Targeted Therapy Slows Progression of Advanced Prostate Cancer

BARCELONA, Spain – Targeting faulty DNA repair mechanisms in advanced castration resistant prostate cancer can slow progression and potentially improve survival, paving the way for a new approach to treatment of the most common form of cancer in men. Data from the PROfound trial, presented at the ESMO Congress 2019, show that olaparib delayed cancer progression by about four months compared to new hormonal agents (enzalutamide or abiraterone acetate) in patients with metastatic, pre-treated prostate cancer whose cancer cells had faulty DNA repair genes. Preliminary data showed that treatment also prolonged overall survival by over three months. (1)

“To see such a significant effect on disease progression and other clinically relevant effects such as pain progression and objective response rate is a remarkable achievement in such heavily pre-treated patients with prostate cancer. Prostate cancer has lagged behind all other common solid tumours in the use of molecularly targeted treatment so it is very exciting that now we can personalise an individual’s treatment based on specific genomic alterations in their cancer cells,” said study author Prof Maha Hussain, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, USA.

Each year, prostate cancer is diagnosed in over 1.2 million men worldwide and kills over 350,000. (2) Initial treatment may include surgery, radiotherapy, chemotherapy or hormonal treatment. However, treatment options are limited if the cancer spreads to other parts of the body and becomes resistant to hormonal treatment (metastatic castration-resistant prostate cancer, mCRPC).

In the PROfound trial, researchers from across Europe, North America, South America, Asia and Australia compared the poly-ADP ribose polymerase (PARP) inhibitor, olaparib, with the latest forms of hormonal treatment in patients with mCRPC and key faulty DNA repair genes.

“We saw the benefits of olaparib in all sub-groups of patients, regardless of country, age, prior therapy and severity of disease, including in those with worse disease that had spread to their liver or lungs,” Hussain pointed out. 

Targeting DNA repair pathways in cancer cells is already used to treat breast and ovarian cancer in patients with mistakes in two types of DNA repair gene, BRCA1 and BRCA2. Changes in other genes that are involved in DNA repair, such as ATM, can also make cancer cells more susceptible to PARP inhibitors. In the PROfound trial, olaparib was compared with new hormonal agents in two groups: one group of men with BRCA1, BRCA2 and ATM mutations and in a second group with a broader range of less well studied faulty DNA repair genes.

Commenting on the PROfound data, Dr Eleni Efstathiou, MD Anderson Cancer Center, Houston, USA, said: “This is a landmark trial as it is the first phase III trial looking specifically at tumours harboring a targetable molecular alteration. In patients with such tumours, treatment with olaparib resulted in a 66% greater delay in progression than the new hormonal agents which were used in PROfound. This is impressive because it is considerably higher than the 35-40% improvements with which we’ve been very satisfied in previous prostate cancer studies in this more advanced disease setting. There is a trend towards improved survival, but we need to wait for the final analysis.”

She added: “We should not ignore that significant adverse events, such as anaemia and nausea, were more common with olaparib as these can have an important effect on a patient’s ability to take the drug. In practice, patients will need to be carefully monitored.”

“Overall, these data show that, like breast and lung cancers, prostate cancer is not one but many different diseases and we need to start identifying different groups of patients and treating them with targeted therapy,” she concluded.

Study results

The Phase 3 PROfound trial compared the efficacy of the PARP inhibitor, olaparib, and physician’s choice of new hormonal agent treatment with enzalutamide or abiraterone in two groups of men with mCRPC.  Those in Cohort A had alterations in BRCA1, BRCA2 or ATM genes while those in Cohort B had alterations in any one of 12 other genes known to be involved in DNA repair. In Cohort A, median PFS was 7.39 months with olaparib compared to 3.55 months with hormonal treatment (hazard ratio [HR] 0.34, p<0.0001). In the overall population (Cohort A+B), median PFS was 5.82 vs 3.52 months respectively (HR 0.49, p<0.0001).

