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In this edition of “How I will treat my next patient,” I review two recent presentations at the European Society of Medical Oncology Congress regarding the expanded use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in patients with advanced solid tumors, potentially broadening the indications for this important class of agents.
Metastatic CRPC
Perhaps 25% of prostate cancer patients have loss-of-function mutations – BRCA1, BRCA2, and ATM – or alterations in homologous recombinant repair (HRR) genes. In the PROfound trial, men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on either abiraterone or enzalutamide and who had DNA-repair mutations were randomized to either olaparib (300 mg b.i.d.) or treatment of physician’s choice (TPC) with either abiraterone or enzalutamide plus prednisone (Hussain M et al. ESMO 2019, Abstract LBA-12).
Two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L). After disease progression, patients could cross over to receive PARPi, which more than 80% of patients eventually did.
Median radiographic progression-free survival (PFS) in cohort A was 7.39 months with PARPi, compared with 3.55 months with TPC, for a hazard ratio for progression on PARPi of 0.34 (P less than .0001). A significant benefit was seen for PARPi in the overall population (both cohorts), with a median radiographic PFS of 5.82 months va. 3.52 months, respectively (HR, 0.49; P less than .0001).
Among patients in cohort A, the objective response rate (ORR) was 33.3% with PARPi, compared with 2.3% for TPC, resulting in an odds ratio for ORR of 20.86 (P less than .0001).
PARPi demonstrated a longer time to pain progression in cohort A, with the median not reached, compared with 9.92 months with TPC (HR, 0.44; P = .0192). Perhaps because of the high proportion of TPC patients who eventually received PARPi, no statistically significant differences in overall survival have yet been seen.
What this means in practice
During my fellowship, a mentor taught that “because quality of life is generally better before progression than afterwards, PFS is a worthy endpoint in its own right.” For that reason, although I would have liked to see the data for cohort B alone, it appears worthwhile for physicians to make every effort to obtain PARPi. The difference in ORR, pain progression, and PFS at 12 months is clinically dramatic.
Of equal significance, however, is that PROfound is the first positive phase 3 biomarker-selected study evaluating a targeted treatment in patients with mCRPC. For prostate cancer – as for breast, ovarian, pancreatic, and several other cancers – the molecular biology and genetic background of our patients dictates the other tumors for which they and their family members are at risk, and expands the treatment armamentarium for them.
For those clinicians who needed to be convinced that “precision medicine” for prostate cancer patients was worthwhile, the PROfound trial should have a profound impact.
Advanced ovarian cancer
The randomized, double-blind, placebo-controlled, phase 3 PAOLA-1/ENGOT-ov25 trial studied patients with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer who had surgery, platinum-taxane chemotherapy, and at least 3 months of bevacizumab. Patients were randomized to maintenance treatment with an additional 12 months of bevacizumab plus 24 months of PARPi with olaparib or placebo. Germline BRCA mutations were not required (Ray-Coquard I et al. ESMO 2019, Abstract LBA2).
As reported at ESMO, adding PARPi to bevacizumab maintenance provided a clinically meaningful PFS benefit of 22.1 months, in comparison with 16.6 months for bevacizumab alone. The difference was statistically significant.
For patients with tumor BRCA mutations (tBRCAm), PFS was 37.2 months with olaparib vs. 21.7 months for placebo (HR, 0.31). The PFS benefit was even more impressive for homologous recombination deficient (HRD)–positive patients, inclusive of those with tBRCAm (PFS 37.2 months for PARPi vs. 17.7 months for placebo; and in the 152 HRD-positive patients without tBRCAm, (median PFS 28.1 months vs. 16.6 months; HR, 0.43).
The improved PFS in patients with tBRCAm is similar to that reported in the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer (N Engl J Med. 2018; 379:2495-2505), but the PFS in the control arm was longer in PAOLA-1 than in SOLO1, perhaps because of the use of bevacizumab in PAOLA-1. PARPi did not affect tolerance to bevacizumab.
In PAOLA-1, the HRD-positive patients who lacked tBRCAm and, by extension, lacked germline BRCA mutations – a new population of patients – was identified who benefited substantially from maintenance PARPi in the first-line setting.
What this means in practice
PAOLA-1 demonstrates that PARPi can improve outcomes in first-line treatment – and in patients beyond those with germline BRCA mutations. As a result, PAOLA-1 potentially changes the standard of care for initial treatment of the respectable fraction of patients with previously untreated, advanced müllerian cancers who have either tBRCAm or HRD positive tumors.
Importantly, PAOLA-1 is one of many published trials that stimulates the discussion of cost vs. value for combinations of biologics. The incremental benefit from the second biologic (in this case PARPi) is almost never completely additive or supra-additive to the benefit associated with the first biologic (in this case, bevacizumab). In that regard, despite the fact that PARPi showed a PFS benefit in the intent-to-treat population overall, precisely defining the patient population that has the greatest benefit will facilitate the goal of getting the treatments of greatest “value for cost” to our patients in the most responsible way.
