebo controlled randomized trials of novel anti-androgen therapies in the non-metastatic castration resistant space.1–3 These novel therapies improve metastasis free survival, however, even from these trials, it is unclear when and why ADT was initiated and without that, it is hard to understand how to use these data in daily practice.
In our article,4 we seek to shed light on the risk of metastasis in men with BCR prostate cancer. The article examines the association of absolute PSA values and PSA doubling time (PSADT) on the subsequent risk of metastasis. We used two large datasets of over 30,000 men combined– Center for Prostate Disease Research multicenter national database and the Johns Hopkins University prostate cancer database. They included all men who had a radical prostatectomy, never had hormone or radiation therapy and developed BCR. The PSADT was calculated based on all available PSA values and the absolute PSA value used was that which occurred within 6 to 18 months of the first documented metastasis (or censoring). We found that those with a PSADT <7.5 months and those with an absolute PSA > 0.5ng/mL independently increased subsequent risk of metastasis. We also show that the risk of metastasis continues to increase as PSADT gets shorter.
This has a number of relevant clinical implications. First, it allows clinicians to discuss the subsequent risk of metastasis and expected time of metastasis around the PSA cutpoint of 0.5ng/mL. It also supports early salvage radiotherapy when the PSA is < 0.5ng/mL as the risk of distant metastasis is lower. Furthermore, this may help add to the discussion around criteria for implementation of ADT in patients with BCR. Most importantly, it provides patients and clinicians information on when there is a low risk of metastasis and a basis for delaying ADT. As we have shown recently, the overall survival for men who develop BCR and delay ADT – from the time of diagnosis to time of death – is quite long and comparable to what was seen in the trials of novel anti-androgens.5 The data presented here helps to counsel patients on who is at low risk of metastasis and may be able to avoid or at least delay ADT.
Written by: Catherine H. Marshall, Mario A. Eisenberger, and Mark C. Markowski, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
References:
- Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. New England Journal of Medicine. 2018;378:1408–1418.
- Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, Ivashchenko P, Demirhan E, Modelska K, Phung D, Krivoshik A, Sternberg CN. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2018;378:2465–2474.
- Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith MR. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2019;380:1235–1246.
- Markowski MC, Chen Y, Feng Z, Cullen J, Trock BJ, Suzman D, Antonarakis ES, Paller CJ, Rosner I, Han M, Walsh PC, Partin AW, Eisenberger M. PSA Doubling Time and Absolute PSA Predict Metastasis-free Survival in Men With Biochemically Recurrent Prostate Cancer After Radical Prostatectomy. Clin Genitourin Cancer. 2019;
- Marshall CH, Fu W, Wang H, Trock BJ, Eisenberger MA. Outcomes of men with recurrent M0 prostate cancer who defer androgen deprivation therapy until metastasis. JCO. 2019;37:5016–5016.