Although insufficient deaths had occurred for a conclusive result, interim overall survival analysis in Cohort A showed that median overall survival was 18.5 months with olaparib compared to 15.11 with hormonal treatment (HR 0.64, p=0.0173). Median overall survival in the overall population (Cohort A+B) was 17.51 vs 14.26 months (HR 0.67, p=0.0063 [nominal]) with olaparib vs hormonal treatment respectively. Adverse events were more common with olaparib than with hormonal treatment, though median treatment duration was longer with olaparib (7.4 months) than hormone treatment (3.9 months). In the olaparib group, 16.4% of patients discontinued treatment due to adverse events, compared to 8.5% with hormonal treatment.

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References

1. LBA12_PR ‘PROFOUND: Phase 3 study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (MCRPC) with homologous recombination repair (HRR) gene alterations’ will be presented by Maha Hussain during the Presidential Symposium III, Monday 30 September 2019, 16:30-18:15 CEST in Barcelona Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019 
   The PROfound trial is co-led by The Institute of Cancer Research, London, The Royal Marsden NHS Foundation Trust
2. International Agency for Research on Cancer/World Health Organization. Prostate. Globocan, 2018.

LBA12_PR - PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations

M. Hussain¹, J. Mateo², K. Fizazi³, F. Saad⁴, N.D. Shore⁵, S. Sandhu⁶, K.N. Chi⁷, O. Sartor⁸, N. Agarwal⁹, D. Olmos¹⁰, A. Thiery-Vuillemin¹¹, P. Twardowski¹², N. Mehra¹³, C. Goessl¹⁴, J. Kang¹⁴, J. Burgents¹⁵, W. Wu¹⁴, A. Kohlmann¹⁶, C.A. Adelman¹⁶, J. de Bono^17
1Lurie Comprehensive Cancer Center, Northwestern University, Chicago, United States of America, ²Grupo De Investigación Traslacional En Cáncer De Próstata, Vall d'Hebron University Hospital, Barcelona, Spain, ³Oncology, Gustave Roussy, University of Paris Sud, Villejuif, France, ⁴,, Centre Hospitalier de l’Université de Montréal/CRCHUM, Montreal, Canada, ⁵Medical Oncology, Carolina Urologic Research Center, Myrtle Beach, United States of America, ⁶,, Peter MacCallum Cancer Centre, Melbourne, Australia, ⁷Medical Oncology, BC Cancer Vancouver, Vancouver, Canada, ⁸Tulane University School of Medicine, New Orleans, United States of America, ⁹Department Of Oncology/ Internal Medicine, Huntsman Cancer Hospital, Salt Lake City, United States of America, ¹⁰Spanish National Cancer Research Centre (CNIO), Madrid & Hospitales Universitarios Virgen de la Victoria y Regional de Málaga, Madrid, Spain, ¹¹Medical Oncology, University Hospital of Besançon, Besançon, France, ¹²Medical Oncology, John Wayne Cancer Institute, Santa Monica, United States of America, ¹³Medical Oncology, Radboudumc, Nijmegen, Netherlands, ¹⁴,, AstraZeneca, Gaithersburg, United States of America, ¹⁵Medical Oncology, Merck & Co., Inc., Kenilworth, United States of America, ¹⁶Drug Development Department, AstraZeneca, Cambridge, United Kingdom, ¹⁷The Institute of Cancer Research and Royal Marsden, London, United Kingdom

Background: Loss-of-function alterations in HRR genes are associated with response to PARP inhibition. PROfound (NCT02987543) is a randomized, open-label, Phase 3 trial evaluating efficacy and safety of olaparib (ola) vs enzalutamide (enza) or abiraterone (abi) in patients (pts) with mCRPC with alterations in any of 15 predefined genes with a direct or indirect role in HRR whose disease had progressed on prior new hormonal agent (NHA) therapy.
Methods: Qualifying tumour tissue HRR alterations were centrally and prospectively identified using an investigational next-generation sequencing test (Foundation Medicine, Inc). Cohort A included pts with alterations in BRCA1, BRCA2 or ATM; Cohort B pts with any 1 of 12 other HRR alterations (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L). Pts were randomized (2:1) to ola (300 mg bid) or physician’s choice (pcNHA) of enza (160 mg/d) or abi (1000 mg/d + prednisone 5 mg bid). Primary endpoint was radiographic progression-free survival (rPFS) in Cohort A, assessed by blinded independent central review (BICR) and analysed via stratified log-rank test. Crossover to ola was allowed after BICR progression.
Results: 4425 men were screened; 245 randomized to Cohort A, 142 to Cohort B (65.6% had prior taxane). Efficacy is shown in Table. Most common adverse events (AEs) were anaemia (46.1 v 15.4%), nausea (41.4 v 19.2%), decreased appetite (30.1 v 17.7%) and fatigue (26.2 v 20.8%) for ola vs pcNHA; 16.4 and 8.5% of pts, respectively, discontinued due to AE. Table. Efficacy summary*

