Starting Treatment Early for Metastatic Prostate Cancer

Provenge. Dendreon Corporation

In 2010 the FDA approved Provenge for hormone-refractory prostate cancer. Provenge is a treatment that functions by enhancing the immune system. Some critics have called the effectiveness of Provenge into question because the effectiveness of most cancer treatments is reflected in a PSA decline after treatment. However, with Provenge therapy PSA levels usually do not drop. Having personally supervised several hundred Provenge-treated men, I have observed exceptional cases in which Provenge lowers PSA. However, a decline in PSA is certainly not the general rule as most of the time PSA continues rising after Provenge.

If PSA is not dropping, how can Provenge prolong survival? Many forget that even though Provenge treatment is completed over a six-week period, once the immune system is activated its effects persist.  Therefore, even if Provenge is only impeding disease growth to a slight degree, the continuous inhibitory effect on cancer growth has a cumulative impact over time. Over a period of years, even a mild inhibitory effect can add up to a substantial survival benefit.

The Research

If the hypothesis that Provenge is inducing a mild, long-lasting anticancer effect is correct, then men who receive treatment with Provenge at an earlier stage (who have a longer projected survival) should receive a bigger survival benefit than men treated at a later stage. To test this premise, Dendreon, the manufacturer of Provenge analyzed data from the original studies that led to FDA approval. Please note, the researchers did not compare the survival of men treated earlier versus the survival of men treated later. Obviously, men treated at an earlier stage live longer. Rather they compared the survival of Provenge-treated men with earlier-stage disease with similar-stage placebo-treated men. They did the same analysis (Provenge-treated men versus placebo-treated men) in men with various stages of disease varying from early to late stage. Actually, subdivided the men into four categories: Early stage, low-intermediate stage, high-intermediate stage and late stage. The different “stages” were defined by how high the PSA levels were at the time that Provenge was started.

For example, early-stage was a PSA of less than 22; low-intermediate stage was a PSA between 22-50; high-intermediate stage was a PSA between 50-134; and high-stage was a PSA greater than 134.

The table below summarizes the results of their analysis.

Patients Grouped by Baseline PSA ≤22 22–50 50–134 >134
NUMBER 128 128 128 128
PROVENGE 41.3 27.1 20.4 18.4
PLACEBO 28.3 20.1 15.0 15.6
SURVIVAL DIFFERENCE 13.0 7.1 5.4 2.8

As can be seen from the table, all groups that were treated with Provenge, showed a survival advantage compared to the same stage men treated with placebo. However, when Provenge was given at an earlier stage, the survival advantages were greater. Men with the earliest stage (PSA < 22) lived 13 months longer than similar stage men who were placebo-treated. Men with advanced stage only lived a couple months longer than advanced-stage placebo-treated men.

This pattern of improved survival with earlier stage disease seems to fit the hypothesis that the inhibitory immune effect of Provenge results in a progressively bigger survival effect when it is allowed to accumulate over a longer lifespan. Another hypothesis to explain this data is that smaller amounts of cancer have fewer clones and are therefore more responsive to the therapy. Whether it is one rationale or the other, or both taken together, the evidence that earlier administration of therapy improves results continues to be validated whenever the hypothesis is tested. Certainly, based on this data, one could only logically conclude that Provenge induces the biggest benefits when administered at the earliest possible stage.

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