Additional research will hopefully define the relative contribution of bevacizumab to PARPi in patients who benefited so dramatically from PARPi in PAOLA-1.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I review two recent presentations at the European Society of Medical Oncology Congress regarding the expanded use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in patients with advanced solid tumors, potentially broadening the indications for this important class of agents.
Metastatic CRPC
Perhaps 25% of prostate cancer patients have loss-of-function mutations – BRCA1, BRCA2, and ATM – or alterations in homologous recombinant repair (HRR) genes. In the PROfound trial, men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on either abiraterone or enzalutamide and who had DNA-repair mutations were randomized to either olaparib (300 mg b.i.d.) or treatment of physician’s choice (TPC) with either abiraterone or enzalutamide plus prednisone (Hussain M et al. ESMO 2019, Abstract LBA-12).
Two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L). After disease progression, patients could cross over to receive PARPi, which more than 80% of patients eventually did.
Median radiographic progression-free survival (PFS) in cohort A was 7.39 months with PARPi, compared with 3.55 months with TPC, for a hazard ratio for progression on PARPi of 0.34 (P less than .0001). A significant benefit was seen for PARPi in the overall population (both cohorts), with a median radiographic PFS of 5.82 months va. 3.52 months, respectively (HR, 0.49; P less than .0001).
Among patients in cohort A, the objective response rate (ORR) was 33.3% with PARPi, compared with 2.3% for TPC, resulting in an odds ratio for ORR of 20.86 (P less than .0001).
PARPi demonstrated a longer time to pain progression in cohort A, with the median not reached, compared with 9.92 months with TPC (HR, 0.44; P = .0192). Perhaps because of the high proportion of TPC patients who eventually received PARPi, no statistically significant differences in overall survival have yet been seen.
What this means in practice
During my fellowship, a mentor taught that “because quality of life is generally better before progression than afterwards, PFS is a worthy endpoint in its own right.” For that reason, although I would have liked to see the data for cohort B alone, it appears worthwhile for physicians to make every effort to obtain PARPi. The difference in ORR, pain progression, and PFS at 12 months is clinically dramatic.
Of equal significance, however, is that PROfound is the first positive phase 3 biomarker-selected study evaluating a targeted treatment in patients with mCRPC. For prostate cancer – as for breast, ovarian, pancreatic, and several other cancers – the molecular biology and genetic background of our patients dictates the other tumors for which they and their family members are at risk, and expands the treatment armamentarium for them.
For those clinicians who needed to be convinced that “precision medicine” for prostate cancer patients was worthwhile, the PROfound trial should have a profound impact.
Advanced ovarian cancer
The randomized, double-blind, placebo-controlled, phase 3 PAOLA-1/ENGOT-ov25 trial studied patients with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer who had surgery, platinum-taxane chemotherapy, and at least 3 months of bevacizumab. Patients were randomized to maintenance treatment with an additional 12 months of bevacizumab plus 24 months of PARPi with olaparib or placebo. Germline BRCA mutations were not required (Ray-Coquard I et al. ESMO 2019, Abstract LBA2).
As reported at ESMO, adding PARPi to bevacizumab maintenance provided a clinically meaningful PFS benefit of 22.1 months, in comparison with 16.6 months for bevacizumab alone. The difference was statistically significant.
For patients with tumor BRCA mutations (tBRCAm), PFS was 37.2 months with olaparib vs. 21.7 months for placebo (HR, 0.31). The PFS benefit was even more impressive for homologous recombination deficient (HRD)–positive patients, inclusive of those with tBRCAm (PFS 37.2 months for PARPi vs. 17.7 months for placebo; and in the 152 HRD-positive patients without tBRCAm, (median PFS 28.1 months vs. 16.6 months; HR, 0.43).
The improved PFS in patients with tBRCAm is similar to that reported in the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer (N Engl J Med. 2018; 379:2495-2505), but the PFS in the control arm was longer in PAOLA-1 than in SOLO1, perhaps because of the use of bevacizumab in PAOLA-1. PARPi did not affect tolerance to bevacizumab.
In PAOLA-1, the HRD-positive patients who lacked tBRCAm and, by extension, lacked germline BRCA mutations – a new population of patients – was identified who benefited substantially from maintenance PARPi in the first-line setting.
What this means in practice
PAOLA-1 demonstrates that PARPi can improve outcomes in first-line treatment – and in patients beyond those with germline BRCA mutations. As a result, PAOLA-1 potentially changes the standard of care for initial treatment of the respectable fraction of patients with previously untreated, advanced müllerian cancers who have either tBRCAm or HRD positive tumors.
Importantly, PAOLA-1 is one of many published trials that stimulates the discussion of cost vs. value for combinations of biologics. The incremental benefit from the second biologic (in this case PARPi) is almost never completely additive or supra-additive to the benefit associated with the first biologic (in this case, bevacizumab). In that regard, despite the fact that PARPi showed a PFS benefit in the intent-to-treat population overall, precisely defining the patient population that has the greatest benefit will facilitate the goal of getting the treatments of greatest “value for cost” to our patients in the most responsible way.
