Consider chemotherapy early to increase mCRPC survival

PARIS – Using chemotherapy earlier in the treatment of patients with metastatic prostate cancer could maximize its benefits on patients’ overall survival, a leading expert said at an international congress on anticancer treatment.

“Survival benefit is related to the number of life-extending therapies received, and you should not miss the ‘window of opportunity’ to use chemotherapy early,” Dr. Stéphane Oudard of Georges Pompidou Hospital, René Descartes University, Paris, advised attendees during an educational lecture at the  meeting.

© alexdans/Thinkstock

The treatment of advanced prostate cancer usually starts with hormonal or antiandrogen therapies before the disease becomes castrate resistant. Chemotherapy with docetaxel is then a standard first-line choice and cabazitaxel a second-line chemotherapy option when the disease becomes castrate resistant.

The prostate cancer vaccine sipuleucel-T (Provenge) can also be used first-line, with abiraterone (Zytiga), enzalutamide (Xtandi), and radium-223 possible other first- or second-line choices. All of these treatments have different targets and have been shown in phase III clinical trials to increase survival by around 3-5 months more than control treatments have.

Evidence suggests that overall survival may be at its highest, however, when docetaxel is used first before abiraterone, enzalutamide, and cabazitaxel in the metastatic castration-resistant prostate cancer (mCRPC) setting. Furthermore, recent findings of the CHAARTED trial (J. Clin. Oncol. 2014;32-5s: Abstr, LBA2) suggest that combining docetaxel with androgen deprivation therapy (ADT) in castrate-sensitive disease could dramatically up overall survival by around 14 months vs. ADT alone.

Tailoring treatment in mCRPC

During his talk, Dr. Oudard generally discussed how clinicians might interpret available clinical trial data to help them decide which treatment approach to use for individual patients.

First, he looked at post hoc analysis data from the IMPACT study (Urology 2013;81:1297-302) with sipuleucel-T. In this trial, immunotherapy-treated patients had a median overall survival gain of 13 months over controls, when their baseline prostate-specific antigen (PSA) levels were 22.1 mg/mL or lower. As PSA levels increased, however, survival gains were substantially decreased, with a gain of just 2.8 months when PSA was over 134.1 ng/mL.

“So it means if you want to use immunotherapy you perhaps need to use it in asymptomatic patients with a low disease burden,” Dr. Oudard suggested.

Predicting response to treatment

Looking at the use of abiraterone acetate and enzalutamide after docetaxel, he noted that primary resistance to these agents develops in one-third to one-quarter of patients. This usually happens at around the 3-month mark, so it would be advisable to stop using androgen receptor (AR)-targeted agents at this point and find an alternative approach.

Combining AR-targeted agents might seem like a potential option, but data suggest that this approach does not overcome primary resistance, and research has focused on trying to determine which patients will and will not respond to AR-targeted agents.

Results of this research suggest that the duration of response to first-line ADT might be predictive of the risk for primary resistance to AR-targeted agents, with a shorter (12 months) ADT response, but not the duration of hormonal therapy, being associated with a lower response to subsequent ADT.

Another interesting parameter that might help predict response and outcome to treatment is the neutrophil/lymphocyte ratio, with the higher the ratio, the lower the overall survival to abiraterone, docetaxel, and cabazitaxel.

High residual baseline testosterone, below the level of castration, also seems a promising way to predict better response to endocrine therapies, Dr. Oudard observed, but this requires further validation.

And the presence of a genetic anomaly (the AR-V7 splice variant) in circulating tumor cells is “very promising but requires methodology validation” for use as a marker of abiraterone and enzalutamide resistance (N. Engl. J. Med. 2014;371:1028-38).

Treating refractory patients

So what are the options for patients who are refractory to first-line treatments? Data suggest that better overall survival can be achieved if patients who are “truly refractory to docetaxel” are treated with cabazitaxel rather than an AR-targeted agent, Dr. Oudard said.

It also appears that overall survival is better if docetaxel is used before abiraterone than if it is used after, and “interesting” in vitro data show that cabazitaxel seems to have greater antitumor activity than does docetaxel in enzalutamide-resistant xenografts.

Dr. Oudard also presented data showing that the PSA response achieved with cabazitaxel does not appear to be influenced by the prior use of AR-targeted agents.

Higher overall survival can be achieved in the post-docetaxel setting if cabazitaxel is used before abiraterone than if it was used after, he observed, His own data have shown a trend for better survival if the sequence of treatment starts with docetaxel, changes to cabazitaxel, and then goes to abiraterone rather than if patients receive abiraterone before cabazitaxel. The sequence of these three drugs also seems preferable rather than using docetaxel followed by cabazitaxel, he said. Large retrospective or observational studies need to address these points.

“We need to think about the sequence of treatment as early as possible,” Dr. Oudard concluded. Considering the CHAARTED study findings, he added: “We maybe need to propose chemotherapy much earlier” in order to overcome resistance. “The difference in using docetaxel much earlier is huge in terms of overall survival outcome.”

Dr. Oudard has consulting agreements with Bayer, GSK, Janssen, Keocyt, Novartis, Pfizer, Roche, Sanofi, and Takeda.

