Quest for Prostate Cancer Risk Reduction Indication Pits Statistical vs. Clinical Significance

For the sponsors of two benign prostatic hyperplasia drugs – Avodart (dutasteride) and Proscar (finasteride) – the task is to convince the Food and Drug Administration, an advisory panel, and ultimately physicians and patients that reduction in the risk of low-grade prostate cancer using their products is desirable. At the moment, the companies are trying to do it without mortality data.

Avodart-maker GlaxoSmithKline has filed a supplemental new drug application (sNDA) for an indication of reduction in prostate cancer risk (which would be a first in the United States), but Merck & Co. is not explicitly seeking such a claim for Proscar. However, Merck is seeking permission to include the results of the Prostate Cancer Prevention Trial (PCPT) of Proscar in the drug’s label.

"The proposed changes could be interpreted to suggest that Proscar is safe and effective for the prevention of prostate cancer in healthy men," the FDA noted in background materials prepared for the Dec. 1 meeting of the Oncologic Drugs Advisory Committee.

Both drugs are 5-alpha reductase inhibitors, and their similarities extend beyond their class to include design features of the pivotal studies they are using to prove their case – PCPT for Proscar and REDUCE for Avodart – that the agency finds questionable.

"Neither trial was adequately designed and conducted to characterize the ultimate outcomes of interest, specifically whether 5-alpha reductase treatment decreases the incidence of metastatic prostate cancer, prostate cancer–specific mortality or overall mortality," the FDA argued.

"In both trials, there was also an unexpected finding of an increased incidence of high-risk prostate cancers among men receiving 5-alpha reductase inhibitors," the agency said, adding that it is not convinced by the sponsors’ explanations of this finding that the risk isn’t real.

Are The Benefits – and the Biopsies – Worthwhile?

The FDA argued in similar terms for both Proscar and Avodart that the increase in high Gleason score prostate cancers seen among those treated with the drugs – that is, more aggressive cancers with a poorer prognosis – calls into question whether the risk reduction for lower-grade cancers is worth while. The sponsors argued that their drugs reduced prostate volumes, which may have made the high-risk cancers easier to detect.

More critically yet, that benefit is itself a questionable one, the FDA suggested, because it was established using procedures not followed in the practice of medicine and the results offer limited clinical guidance for patients and practitioners.

For Proscar, "the primary efficacy results for the PCPT are driven by ‘end of study’ biopsies and therefore raise questions regarding the applicability of the results to the current standard of care for the management of healthy middle-aged and elderly men with no clinical evidence of prostate cancer," the agency argued.

Similarly, the agency said, the results of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial of Avodart are of "questionable relevance ... to clinical practice, where only ‘for-cause biopsies’ are performed. The high prevalence of latent prostate cancer at autopsy (30%-70%) in men 50-80 years of age makes time-mandated, repeated biopsies without a clinical indication [as were done in both the PCPT and REDUCE studies] of questionable relevance."

As an FDA reviewer noted with regard to the REDUCE trial, "It is apparent that if men are biopsied frequently without cause, a high incidence of latent low-risk prostate cancers will be detected, most of which pose little threat to men during their lifetime. A decrease in incidence of these latent cancers is of limited value to patients."

The agency also criticized the low rate at which African American men, who are at heightened risk of prostate cancer, enrolled in the studies, constituting 4% of the PCPT trial population and 2% of REDUCE.

Sponsors Say Results Will Offer Patients Options

The trials did differ in enrollment criteria, length, and precise results. PCPT enrolled 18,882 men aged 55 and up with normal digital rectal examinations and prostate-specific antigen levels less than or equal to 3 mg/mL at study entry, with men at higher risk for developing prostate cancer being excluded. Equal numbers of participants were randomized to 5 mg of Proscar per day or placebo, with treatment continuing for 7 years or until diagnosis with prostate cancer. The cumulative incidence of prostate cancer was 18.4% in the active arm and 24.9% in the placebo arm.

In the REDUCE trial, 8,231 men at heightened risk of prostate cancer were randomized to 0.5 mg of Avodart daily or placebo for 4 years or until diagnosis of prostate cancer. Participants underwent transrectal ultrasound-guided biopsies at 2 and 4 years after enrollment. Men in the active arm enjoyed a 23% lower risk of being diagnosed with biopsy-detectable prostate cancer than did men on placebo.

For the sponsors, these results are worthwhile. The data from the PCPT trial "suggest that administration of finasteride to men at risk of prostate cancer significantly reduces the risk of the disease, thereby reducing the side effects and complications that accompany diagnosis and treatment," Merck argued.

Similarly, GSK stated, "Therapies to reduce the risk of developing prostate cancer would be an important addition to current management options for both patients and prescribers." Based on results from REDUCE, 19 men at heightened risk of prostate cancer would need to take Avodart for 4 years to prevent one prostate cancer diagnosis, GSK added.

Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

For the sponsors of two benign prostatic hyperplasia drugs – Avodart (dutasteride) and Proscar (finasteride) – the task is to convince the Food and Drug Administration, an advisory panel, and ultimately physicians and patients that reduction in the risk of low-grade prostate cancer using their products is desirable. At the moment, the companies are trying to do it without mortality data.

Avodart-maker GlaxoSmithKline has filed a supplemental new drug application (sNDA) for an indication of reduction in prostate cancer risk (which would be a first in the United States), but Merck & Co. is not explicitly seeking such a claim for Proscar. However, Merck is seeking permission to include the results of the Prostate Cancer Prevention Trial (PCPT) of Proscar in the drug’s label.

"The proposed changes could be interpreted to suggest that Proscar is safe and effective for the prevention of prostate cancer in healthy men," the FDA noted in background materials prepared for the Dec. 1 meeting of the Oncologic Drugs Advisory Committee.

Both drugs are 5-alpha reductase inhibitors, and their similarities extend beyond their class to include design features of the pivotal studies they are using to prove their case – PCPT for Proscar and REDUCE for Avodart – that the agency finds questionable.

"Neither trial was adequately designed and conducted to characterize the ultimate outcomes of interest, specifically whether 5-alpha reductase treatment decreases the incidence of metastatic prostate cancer, prostate cancer–specific mortality or overall mortality," the FDA argued.

"In both trials, there was also an unexpected finding of an increased incidence of high-risk prostate cancers among men receiving 5-alpha reductase inhibitors," the agency said, adding that it is not convinced by the sponsors’ explanations of this finding that the risk isn’t real.

Are The Benefits – and the Biopsies – Worthwhile?

The FDA argued in similar terms for both Proscar and Avodart that the increase in high Gleason score prostate cancers seen among those treated with the drugs – that is, more aggressive cancers with a poorer prognosis – calls into question whether the risk reduction for lower-grade cancers is worth while. The sponsors argued that their drugs reduced prostate volumes, which may have made the high-risk cancers easier to detect.

More critically yet, that benefit is itself a questionable one, the FDA suggested, because it was established using procedures not followed in the practice of medicine and the results offer limited clinical guidance for patients and practitioners.

For Proscar, "the primary efficacy results for the PCPT are driven by ‘end of study’ biopsies and therefore raise questions regarding the applicability of the results to the current standard of care for the management of healthy middle-aged and elderly men with no clinical evidence of prostate cancer," the agency argued.

Similarly, the agency said, the results of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial of Avodart are of "questionable relevance ... to clinical practice, where only ‘for-cause biopsies’ are performed. The high prevalence of latent prostate cancer at autopsy (30%-70%) in men 50-80 years of age makes time-mandated, repeated biopsies without a clinical indication [as were done in both the PCPT and REDUCE studies] of questionable relevance."

As an FDA reviewer noted with regard to the REDUCE trial, "It is apparent that if men are biopsied frequently without cause, a high incidence of latent low-risk prostate cancers will be detected, most of which pose little threat to men during their lifetime. A decrease in incidence of these latent cancers is of limited value to patients."

The agency also criticized the low rate at which African American men, who are at heightened risk of prostate cancer, enrolled in the studies, constituting 4% of the PCPT trial population and 2% of REDUCE.

Sponsors Say Results Will Offer Patients Options

The trials did differ in enrollment criteria, length, and precise results. PCPT enrolled 18,882 men aged 55 and up with normal digital rectal examinations and prostate-specific antigen levels less than or equal to 3 mg/mL at study entry, with men at higher risk for developing prostate cancer being excluded. Equal numbers of participants were randomized to 5 mg of Proscar per day or placebo, with treatment continuing for 7 years or until diagnosis with prostate cancer. The cumulative incidence of prostate cancer was 18.4% in the active arm and 24.9% in the placebo arm.

In the REDUCE trial, 8,231 men at heightened risk of prostate cancer were randomized to 0.5 mg of Avodart daily or placebo for 4 years or until diagnosis of prostate cancer. Participants underwent transrectal ultrasound-guided biopsies at 2 and 4 years after enrollment. Men in the active arm enjoyed a 23% lower risk of being diagnosed with biopsy-detectable prostate cancer than did men on placebo.

For the sponsors, these results are worthwhile. The data from the PCPT trial "suggest that administration of finasteride to men at risk of prostate cancer significantly reduces the risk of the disease, thereby reducing the side effects and complications that accompany diagnosis and treatment," Merck argued.

Similarly, GSK stated, "Therapies to reduce the risk of developing prostate cancer would be an important addition to current management options for both patients and prescribers." Based on results from REDUCE, 19 men at heightened risk of prostate cancer would need to take Avodart for 4 years to prevent one prostate cancer diagnosis, GSK added.

Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

For the sponsors of two benign prostatic hyperplasia drugs – Avodart (dutasteride) and Proscar (finasteride) – the task is to convince the Food and Drug Administration, an advisory panel, and ultimately physicians and patients that reduction in the risk of low-grade prostate cancer using their products is desirable. At the moment, the companies are trying to do it without mortality data.

Avodart-maker GlaxoSmithKline has filed a supplemental new drug application (sNDA) for an indication of reduction in prostate cancer risk (which would be a first in the United States), but Merck & Co. is not explicitly seeking such a claim for Proscar. However, Merck is seeking permission to include the results of the Prostate Cancer Prevention Trial (PCPT) of Proscar in the drug’s label.

"The proposed changes could be interpreted to suggest that Proscar is safe and effective for the prevention of prostate cancer in healthy men," the FDA noted in background materials prepared for the Dec. 1 meeting of the Oncologic Drugs Advisory Committee.

Both drugs are 5-alpha reductase inhibitors, and their similarities extend beyond their class to include design features of the pivotal studies they are using to prove their case – PCPT for Proscar and REDUCE for Avodart – that the agency finds questionable.

"Neither trial was adequately designed and conducted to characterize the ultimate outcomes of interest, specifically whether 5-alpha reductase treatment decreases the incidence of metastatic prostate cancer, prostate cancer–specific mortality or overall mortality," the FDA argued.

"In both trials, there was also an unexpected finding of an increased incidence of high-risk prostate cancers among men receiving 5-alpha reductase inhibitors," the agency said, adding that it is not convinced by the sponsors’ explanations of this finding that the risk isn’t real.

Are The Benefits – and the Biopsies – Worthwhile?

The FDA argued in similar terms for both Proscar and Avodart that the increase in high Gleason score prostate cancers seen among those treated with the drugs – that is, more aggressive cancers with a poorer prognosis – calls into question whether the risk reduction for lower-grade cancers is worth while. The sponsors argued that their drugs reduced prostate volumes, which may have made the high-risk cancers easier to detect.

More critically yet, that benefit is itself a questionable one, the FDA suggested, because it was established using procedures not followed in the practice of medicine and the results offer limited clinical guidance for patients and practitioners.

For Proscar, "the primary efficacy results for the PCPT are driven by ‘end of study’ biopsies and therefore raise questions regarding the applicability of the results to the current standard of care for the management of healthy middle-aged and elderly men with no clinical evidence of prostate cancer," the agency argued.

Similarly, the agency said, the results of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial of Avodart are of "questionable relevance ... to clinical practice, where only ‘for-cause biopsies’ are performed. The high prevalence of latent prostate cancer at autopsy (30%-70%) in men 50-80 years of age makes time-mandated, repeated biopsies without a clinical indication [as were done in both the PCPT and REDUCE studies] of questionable relevance."

As an FDA reviewer noted with regard to the REDUCE trial, "It is apparent that if men are biopsied frequently without cause, a high incidence of latent low-risk prostate cancers will be detected, most of which pose little threat to men during their lifetime. A decrease in incidence of these latent cancers is of limited value to patients."

The agency also criticized the low rate at which African American men, who are at heightened risk of prostate cancer, enrolled in the studies, constituting 4% of the PCPT trial population and 2% of REDUCE.

Sponsors Say Results Will Offer Patients Options

The trials did differ in enrollment criteria, length, and precise results. PCPT enrolled 18,882 men aged 55 and up with normal digital rectal examinations and prostate-specific antigen levels less than or equal to 3 mg/mL at study entry, with men at higher risk for developing prostate cancer being excluded. Equal numbers of participants were randomized to 5 mg of Proscar per day or placebo, with treatment continuing for 7 years or until diagnosis with prostate cancer. The cumulative incidence of prostate cancer was 18.4% in the active arm and 24.9% in the placebo arm.

In the REDUCE trial, 8,231 men at heightened risk of prostate cancer were randomized to 0.5 mg of Avodart daily or placebo for 4 years or until diagnosis of prostate cancer. Participants underwent transrectal ultrasound-guided biopsies at 2 and 4 years after enrollment. Men in the active arm enjoyed a 23% lower risk of being diagnosed with biopsy-detectable prostate cancer than did men on placebo.

For the sponsors, these results are worthwhile. The data from the PCPT trial "suggest that administration of finasteride to men at risk of prostate cancer significantly reduces the risk of the disease, thereby reducing the side effects and complications that accompany diagnosis and treatment," Merck argued.

Similarly, GSK stated, "Therapies to reduce the risk of developing prostate cancer would be an important addition to current management options for both patients and prescribers." Based on results from REDUCE, 19 men at heightened risk of prostate cancer would need to take Avodart for 4 years to prevent one prostate cancer diagnosis, GSK added.

Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.