Additional research will hopefully define the relative contribution of bevacizumab to PARPi in patients who benefited so dramatically from PARPi in PAOLA-1.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I review two recent presentations at the European Society of Medical Oncology Congress regarding the expanded use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in patients with advanced solid tumors, potentially broadening the indications for this important class of agents.
Metastatic CRPC
Perhaps 25% of prostate cancer patients have loss-of-function mutations – BRCA1, BRCA2, and ATM – or alterations in homologous recombinant repair (HRR) genes. In the PROfound trial, men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on either abiraterone or enzalutamide and who had DNA-repair mutations were randomized to either olaparib (300 mg b.i.d.) or treatment of physician’s choice (TPC) with either abiraterone or enzalutamide plus prednisone (Hussain M et al. ESMO 2019, Abstract LBA-12).
Two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L). After disease progression, patients could cross over to receive PARPi, which more than 80% of patients eventually did.
Median radiographic progression-free survival (PFS) in cohort A was 7.39 months with PARPi, compared with 3.55 months with TPC, for a hazard ratio for progression on PARPi of 0.34 (P less than .0001). A significant benefit was seen for PARPi in the overall population (both cohorts), with a median radiographic PFS of 5.82 months va. 3.52 months, respectively (HR, 0.49; P less than .0001).
Among patients in cohort A, the objective response rate (ORR) was 33.3% with PARPi, compared with 2.3% for TPC, resulting in an odds ratio for ORR of 20.86 (P less than .0001).
PARPi demonstrated a longer time to pain progression in cohort A, with the median not reached, compared with 9.92 months with TPC (HR, 0.44; P = .0192). Perhaps because of the high proportion of TPC patients who eventually received PARPi, no statistically significant differences in overall survival have yet been seen.
What this means in practice
During my fellowship, a mentor taught that “because quality of life is generally better before progression than afterwards, PFS is a worthy endpoint in its own right.” For that reason, although I would have liked to see the data for cohort B alone, it appears worthwhile for physicians to make every effort to obtain PARPi. The difference in ORR, pain progression, and PFS at 12 months is clinically dramatic.
Of equal significance, however, is that PROfound is the first positive phase 3 biomarker-selected study evaluating a targeted treatment in patients with mCRPC. For prostate cancer – as for breast, ovarian, pancreatic, and several other cancers – the molecular biology and genetic background of our patients dictates the other tumors for which they and their family members are at risk, and expands the treatment armamentarium for them.
For those clinicians who needed to be convinced that “precision medicine” for prostate cancer patients was worthwhile, the PROfound trial should have a profound impact.
Advanced ovarian cancer
The randomized, double-blind, placebo-controlled, phase 3 PAOLA-1/ENGOT-ov25 trial studied patients with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer who had surgery, platinum-taxane chemotherapy, and at least 3 months of bevacizumab. Patients were randomized to maintenance treatment with an additional 12 months of bevacizumab plus 24 months of PARPi with olaparib or placebo. Germline BRCA mutations were not required (Ray-Coquard I et al. ESMO 2019, Abstract LBA2).
As reported at ESMO, adding PARPi to bevacizumab maintenance provided a clinically meaningful PFS benefit of 22.1 months, in comparison with 16.6 months for bevacizumab alone. The difference was statistically significant.
For patients with tumor BRCA mutations (tBRCAm), PFS was 37.2 months with olaparib vs. 21.7 months for placebo (HR, 0.31). The PFS benefit was even more impressive for homologous recombination deficient (HRD)–positive patients, inclusive of those with tBRCAm (PFS 37.2 months for PARPi vs. 17.7 months for placebo; and in the 152 HRD-positive patients without tBRCAm, (median PFS 28.1 months vs. 16.6 months; HR, 0.43).
The improved PFS in patients with tBRCAm is similar to that reported in the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer (N Engl J Med. 2018; 379:2495-2505), but the PFS in the control arm was longer in PAOLA-1 than in SOLO1, perhaps because of the use of bevacizumab in PAOLA-1. PARPi did not affect tolerance to bevacizumab.
In PAOLA-1, the HRD-positive patients who lacked tBRCAm and, by extension, lacked germline BRCA mutations – a new population of patients – was identified who benefited substantially from maintenance PARPi in the first-line setting.
What this means in practice
PAOLA-1 demonstrates that PARPi can improve outcomes in first-line treatment – and in patients beyond those with germline BRCA mutations. As a result, PAOLA-1 potentially changes the standard of care for initial treatment of the respectable fraction of patients with previously untreated, advanced müllerian cancers who have either tBRCAm or HRD positive tumors.
Importantly, PAOLA-1 is one of many published trials that stimulates the discussion of cost vs. value for combinations of biologics. The incremental benefit from the second biologic (in this case PARPi) is almost never completely additive or supra-additive to the benefit associated with the first biologic (in this case, bevacizumab). In that regard, despite the fact that PARPi showed a PFS benefit in the intent-to-treat population overall, precisely defining the patient population that has the greatest benefit will facilitate the goal of getting the treatments of greatest “value for cost” to our patients in the most responsible way.
Additional research will hopefully define the relative contribution of bevacizumab to PARPi in patients who benefited so dramatically from PARPi in PAOLA-1.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.