PARIS – Using chemotherapy earlier in the treatment of patients with metastatic prostate cancer could maximize its benefits on patients’ overall survival, a leading expert said at an international congress on anticancer treatment.

“Survival benefit is related to the number of life-extending therapies received, and you should not miss the ‘window of opportunity’ to use chemotherapy early,” Dr. Stéphane Oudard of Georges Pompidou Hospital, René Descartes University, Paris, advised attendees during an educational lecture at the  meeting.

© alexdans/Thinkstock

The treatment of advanced prostate cancer usually starts with hormonal or antiandrogen therapies before the disease becomes castrate resistant. Chemotherapy with docetaxel is then a standard first-line choice and cabazitaxel a second-line chemotherapy option when the disease becomes castrate resistant.

The prostate cancer vaccine sipuleucel-T (Provenge) can also be used first-line, with abiraterone (Zytiga), enzalutamide (Xtandi), and radium-223 possible other first- or second-line choices. All of these treatments have different targets and have been shown in phase III clinical trials to increase survival by around 3-5 months more than control treatments have.

Evidence suggests that overall survival may be at its highest, however, when docetaxel is used first before abiraterone, enzalutamide, and cabazitaxel in the metastatic castration-resistant prostate cancer (mCRPC) setting. Furthermore, recent findings of the CHAARTED trial (J. Clin. Oncol. 2014;32-5s: Abstr, LBA2) suggest that combining docetaxel with androgen deprivation therapy (ADT) in castrate-sensitive disease could dramatically up overall survival by around 14 months vs. ADT alone.

Tailoring treatment in mCRPC

During his talk, Dr. Oudard generally discussed how clinicians might interpret available clinical trial data to help them decide which treatment approach to use for individual patients.

First, he looked at post hoc analysis data from the IMPACT study (Urology 2013;81:1297-302) with sipuleucel-T. In this trial, immunotherapy-treated patients had a median overall survival gain of 13 months over controls, when their baseline prostate-specific antigen (PSA) levels were 22.1 mg/mL or lower. As PSA levels increased, however, survival gains were substantially decreased, with a gain of just 2.8 months when PSA was over 134.1 ng/mL.

“So it means if you want to use immunotherapy you perhaps need to use it in asymptomatic patients with a low disease burden,” Dr. Oudard suggested.

Predicting response to treatment

Looking at the use of abiraterone acetate and enzalutamide after docetaxel, he noted that primary resistance to these agents develops in one-third to one-quarter of patients. This usually happens at around the 3-month mark, so it would be advisable to stop using androgen receptor (AR)-targeted agents at this point and find an alternative approach.

Combining AR-targeted agents might seem like a potential option, but data suggest that this approach does not overcome primary resistance, and research has focused on trying to determine which patients will and will not respond to AR-targeted agents.

Results of this research suggest that the duration of response to first-line ADT might be predictive of the risk for primary resistance to AR-targeted agents, with a shorter (12 months) ADT response, but not the duration of hormonal therapy, being associated with a lower response to subsequent ADT.

Another interesting parameter that might help predict response and outcome to treatment is the neutrophil/lymphocyte ratio, with the higher the ratio, the lower the overall survival to abiraterone, docetaxel, and cabazitaxel.

High residual baseline testosterone, below the level of castration, also seems a promising way to predict better response to endocrine therapies, Dr. Oudard observed, but this requires further validation.

And the presence of a genetic anomaly (the AR-V7 splice variant) in circulating tumor cells is “very promising but requires methodology validation” for use as a marker of abiraterone and enzalutamide resistance (N. Engl. J. Med. 2014;371:1028-38).

Treating refractory patients

So what are the options for patients who are refractory to first-line treatments? Data suggest that better overall survival can be achieved if patients who are “truly refractory to docetaxel” are treated with cabazitaxel rather than an AR-targeted agent, Dr. Oudard said.

It also appears that overall survival is better if docetaxel is used before abiraterone than if it is used after, and “interesting” in vitro data show that cabazitaxel seems to have greater antitumor activity than does docetaxel in enzalutamide-resistant xenografts.

Dr. Oudard also presented data showing that the PSA response achieved with cabazitaxel does not appear to be influenced by the prior use of AR-targeted agents.

Higher overall survival can be achieved in the post-docetaxel setting if cabazitaxel is used before abiraterone than if it was used after, he observed, His own data have shown a trend for better survival if the sequence of treatment starts with docetaxel, changes to cabazitaxel, and then goes to abiraterone rather than if patients receive abiraterone before cabazitaxel. The sequence of these three drugs also seems preferable rather than using docetaxel followed by cabazitaxel, he said. Large retrospective or observational studies need to address these points.

“We need to think about the sequence of treatment as early as possible,” Dr. Oudard concluded. Considering the CHAARTED study findings, he added: “We maybe need to propose chemotherapy much earlier” in order to overcome resistance. “The difference in using docetaxel much earlier is huge in terms of overall survival outcome.”

Dr. Oudard has consulting agreements with Bayer, GSK, Janssen, Keocyt, Novartis, Pfizer, Roche, Sanofi, and Takeda.