Conclusions: In pts with mCRPC and HRR alterations with prior NHA treatment, ola improved rPFS and ORR vs pcNHA, with a favourable trend for OS despite crossover. Safety was generally consistent with the known profile of ola. PROfound is the first positive Phase 3 biomarker-selected study evaluating a targeted treatment in pts with mCRPC.

Clinical trial identification: NCT02987543
Editorial acknowledgement: Medical writing assistance was provided by Debbi Gorman, PhD, from Mudskipper Business, Ltd, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD).
Legal entity responsible for the study: AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD). 
Funding: AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD).
Disclosure: M. Hussain: Honoraria (self), Women in Pca (lectures): Sanofi/Genzyme; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Lectures: Genentech; Honoraria (self), Lectures: Research to Practice; Honoraria (self), Lectures: Aptitude Health; Honoraria (self), Covering 2019 GU ASCO (lectures): Epics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Ad board: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Ad board: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Ad board: Pfizer; Honoraria (self), Lectures: PER; Honoraria (self), Travel / Accommodation / Expenses, Lectures: Astellas.
J. Mateo: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Sanofi.
K. Fizazi: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AAA; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Curevac; Honoraria (self), Advisory / Consultancy: Essa; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Orion; Honoraria (self), Advisory / Consultancy: Sanofi.
F. Saad: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas.
N.D. Shore: Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: Dendreon; Advisory / Consultancy: Ferring; Advisory / Consultancy: Janssen; Advisory / Consultancy: Merck; Advisory / Consultancy: MDx Health; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Tolmar.
S. Sandhu: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck Serono; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Honoraria (institution), Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche Genentech; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution): Endocyte; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck.
K.N. Chi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca.
O. Sartor: Shareholder / Stockholder / Stock options: Eli Lilly, GlaxoSmithKline, Noria; Advisory / Consultancy: Bayer HealthCare Pharmaceuticals, Bellicum Pharmaceuticals, Johnson & Johnson, Sanofi, AstraZeneca, Dendreon, Endocyte, Constellation Pharmaceuticals, Advanced Accelerator Applications, Pfizer, Bristol-Myers Squibb, Celgene, Bavarian Nordic, Oncogenex, EM; Research grant / Funding (institution): Bayer HealthCare Pharmaceuticals, Johnson & Johnson, Sanofi, Endocyte, Innocrin Pharma, Merck, InVitae; Speaker Bureau / Expert testimony: Sanofi; Travel / Accommodation / Expenses: Bayer HealthCare Pharmaceuticals, Johnson & Johnson, Sanofi, AstraZeneca, Progenics.
N. Agarwal: Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Argos; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Ely Lilly; Advisory / Consultancy: Foundation One; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Medivation; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Pharmacyclics; Research grant / Funding (institution): Bavarian Nordic, Calithera, Celldex, GSK, Immunomedics, New Link Genetics, Prometheus, Rexahn, Sanofi, Takeda, Tracon.
D. Olmos: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Speaker Bureau / Expert testimony: Sanofi-Aventis; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Tokai; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Roche; Officer / Board of Directors, Directors Board Committee, Member: EORTC; Non-remunerated activity/ies: BioOncoTech & Tokai.
A. Thiery-Vuillemin: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self): Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche.
P. Twardowski: Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: BMS.
N. Mehra: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Sanofi.
C. Goessl: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca.
J. Kang: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca.
J. Burgents: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck and Co, Inc..
W. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca.
A. Kohlmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca.
C.A. Adelman: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca.
J. de Bono: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: GSK; Licensing / Royalties, Abiraterone rewards to inventors with royalties paid to institution, no personal income: Janssen Oncology; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Genmab, Orion Pharma, Taiho Pharma, Vertex; Licensing / Royalties, A patent PARP inhibitors and DNA repair defects with royalties paid to institution, no personal income: N/A.