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All cells that produce the PSA protein should be gone after a radical prostatectomy, therefore slight elevations in PSA levels are indicative of cancer recurrence. The exact level that defines PSA recurrence is debated. However in general, a PSA level higher than 0.2-0.4ng/mL has been most commonly used. Two specific factors - the PSA doubling time (the time it takes for a patient's PSA level to double) and the PSA velocity (the rate of rise in the PSA level) are used to monitor progression of the disease. For those men with rising PSA levels after treatment, therapy is directed toward preventing the disease from progressing to the point that it is detectable on a scan or by physical examination, or develops to the point of causing symptoms. While hormonal treatments are most commonly used, approaches may include observation alone, radiation therapy to relieve symptoms in areas of metastatic disease (such as the spine or lung), or "salvage" surgery.

Chemotherapy for prostate cancer is generally only reserved for very advanced cancers that are no longer responsive to hormonal therapy. There are a number of chemotherapy drugs that can be used for prostate cancer, and they are often used in combinations. A common chemotherapy regimen is mitoxantrone with coritcosteroids; and other regimens that are becoming increasingly popular use a drug called estramustane with drugs called taxanes.