PARIS – Using chemotherapy earlier in the treatment of patients with metastatic prostate cancer could maximize its benefits on patients’ overall survival, a leading expert said at an international congress on anticancer treatment.

“Survival benefit is related to the number of life-extending therapies received, and you should not miss the ‘window of opportunity’ to use chemotherapy early,” Dr. Stéphane Oudard of Georges Pompidou Hospital, René Descartes University, Paris, advised attendees during an educational lecture at the  meeting.

© alexdans/Thinkstock

The treatment of advanced prostate cancer usually starts with hormonal or antiandrogen therapies before the disease becomes castrate resistant. Chemotherapy with docetaxel is then a standard first-line choice and cabazitaxel a second-line chemotherapy option when the disease becomes castrate resistant.

The prostate cancer vaccine sipuleucel-T (Provenge) can also be used first-line, with abiraterone (Zytiga), enzalutamide (Xtandi), and radium-223 possible other first- or second-line choices. All of these treatments have different targets and have been shown in phase III clinical trials to increase survival by around 3-5 months more than control treatments have.

Evidence suggests that overall survival may be at its highest, however, when docetaxel is used first before abiraterone, enzalutamide, and cabazitaxel in the metastatic castration-resistant prostate cancer (mCRPC) setting. Furthermore, recent findings of the CHAARTED trial (J. Clin. Oncol. 2014;32-5s: Abstr, LBA2) suggest that combining docetaxel with androgen deprivation therapy (ADT) in castrate-sensitive disease could dramatically up overall survival by around 14 months vs. ADT alone.

Tailoring treatment in mCRPC

During his talk, Dr. Oudard generally discussed how clinicians might interpret available clinical trial data to help them decide which treatment approach to use for individual patients.

First, he looked at post hoc analysis data from the IMPACT study (Urology 2013;81:1297-302) with sipuleucel-T. In this trial, immunotherapy-treated patients had a median overall survival gain of 13 months over controls, when their baseline prostate-specific antigen (PSA) levels were 22.1 mg/mL or lower. As PSA levels increased, however, survival gains were substantially decreased, with a gain of just 2.8 months when PSA was over 134.1 ng/mL.

“So it means if you want to use immunotherapy you perhaps need to use it in asymptomatic patients with a low disease burden,” Dr. Oudard suggested.

Predicting response to treatment

Looking at the use of abiraterone acetate and enzalutamide after docetaxel, he noted that primary resistance to these agents develops in one-third to one-quarter of patients. This usually happens at around the 3-month mark, so it would be advisable to stop using androgen receptor (AR)-targeted agents at this point and find an alternative approach.

Combining AR-targeted agents might seem like a potential option, but data suggest that this approach does not overcome primary resistance, and research has focused on trying to determine which patients will and will not respond to AR-targeted agents.

Results of this research suggest that the duration of response to first-line ADT might be predictive of the risk for primary resistance to AR-targeted agents, with a shorter (12 months) ADT response, but not the duration of hormonal therapy, being associated with a lower response to subsequent ADT.

Another interesting parameter that might help predict response and outcome to treatment is the neutrophil/lymphocyte ratio, with the higher the ratio, the lower the overall survival to abiraterone, docetaxel, and cabazitaxel.

High residual baseline testosterone, below the level of castration, also seems a promising way to predict better response to endocrine therapies, Dr. Oudard observed, but this requires further validation.

And the presence of a genetic anomaly (the AR-V7 splice variant) in circulating tumor cells is “very promising but requires methodology validation” for use as a marker of abiraterone and enzalutamide resistance (N. Engl. J. Med. 2014;371:1028-38).

Treating refractory patients

So what are the options for patients who are refractory to first-line treatments? Data suggest that better overall survival can be achieved if patients who are “truly refractory to docetaxel” are treated with cabazitaxel rather than an AR-targeted agent, Dr. Oudard said.

It also appears that overall survival is better if docetaxel is used before abiraterone than if it is used after, and “interesting” in vitro data show that cabazitaxel seems to have greater antitumor activity than does docetaxel in enzalutamide-resistant xenografts.

Dr. Oudard also presented data showing that the PSA response achieved with cabazitaxel does not appear to be influenced by the prior use of AR-targeted agents.

Higher overall survival can be achieved in the post-docetaxel setting if cabazitaxel is used before abiraterone than if it was used after, he observed, His own data have shown a trend for better survival if the sequence of treatment starts with docetaxel, changes to cabazitaxel, and then goes to abiraterone rather than if patients receive abiraterone before cabazitaxel. The sequence of these three drugs also seems preferable rather than using docetaxel followed by cabazitaxel, he said. Large retrospective or observational studies need to address these points.

“We need to think about the sequence of treatment as early as possible,” Dr. Oudard concluded. Considering the CHAARTED study findings, he added: “We maybe need to propose chemotherapy much earlier” in order to overcome resistance. “The difference in using docetaxel much earlier is huge in terms of overall survival outcome.”

Dr. Oudard has consulting agreements with Bayer, GSK, Janssen, Keocyt, Novartis, Pfizer, Roche, Sanofi, and Takeda.